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Xie H, Zheng Y, Zhang H, Guo Y, Liu M, Weng Q, Wu X. Association of NR1I2 Polymorphism with Midazolam Clearance in Mechanically Ventilated ICU Patients: A Population Pharmacokinetic and Pharmacogenetic Study. Drug Des Devel Ther 2025; 19:1527-1541. [PMID: 40066084 PMCID: PMC11891766 DOI: 10.2147/dddt.s495647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 02/04/2025] [Indexed: 05/13/2025] Open
Abstract
Background Significant variability in the metabolism of midazolam (MDZ) exists among mechanically ventilated (MV) patients in the intensive care unit (ICU) due to complex clinical conditions and genetic factors. The NR1I2 gene (PXR), which encodes a nuclear receptor that regulates drug-metabolizing enzymes like CYP3A4, plays a critical role in MDZ metabolism. Polymorphisms in NR1I2, along with variations in genes such as CYP3A4, CYP3A5, and ABCB1, may influence enzyme activity and MDZ pharmacokinetics (PK). Understanding these factors is essential for optimizing MDZ dosing in high-risk patient populations. Methods We studied 61 MV ICU patients receiving continuous MDZ infusion. A population pharmacokinetic (PopPK) model was used to assess MDZ PK, with genetic factors (NR1I2 rs2461817, CYP3A4, CYP3A5, ABCB1, and other PXR polymorphisms) and clinical covariates (body weight (BW), aspartate aminotransferase (AST) levels) evaluated for their impact on MDZ clearance (CL). Results The PK of MDZ and its metabolite, 1-hydroxymidazolam (1-OH-MDZ), were accurately described using a one-compartment model. The estimated population means for MDZ and 1-OH-MDZ CL were 22.6 L/h (inter-individual variability [IIV] 59.4%) and 67.1 L/h (IIV 57.7%), respectively. MDZ CL was significantly associated with the NR1I2 rs2461817 polymorphism and AST levels, accounting for 11.3% of the variability. MDZ CL decreased by 32.7% as AST increased from 22 IU/L to 60 IU/L, and by 40.7% in patients homozygous for the NR1I2 rs2461817 variant. BW also influenced the CL of 1-OH-MDZ, demonstrating a 34.2% increase as weight increased from 54 kg to 65 kg. Simulations confirmed the significant impact of NR1I2 rs2461817 on MDZ CL. Conclusion The PopPK model highlights the significant impact of NR1I2 rs2461817 polymorphism on MDZ CL in Chinese MV patients, emphasizing the need to consider genetic and clinical factors for optimizing MDZ dosing in ICU settings.
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Affiliation(s)
- Helin Xie
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, People’s Republic of China
| | - You Zheng
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, People’s Republic of China
- College of Pharmacy, Fujian Medical University, Fuzhou, Fujian, 350000, People’s Republic of China
| | - Hui Zhang
- Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China
| | - Yanmei Guo
- Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China
| | - Maobai Liu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, People’s Republic of China
| | - Qinyong Weng
- Department of Critical Care Medicine, Fujian Medical University Union Hospital, Fuzhou, 350001, People’s Republic of China
| | - Xuemei Wu
- Department of Pharmacy, Fujian Medical University Union Hospital, Fuzhou, Fujian, 350001, People’s Republic of China
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Kineman RD, Del Rio-Moreno M, Waxman DJ. Liver-specific actions of GH and IGF1 that protect against MASLD. Nat Rev Endocrinol 2025; 21:105-117. [PMID: 39322791 DOI: 10.1038/s41574-024-01037-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/29/2024] [Indexed: 09/27/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD; also known as nonalcoholic fatty liver disease) is a chronic condition associated with metabolic syndrome, a group of conditions that includes obesity, insulin resistance, hyperlipidaemia and cardiovascular disease. Primary growth hormone (GH) deficiency is associated with MASLD, and the decline in circulating levels of GH with weight gain might contribute to the development of MASLD. Raising endogenous GH secretion or administering GH replacement therapy in the context of MASLD enhances insulin-like growth factor 1 (IGF1) production and reduces steatosis and the severity of liver injury. GH and IGF1 indirectly control MASLD progression by regulating systemic metabolic function. Evidence supports the proposal that GH and IGF1 also have a direct role in regulating liver metabolism and health. This Review focuses on how GH acts on the hepatocyte in a sex-dependent manner to limit lipid accumulation, reduce stress, and promote survival and regeneration. In addition, we discuss how GH and IGF1 might regulate non-parenchymal cells of the liver to control inflammation and fibrosis, which have a major effect on hepatocyte survival and regeneration. Development of a better understanding of how GH and IGF1 coordinate the functions of specific, individual liver cell types might provide insight into the aetiology of MASLD initiation and progression and suggest novel approaches for the treatment of MASLD.
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Affiliation(s)
- Rhonda D Kineman
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL, USA.
- Jesse Brown VA Medical Center, Research and Development Division, Chicago, IL, USA.
| | - Mercedes Del Rio-Moreno
- Department of Medicine, Section of Endocrinology, Diabetes, and Metabolism, University of Illinois at Chicago, Chicago, IL, USA
- Jesse Brown VA Medical Center, Research and Development Division, Chicago, IL, USA
| | - David J Waxman
- Department of Biology and Bioinformatics Program, Boston University, Boston, MA, USA
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Kipp ZA, Badmus OO, Stec DE, Hall B, Hinds TD. Bilirubin bioconversion to urobilin in the gut-liver-kidney axis: A biomarker for insulin resistance in the Cardiovascular-Kidney-Metabolic (CKM) Syndrome. Metabolism 2025; 163:156081. [PMID: 39580049 DOI: 10.1016/j.metabol.2024.156081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/17/2024] [Accepted: 11/16/2024] [Indexed: 11/25/2024]
Abstract
The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies that demonstrate that urobilin is frequently raised in the urine of persons with CVD and its probable role in acquiring the disease. Urobilin is excreted from the kidneys into the urine and may serve as a biomarker for Cardiovascular-Kidney-Metabolic (CKM) Syndrome. We deliberate on the newly discovered bilirubin reductase (BilR) bacterial enzyme that produces urobilin. We discuss the bacterial species expressing BilR, how they impact CVD, and whether suppressing urobilin production and increasing bilirubin may provide new therapeutic strategies for CKM. Possible therapeutic mechanisms for achieving this goal are discussed.
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Affiliation(s)
- Zachary A Kipp
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Olufunto O Badmus
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS, USA
| | - Brantley Hall
- Center for Bioinformatics and Computational Biology, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, College Park, MD, USA
| | - Terry D Hinds
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA.
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Lee WH, Kipp ZA, Pauss SN, Martinez GJ, Bates EA, Badmus OO, Stec DE, Hinds TD. Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: a focus on diabetes and therapeutics. Clin Sci (Lond) 2025; 139:CS20242825. [PMID: 39873298 DOI: 10.1042/cs20242825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/18/2024] [Accepted: 12/20/2024] [Indexed: 01/30/2025]
Abstract
Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.
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Affiliation(s)
- Wang-Hsin Lee
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Zachary A Kipp
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Sally N Pauss
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Genesee J Martinez
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Evelyn A Bates
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Olufunto O Badmus
- Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, USA
| | - David E Stec
- Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, USA
| | - Terry D Hinds
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
- Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
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Sinigaglia B, Escudero J, Biagini SA, Garcia-Calleja J, Moreno J, Dobon B, Acosta S, Mondal M, Walsh S, Aguileta G, Vallès M, Forrow S, Martin-Caballero J, Migliano AB, Bertranpetit J, Muñoz FJ, Bosch E. Exploring Adaptive Phenotypes for the Human Calcium-Sensing Receptor Polymorphism R990G. Mol Biol Evol 2024; 41:msae015. [PMID: 38285634 PMCID: PMC10859840 DOI: 10.1093/molbev/msae015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 01/23/2024] [Accepted: 01/23/2024] [Indexed: 01/31/2024] Open
Abstract
Rainforest hunter-gatherers from Southeast Asia are characterized by specific morphological features including a particularly dark skin color (D), short stature (S), woolly hair (W), and the presence of steatopygia (S)-fat accumulation localized in the hips (DSWS phenotype). Based on previous evidence in the Andamanese population, we first characterized signatures of adaptive natural selection around the calcium-sensing receptor gene in Southeast Asian rainforest groups presenting the DSWS phenotype and identified the R990G substitution (rs1042636) as a putative adaptive variant for experimental follow-up. Although the calcium-sensing receptor has a critical role in calcium homeostasis by directly regulating the parathyroid hormone secretion, it is expressed in different tissues and has been described to be involved in many biological functions. Previous works have also characterized the R990G substitution as an activating polymorphism of the calcium-sensing receptor associated with hypocalcemia. Therefore, we generated a knock-in mouse for this substitution and investigated organismal phenotypes that could have become adaptive in rainforest hunter-gatherers from Southeast Asia. Interestingly, we found that mouse homozygous for the derived allele show not only lower serum calcium concentration but also greater body weight and fat accumulation, probably because of enhanced preadipocyte differentiation and lipolysis impairment resulting from the calcium-sensing receptor activation mediated by R990G. We speculate that such differential features in humans could have facilitated the survival of hunter-gatherer groups during periods of nutritional stress in the challenging conditions of the Southeast Asian tropical rainforests.
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Affiliation(s)
- Barbara Sinigaglia
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Jorge Escudero
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Simone A Biagini
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Jorge Garcia-Calleja
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Josep Moreno
- PCB-PRBB Animal Facility Alliance, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Begoña Dobon
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Sandra Acosta
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
- UB Institute of Neuroscience, Department of Pathology and Experimental Therapeutics, Universitat de Barcelona, Barcelona 08007, Spain
| | - Mayukh Mondal
- Institute of Genomics, University of Tartu, Tartu 51010, Estonia
- Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel, Kiel 24118, Germany
| | - Sandra Walsh
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Gabriela Aguileta
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Mònica Vallès
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Stephen Forrow
- Mouse Mutant Core Facility, Institute for Research in Biomedicine (IRB), Barcelona 08028, Spain
| | - Juan Martin-Caballero
- PCB-PRBB Animal Facility Alliance, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Andrea Bamberg Migliano
- Human Evolutionary Ecology Group, Department of Evolutionary Anthropology, University of Zurich, Zurich 8057, Switzerland
| | - Jaume Bertranpetit
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Francisco J Muñoz
- Laboratory of Molecular Physiology, Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
| | - Elena Bosch
- Institut de Biologia Evolutiva (UPF-CSIC), Departament de Medicina i Ciències de la Vida, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona 08003, Spain
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Xu W, Lai S, Zhao J, Wei S, Fang X, Liu Y, Rong X, Guo J. The blockade of the TGF-β pathway alleviates abnormal glucose and lipid metabolism of lipodystrophy not obesity. Pharmacol Res Perspect 2024; 12:e1160. [PMID: 38174807 PMCID: PMC10765454 DOI: 10.1002/prp2.1160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 11/21/2023] [Indexed: 01/05/2024] Open
Abstract
TGF-β is thought to be involved in the physiological functions of early organ development and pathological changes in substantial organ fibrosis, while studies around adipose tissue function and systemic disorders of glucolipid metabolism are still scarce. In this investigation, two animal models, aP2-SREBP-1c mice and ob/ob mice, were used. TGF-β pathway showed up-regulated in the inguinal white adipose tissue (iWAT) of the two models. SB431542, a TGF-β inhibitor, successfully increased inguinal white adipocyte size by more than 1.5 times and decreased the weight of Peripheral organs including liver, Spleen and Kidney to 73.05%/62.18%/73.23% of pre-administration weights. The iWAT showed elevated expression of GLUTs and lipases, followed by a recovery of circulation GLU, TG, NEFA, and GLYCEROL to the wild-type levels in aP2-SREBP-1c mice. In contrast, TGF-β inhibition did not have similar effects on that of ob/ob mice. In vitro, TGF-β blocker treated mature adipocytes had considerably higher levels of glycerol and triglycerides than the control group, whereas GLUTs and lipases expression levels were unchanged. These findings show that inhibiting the abnormally upregulated TGF-β pathway will only restore iWAT expansion and ameliorate the global metabolic malfunction of glucose and lipids in lipodystrophy, not obesity.
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Affiliation(s)
- Wen‐Dong Xu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Shui‐Zheng Lai
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Jia Zhao
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Shi‐Jie Wei
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Xue‐Ying Fang
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Yi‐Yi Liu
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Xiang‐Lu Rong
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
| | - Jiao Guo
- Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of ChinaGuangdong Pharmaceutical UniversityGuangzhouChina
- Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina
- Guangdong TCM Key Laboratory for Metabolic DiseasesGuangdong Pharmaceutical UniversityGuangzhouChina
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Wagner JB, Abdel-Rahman S, Raghuveer G, Gaedigk A, Boone EC, Gaedigk R, Staggs VS, Reed GA, Zhang N, Leeder JS. SLCO1B1 Genetic Variation Influence on Atorvastatin Systemic Exposure in Pediatric Hypercholesterolemia. Genes (Basel) 2024; 15:99. [PMID: 38254988 PMCID: PMC10815823 DOI: 10.3390/genes15010099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/04/2024] [Accepted: 01/10/2024] [Indexed: 01/24/2024] Open
Abstract
This clinical study examined the influence of SLCO1B1 c.521T>C (rs4149056) on plasma atorvastatin concentrations in pediatric hypercholesterolemia. The participants (8-21 years), including heterozygous (c.521T/C, n = 13), homozygous (c.521C/C, n = 2) and controls (c.521T/T, n = 13), completed a single-oral-dose pharmacokinetic study. Similar to in adults, the atorvastatin (AVA) area-under-concentration-time curve from 0 to 24 h (AUC0-24) was 1.7-fold and 2.8-fold higher in participants with c.521T/C and c.521C/C compared to the c.521T/T participants, respectively. The inter-individual variability in AVA exposure within these genotype groups ranged from 2.3 to 4.8-fold, indicating that additional factors contribute to the inter-individual variability in the AVA dose-exposure relationship. A multivariate model reinforced the SLCO1B1 c.521T>C variant as the central factor contributing to AVA systemic exposure in this pediatric cohort, accounting for ~65% of the variability in AVA AUC0-24. Furthermore, lower AVA lactone concentrations in participants with increased body mass index contributed to higher exposure within the c.521T/T and c.521T/C genotype groups. Collectively, these factors contributing to higher systemic exposure could increase the risk of toxicity and should be accounted for when individualizing the dosing of atorvastatin in eligible pediatric patients.
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Affiliation(s)
- Jonathan B. Wagner
- Ward Family Heart Center, Children’s Mercy, Kansas City, MO 64108, USA
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Susan Abdel-Rahman
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Geetha Raghuveer
- Ward Family Heart Center, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Andrea Gaedigk
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Erin C. Boone
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
| | - Roger Gaedigk
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
| | - Vincent S. Staggs
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
- Health Services & Outcomes Research, Children’s Mercy, Kansas City, MO 64108, USA
| | - Gregory A. Reed
- Clinical Pharmacology Shared Resource, University of Kansas Cancer Center, Fairway, KS 66205, USA
| | - Na Zhang
- Clinical Pharmacology Shared Resource, University of Kansas Cancer Center, Fairway, KS 66205, USA
| | - J. Steven Leeder
- Division of Clinical Pharmacology and Toxicology, Children’s Mercy, Kansas City, MO 64108, USA
- Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, MO 64108, USA
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8
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Shintani T, Imamura C, Ueyama-Toba Y, Inui J, Watanabe A, Mizuguchi H. Establishment of UGT1A1-knockout human iPS-derived hepatic organoids for UGT1A1-specific kinetics and toxicity evaluation. Mol Ther Methods Clin Dev 2023; 30:429-442. [PMID: 37663646 PMCID: PMC10471830 DOI: 10.1016/j.omtm.2023.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 08/08/2023] [Indexed: 09/05/2023]
Abstract
Uridine diphosphate glucuronosyltransferases (UGTs) are highly expressed in the liver and are involved in the metabolism of many drugs. In particular, UGT1A1 has a genetic polymorphism that causes decreased activity, leading to drug-induced hepatotoxicity. Therefore, an in vitro evaluation system that accurately predicts the kinetics of drugs involving UGT1A1 is required. However, there is no such evaluation system because of the absence of the UGT1A1-selective inhibitor. Here, using human induced pluripotent stem (iPS) cells, genome editing technology, and organoid technology, we generated UGT1A1-knockout human iPS hepatocyte-derived liver organoids (UGT1A1-KO i-HOs) as a model for UGT1A1-specific kinetics and toxicity evaluation. i-HOs showed higher gene expression of many drug-metabolizing enzymes including UGT1A1 than human iPS cell-derived hepatocyte-like cells (iPS-HLCs), suggesting that hepatic organoid technology improves liver functions. Wild-type (WT) i-HOs showed similar levels of UGT1A1 activity to primary human (cryopreserved) hepatocytes, while UGT1A1-KO i-HOs completely lost the activity. Additionally, to evaluate whether this model can be used to predict drug-induced hepatotoxicity, UGT1A1-KO i-HOs were exposed to SN-38, the active metabolite of irinotecan, an anticancer drug, and acetaminophen and confirmed that these cells could predict UGT1A1-mediated toxicity. Thus, we succeeded in generating model cells that enable evaluation of UGT1A1-specific kinetics and toxicity.
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Affiliation(s)
- Tomohiro Shintani
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Chiharu Imamura
- Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Yukiko Ueyama-Toba
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
- Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
- Laboratory of Functional Organoid for Drug Discovery, National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan
| | - Jumpei Inui
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Akira Watanabe
- Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
| | - Hiroyuki Mizuguchi
- Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
- Laboratory of Biochemistry and Molecular Biology, School of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
- Laboratory of Functional Organoid for Drug Discovery, National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Osaka 565-0871, Japan
- Global Center for Medical Engineering and Informatics, Osaka University, Osaka 565-0871, Japan
- Center for Infectious Disease Education and Research, Osaka University, Osaka 565-0871, Japan
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9
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Chen J, Cai B, Tian C, Jiang D, Shi H, Huang Y, Zhu C, Li G, Deng S. RNA Sequencing (RNA-Seq) Analysis Reveals Liver Lipid Metabolism Divergent Adaptive Response to Low- and High-Salinity Stress in Spotted Scat ( Scatophagus argus). Animals (Basel) 2023; 13:ani13091503. [PMID: 37174540 PMCID: PMC10177406 DOI: 10.3390/ani13091503] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Spotted scat (Scatophagus argus) can tolerate a wide range of salinity fluctuations. It is a good model for studying environmental salinity adaptation. Lipid metabolism plays an important role in salinity adaptation in fish. To elucidate the mechanism of lipid metabolism in the osmoregulation, the liver transcriptome was analyzed after 22 d culture with a salinity of 5 ppt (Low-salinity group: LS), 25 ppt (Control group: Ctrl), and 35 ppt (High-salinity group: HS) water by using RNA sequencing (RNA-seq) in spotted scat. RNA-seq analysis showed that 1276 and 2768 differentially expressed genes (DEGs) were identified in the LS vs. Ctrl and HS vs. Ctrl, respectively. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that the pathways of steroid hormone biosynthesis, steroid biosynthesis, glycerophospholipid metabolism, glycerolipid metabolism, and lipid metabolism were significantly enriched in the LS vs. Ctrl. The genes of steroid biosynthesis (sqle, dhcr7, and cyp51a1), steroid hormone biosynthesis (ugt2a1, ugt2a2, ugt2b20, and ugt2b31), and glycerophospholipid metabolism (cept1, pla2g4a, and ptdss2) were significantly down-regulated in the LS vs. Ctrl. The pathways related to lipid metabolisms, such as fatty acid metabolism, fatty acid biosynthesis, peroxisome proliferator-activated receptor (PPAR) signaling pathway, adipocytokine signaling pathway, fatty acid degradation, and unsaturated fatty acid biosynthesis, were significantly enriched in the HS vs. Ctrl. The genes of unsaturated fatty acid biosynthesis (scd1, hacd3, fads2, pecr, and elovl1) and adipocytokine signaling pathway (g6pc1, socs1, socs3, adipor2, pck1, and pparα) were significantly up-regulated in the HS vs. Ctrl. These results suggest that the difference in liver lipid metabolism is important to adapt to low- and high-salinity stress in spotted scat, which clarifies the molecular regulatory mechanisms of salinity adaptation in euryhaline fish.
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Affiliation(s)
- Jieqing Chen
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
| | - Bosheng Cai
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
| | - Changxu Tian
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
| | - Dongneng Jiang
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Zhanjiang 524088, China
| | - Hongjuan Shi
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Zhanjiang 524088, China
| | - Yang Huang
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Zhanjiang 524088, China
| | - Chunhua Zhu
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Zhanjiang 524088, China
| | - Guangli Li
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Guangdong Provincial Key Laboratory of Pathogenic Biology and Epidemiology for Aquatic Economic Animals, Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
| | - Siping Deng
- Fisheries College, Guangdong Ocean University, Zhanjiang 524088, China
- Guangdong Research Center on Reproductive Control and Breeding Technology of Indigenous Valuable Fish Species, Zhanjiang 524088, China
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10
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Vitek L, Hinds TD, Stec DE, Tiribelli C. The physiology of bilirubin: health and disease equilibrium. Trends Mol Med 2023; 29:315-328. [PMID: 36828710 PMCID: PMC10023336 DOI: 10.1016/j.molmed.2023.01.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 02/24/2023]
Abstract
Bilirubin has several physiological functions, both beneficial and harmful. In addition to reactive oxygen species-scavenging activities, bilirubin has potent immunosuppressive effects associated with long-term pathophysiological sequelae. It has been recently recognized as a hormone with endocrine actions and interconnected effects on various cellular signaling pathways. Current studies show that bilirubin also decreases adiposity and prevents metabolic and cardiovascular diseases. All in all, the physiological importance of bilirubin is only now coming to light, and strategies for increasing plasma bilirubin levels to combat chronic diseases are starting to be considered. This review discusses the beneficial effects of increasing plasma bilirubin, incorporates emerging areas of bilirubin biology, and provides key concepts to advance the field.
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Affiliation(s)
- Libor Vitek
- Fourth Department of Internal Medicine and Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 120 00 Prague, Czech Republic
| | - Terry D Hinds
- Department of Pharmacology and Nutritional Sciences, Barnstable Brown Diabetes Center, Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USA
| | - David E Stec
- Department of Physiology and Biophysics, Cardiorenal, and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, MS 39216, USA
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11
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Kipp ZA, Xu M, Bates EA, Lee WH, Kern PA, Hinds TD. Bilirubin Levels Are Negatively Correlated with Adiposity in Obese Men and Women, and Its Catabolized Product, Urobilin, Is Positively Associated with Insulin Resistance. Antioxidants (Basel) 2023; 12:170. [PMID: 36671031 PMCID: PMC9854555 DOI: 10.3390/antiox12010170] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/03/2023] [Accepted: 01/09/2023] [Indexed: 01/12/2023] Open
Abstract
Bilirubin levels in obese humans and rodents have been shown to be lower than in their lean counterparts. Some studies have proposed that the glucuronyl UGT1A1 enzyme that clears bilirubin from the blood increases in the liver with obesity. UGT1A1 clearance of bilirubin allows more conjugated bilirubin to enter the intestine, where it is catabolized into urobilin, which can be then absorbed via the hepatic portal vein. We hypothesized that when bilirubin levels are decreased, the urobilin increases in the plasma of obese humans, as compared to lean humans. To test this, we measured plasma levels of bilirubin and urobilin, body mass index (BMI), adiposity, blood glucose and insulin, and HOMA IR in a small cohort of obese and lean men and women. We found that bilirubin levels negatively correlated with BMI and adiposity in obese men and women, as compared to their lean counterparts. Contrarily, urobilin levels were positively associated with adiposity and BMI. Only obese women were found to be insulin resistant based on significantly higher HOMA IR, as compared to lean women. The urobilin levels were positively associated with HOMA IR in both groups, but women had a stronger linear correlation. These studies indicate that plasma urobilin levels are associated with obesity and its comorbidities, such as insulin resistance.
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Affiliation(s)
- Zachary A. Kipp
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, 760 Press Avenue, Healthy Kentucky Research Building, Lexington, KY 40508, USA
| | - Mei Xu
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, 760 Press Avenue, Healthy Kentucky Research Building, Lexington, KY 40508, USA
| | - Evelyn A. Bates
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, 760 Press Avenue, Healthy Kentucky Research Building, Lexington, KY 40508, USA
| | - Wang-Hsin Lee
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, 760 Press Avenue, Healthy Kentucky Research Building, Lexington, KY 40508, USA
| | - Philip A. Kern
- Department of Internal Medicine, Division of Endocrinology, University of Kentucky, Lexington, KY 40508, USA
| | - Terry D. Hinds
- Department of Pharmacology and Nutritional Sciences, University of Kentucky, 760 Press Avenue, Healthy Kentucky Research Building, Lexington, KY 40508, USA
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY 40508, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY 40508, USA
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12
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Guevara-Ramírez P, Cadena-Ullauri S, Ruiz-Pozo VA, Tamayo-Trujillo R, Paz-Cruz E, Simancas-Racines D, Zambrano AK. Genetics, genomics, and diet interactions in obesity in the Latin American environment. Front Nutr 2022; 9:1063286. [PMID: 36532520 PMCID: PMC9751379 DOI: 10.3389/fnut.2022.1063286] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 10/25/2022] [Indexed: 08/25/2023] Open
Abstract
Obesity is a chronic disease characterized by abnormal or excessive fat accumulation that could impact an individual's health; moreover, the World Health Organization (WHO) has declared obesity a global epidemic since 1997. In Latin America, in 2016, reports indicated that 24.2% of the adult population was obese. The environmental factor or specific behaviors like dietary intake or physical activity have a vital role in the development of a condition like obesity, but the interaction of genes could contribute to that predisposition. Hence, it is vital to understand the relationship between genes and disease. Indeed, genetics in nutrition studies the genetic variations and their effect on dietary response; while genomics in nutrition studies the role of nutrients in gene expression. The present review represents a compendium of the dietary behaviors in the Latin American environment and the interactions of genes with their single nucleotide polymorphisms (SNPs) associated with obesity, including the risk allele frequencies in the Latin American population. Additionally, a bibliographical selection of several studies has been included; these studies examined the impact that dietary patterns in Latin American environments have on the expression of numerous genes involved in obesity-associated metabolic pathways.
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Affiliation(s)
- Patricia Guevara-Ramírez
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Santiago Cadena-Ullauri
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Viviana A. Ruiz-Pozo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Rafael Tamayo-Trujillo
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Elius Paz-Cruz
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Daniel Simancas-Racines
- Centro de Investigación en Salud Pública y Epidemiología Clínica (CISPEC), Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
| | - Ana Karina Zambrano
- Centro de Investigación Genética y Genómica, Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador
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13
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Zhang T, Krekels EHJ, Smit C, Knibbe CAJ. Drug pharmacokinetics in the obese population: challenging common assumptions on predictors of obesity-related parameter changes. Expert Opin Drug Metab Toxicol 2022; 18:657-674. [PMID: 36217846 DOI: 10.1080/17425255.2022.2132931] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Obesity is associated with many physiological changes. We review available evidence regarding five commonly accepted assumptions to a priori predict the impact of obesity on drug pharmacokinetics (PK). AREAS COVERED The investigated assumptions are: 1) lean body weight is the preferred descriptor of clearance and dose adjustments; 2) volume of distribution increases for lipophilic, but not for hydrophilic drugs; 3) CYP-3A4 activity is suppressed and UGT activity is increased, implying decreased and increased dose requirements for substrates of these enzyme systems, respectively; 4) glomerular filtration rate is enhanced, necessitating higher doses for drugs cleared through glomerular filtration; 5) drug dosing information from obese adults can be extrapolated to obese adolescents. EXPERT OPINION Available literature contradicts, or at least limits the generalizability, of all five assumptions. Clinical studies should focus on quantifying the impact of duration and severity of obesity on drug PK in adults and adolescents, and also include oral bioavailability and pharmacodynamics in these studies. Physiologically-based PK approaches can be used to predict PK changes for individual drugs, but can also be used to define in general terms based on patient characteristics and drug properties, when certain assumptions can or cannot be expected to be systematically accurate.
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Affiliation(s)
- Tan Zhang
- Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Elke H J Krekels
- Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands
| | - Cornelis Smit
- Department of Clinical Pharmacy, Antonius Hospital Sneek, The Netherlands
| | - Catherijne A J Knibbe
- Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.,Department of Clinical Pharmacy, St. Antonius Hospital Nieuwegein, The Netherlands
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14
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Berton M, Bettonte S, Stader F, Battegay M, Marzolini C. Repository Describing the Anatomical, Physiological, and Biological Changes in an Obese Population to Inform Physiologically Based Pharmacokinetic Models. Clin Pharmacokinet 2022; 61:1251-1270. [PMID: 35699913 PMCID: PMC9439993 DOI: 10.1007/s40262-022-01132-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/28/2022] [Indexed: 11/24/2022]
Abstract
Background Obesity is associated with physiological changes that can affect drug pharmacokinetics. Obese individuals are underrepresented in clinical trials, leading to a lack of evidence-based dosing recommendations for many drugs. Physiologically based pharmacokinetic (PBPK) modelling can overcome this limitation but necessitates a detailed description of the population characteristics under investigation. Objective The purpose of this study was to develop and verify a repository of the current anatomical, physiological, and biological data of obese individuals, including population variability, to inform a PBPK framework. Methods A systematic literature search was performed to collate anatomical, physiological, and biological parameters for obese individuals. Multiple regression analyses were used to derive mathematical equations describing the continuous effect of body mass index (BMI) within the range 18.5–60 kg/m2 on system parameters. Results In total, 209 studies were included in the database. The literature reported mostly BMI-related changes in organ weight, whereas data on blood flow and biological parameters (i.e. enzyme abundance) were sparse, and hence physiologically plausible assumptions were made when needed. The developed obese population was implemented in Matlab® and the predicted system parameters obtained from 1000 virtual individuals were in agreement with observed data from an independent validation obese population. Our analysis indicates that a threefold increase in BMI, from 20 to 60 kg/m2, leads to an increase in cardiac output (50%), liver weight (100%), kidney weight (60%), both the kidney and liver absolute blood flows (50%), and in total adipose blood flow (160%). Conclusion The developed repository provides an updated description of a population with a BMI from 18.5 to 60 kg/m2 using continuous physiological changes and their variability for each system parameter. It is a tool that can be implemented in PBPK models to simulate drug pharmacokinetics in obese individuals.
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Affiliation(s)
- Mattia Berton
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland. .,University of Basel, Basel, Switzerland.
| | - Sara Bettonte
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | | | - Manuel Battegay
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
| | - Catia Marzolini
- Division of Infectious Diseases and Hospital Epidemiology, Departments of Medicine and Clinical Research, University Hospital Basel, Basel, Switzerland.,University of Basel, Basel, Switzerland
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15
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D'Souza V, Meghashree, Badanthadka M, Mamatha BS, Vijayanarayana K. Effect of nutritional status on acetaminophen pharmacokinetic profile. Toxicol Appl Pharmacol 2022; 438:115888. [PMID: 35065993 DOI: 10.1016/j.taap.2022.115888] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 12/19/2021] [Accepted: 01/14/2022] [Indexed: 02/07/2023]
Abstract
Short-term fasting increases acetaminophen exposure in healthy subjects, whereas no effect was observed after a high-fat diet. These findings suggest the necessity of considering nutritional status when assessing the risk of acetaminophen-induced toxicity. Further role of nutrition status on pharmacokinetic profile of acetaminophen (APAP) at toxic doses are not available. Our study aims to compare the effects of nutrition status on kinetic profile of APAP in 3 different dietary conditions like - Normal diet (ND), Low protein diet (LPD) and High fat diet (HFD) groups. To investigate the pharmacokinetic profile of APAP at toxic dose, 3 groups of animals were separated after weaning and for the next 15 weeks they were fed with their respective diets (ND, LPD and HFD). Animals were dosed with APAP (300 mg/kg p.o) and blood sampling was done at different time intervals. Plasma samples were analyzed using HPLC method. Data analysis was done by Non-compartment analysis using Phoenix WinNonlin 8.3 software. LPD group show higher values of C max, T max, T 1/2, and AUC 0-4, AUC 0-x values compared to ND and HFD groups. Our study compared APAP pharmacokinetic profile at toxic dose in three different diet regimes.
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Affiliation(s)
- Vinitha D'Souza
- Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Nitte University Centre for Animal Research and Experimentation (NUCARE), Paneer campus, Deralakatte, Mangalore 575 018, India
| | - Meghashree
- Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Nitte University Centre for Animal Research and Experimentation (NUCARE), Paneer campus, Deralakatte, Mangalore 575 018, India
| | - Murali Badanthadka
- Nitte (Deemed to be University), NGSM Institute of Pharmaceutical Sciences (NGSMIPS), Department of Nitte University Centre for Animal Research and Experimentation (NUCARE), Paneer campus, Deralakatte, Mangalore 575 018, India.
| | - B S Mamatha
- NUCSER, Nittte (Deemed to be University), Paneer Campus, Deralakatte, Mangalore 575 018, India
| | - K Vijayanarayana
- Dept. of Pharmacy Practice, Manipal college of Pharmaceutical Sciences, Manipal Academy of Higher Education, Madhav Nagar, Manipal, 576104, Karnataka, India
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16
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Hepatocyte-Specific Deficiency of BAP31 Amplified Acetaminophen-Induced Hepatotoxicity via Attenuating Nrf2 Signaling Activation in Mice. Int J Mol Sci 2021; 22:ijms221910788. [PMID: 34639126 PMCID: PMC8509202 DOI: 10.3390/ijms221910788] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 01/18/2023] Open
Abstract
Liver-specific deficiency of B-cell receptor-associated protein 31 knockout mice (BAP31-LKO) and the littermates were injected with acetaminophen (APAP), markers of liver injury, and the potential molecular mechanisms were determined. In response to APAP overdose, serum aspartate aminotransferase and alanine aminotransferase levels were increased in BAP31-LKO mice than in wild-type controls, accompanied by enhanced liver necrosis. APAP-induced apoptosis and mortality were increased. Hepatic glutathione was decreased (1.60 ± 0.31 μmol/g tissue in WT mice vs. 0.85 ± 0.14 μmol/g tissue in BAP31-LKO mice at 6 h, p < 0.05), along with reduced glutathione reductase activity and superoxide dismutase; while malondialdehyde was significantly induced (0.41 ± 0.03 nmol/mg tissue in WT mice vs. 0.50 ± 0.05 nmol/mg tissue in BAP31-LKO mice for 6 h, p < 0.05). JNK signaling activation and APAP-induced hepatic inflammation were increased in BAP31-LKO mice. The mechanism research revealed that BAP31-deficiency decreased Nrf2 mRNA stability (half-life of Nrf2 mRNA decreased from ~1.3 h to ~40 min) and miR-223 expression, led to reduced nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and antioxidant genes induction. BAP31-deficiency decreased mitochondrial membrane potentials, reduced mitochondria-related genes expression, and resulted in mitochondrial dysfunction in the liver. Conclusions: BAP31-deficiency reduced the antioxidant response and Nrf2 signaling activation via reducing Nrf2 mRNA stabilization, enhanced JNK signaling activation, hepatic inflammation, and apoptosis, amplified APAP-induced hepatotoxicity in mice.
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17
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Mozduri Z, Lo B, Marty-Gasset N, Masoudi AA, Arroyo J, Morisson M, Canlet C, Bonnet A, Bonnefont CMD. Application of Metabolomics to Identify Hepatic Biomarkers of Foie Gras Qualities in Duck. Front Physiol 2021; 12:694809. [PMID: 34305649 PMCID: PMC8293271 DOI: 10.3389/fphys.2021.694809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Accepted: 06/03/2021] [Indexed: 12/13/2022] Open
Abstract
Foie gras is a traditional dish in France that contains 50 to 60% of lipids. The high-fat content of the liver improves the organoleptic qualities of foie gras and reduces its technological yield at cooking (TY). As the valorization of the liver as foie gras products is strongly influenced by the TY, classifying the foie gras in their potential technological quality before cooking them is the main challenge for producers. Therefore, the current study aimed to identify hepatic biomarkers of foie gras qualities like liver weight (LW) and TY. A group of 120 male mule ducks was reared and overfed for 6–12 days, and their livers were sampled and analyzed by proton nuclear magnetic resonance (1H-NMR). Eighteen biomarkers of foie gras qualities were identified, nine for LW and TY, five specific to LW, and four specific to TY. All biomarkers were strongly negatively correlated to the liver weights and positively correlated to the technological yield, except for the lactate and the threonine, and also for the creatine that was negatively correlated to foie gras technological quality. As a result, in heavy livers, the liver metabolism was oriented through a reduction of carbohydrate and amino acid metabolisms, and the plasma membrane could be damaged, which may explain the low technological yield of these livers. The detected biomarkers have been strongly discussed with the metabolism of the liver in nonalcoholic steatohepatitis.
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Affiliation(s)
- Zohre Mozduri
- Department of Animal Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
| | - Bara Lo
- GenPhySE, Université de Toulouse, INRAE, ENVT, Castanet Tolosan, France
| | | | - Ali Akbar Masoudi
- Department of Animal Science, Faculty of Agriculture, Tarbiat Modares University, Tehran, Iran
| | - Julien Arroyo
- ASSELDOR, Station d'Expérimentation Appliquée et de Démonstration sur l'oie et le Canard, La Tour de Glane, Coulaures, France
| | - Mireille Morisson
- GenPhySE, Université de Toulouse, INRAE, ENVT, Castanet Tolosan, France
| | - Cécile Canlet
- Toxalim, Université de Toulouse, INRA, ENVT, INP-Purpan, UPS, Toulouse, France.,Axiom Platform, MetaToul-Me, National Infrastructure for Metabolomics and Fluxomics, Toulouse, France
| | - Agnès Bonnet
- GenPhySE, Université de Toulouse, INRAE, ENVT, Castanet Tolosan, France
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18
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Braun A, Bruxner G. "Little more than a gut feeling?"-considerations when prescribing psychotropic medications to patients undergoing bariatric surgery. Australas Psychiatry 2021; 29:272-274. [PMID: 32961098 DOI: 10.1177/1039856220956468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE Bariatric surgical procedures are being commonly performed increasingly, and many surgical candidates are concomitantly taking psychotropic medication. This paper aims to elucidate issues when prescribing psychiatric medication in this setting of substantial anatomical and physiological change. METHOD A hand search of the literature to assess the current understanding of effects of various bariatric procedures on the bioavailability of psychotropic medication. RESULTS Predominantly malabsorptive bariatric procedures may reduce bioavailability of some but not all commonly used psychiatric medications. There is minimal information about the effects of the most commonly performed surgery, vertical sleeve gastrectomy. Lithium prescription and monitoring requires caution. CONCLUSIONS There is limited guidance for prescription for psychotropic medication in the bariatric surgery patient group, and vigilance for unexpected adverse effects or altered efficacy is warranted.
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Affiliation(s)
- Anastasia Braun
- Royal Brisbane and Woman's Hospital Health Service District, Australia
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19
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Wang J, Sun F, Xu P, Zhang Y, Sun X, Deng H. Transient infantile hypertriglyceridemia with jaundice: A case report. Medicine (Baltimore) 2021; 100:e25697. [PMID: 33907148 PMCID: PMC8084070 DOI: 10.1097/md.0000000000025697] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 03/30/2021] [Accepted: 04/08/2021] [Indexed: 12/18/2022] Open
Abstract
RATIONALE Transient infantile hypertriglyceridemia (HTGTI) is a rare autosomal recessive inherited disease caused by inactivating mutations in the glycerol-3-phosphate dehydrogenase 1 gene. To date, only a few patients have been reported worldwide. The symptoms of the affected individuals present a certain degree of transient hypertriglyceridemia, hepatomegaly, elevated liver enzymes, persistent fatty liver and hepatic fibrosis in early infancy. However, the clinical characteristics and pathogenesis of this disease are remain unclear. PATIENT CONCERNS A one month and twenty-five days old girl was admitted to hospital because of persisted jaundice and hepatomegaly for fifty days. DIAGNOSE The girl was diagnosed with HTGTI coincident with a noval mutation in glycerol-3-phosphate dehydrogenase 1. INTERVENTION She was advised to take low-fat diet and supplement of medium-chain fatty acids. OUTCOMES Her jaundice was gradually normal at the age of 4 months without any treatment, and hypertriglyceridemia were normal at the age of 13 months, but still had elevated transaminases and hepatic steatosis. LESSONS Jaundice may be a novel phenotype in HTGTI. The report contributes to the expansion of HTGTI's gene mutation spectrum and its clinical manifestations.
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Affiliation(s)
- Jun Wang
- Second Department of Infectious Diseases
| | - Fang Sun
- Department of Respiratory, Xi’an Children's Hospital
| | - Pengfei Xu
- Second Department of Infectious Diseases
| | | | | | - Huiling Deng
- Second Department of Infectious Diseases
- Xi’an Central Hospital, Xi’an, Shaanxi Province, China
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Wang M, Xu G, Tang Y, Su S, Wang Y, Zhu Z. Investigation of the Molecular Mechanisms of Antioxidant Damage and Immune Response Downregulation in Liver of Coilia nasus Under Starvation Stress. Front Endocrinol (Lausanne) 2021; 12:622315. [PMID: 33732214 PMCID: PMC7959721 DOI: 10.3389/fendo.2021.622315] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/08/2021] [Indexed: 01/11/2023] Open
Abstract
Commercial fishing of estuarine tapertail anchovy (Coilia nasus), an important anadromous fish species in the Yangtze River of China, has been prohibited due to the serious damage overfishing has caused to the wild population. Research regarding the energy metabolism is important for migratory fish to ensure the continuation of their existence. In this study, we performed, for the first time, a comparative transcriptome analysis of the liver of C. nasus subjected to long-term starvation stress. The results indicated that the damaging effects involved downregulation of the antioxidant capacity and immune response. The positive response to starvation involved upregulation of the anti-allergy and anticancer capacity, which supports the function of starvation in cancer inhibition, as has also been determined for human beings. This study revealed regulatory pathways, differentially expressed genes (DEGs), and mechanisms leading to damage of the liver in C. nasus affected by starvation. This research contributes information for the further study of the energy metabolism mechanism of C. nasus and provides a theoretical reference for starvation metabolism research of other fish species and even human beings.
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Affiliation(s)
- Meiyao Wang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
- Aquatic Animal Genome Center of Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
| | - Gangchun Xu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
- *Correspondence: Gangchun Xu, ; Yongkai Tang,
| | - Yongkai Tang
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
- Aquatic Animal Genome Center of Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
- *Correspondence: Gangchun Xu, ; Yongkai Tang,
| | - Shengyan Su
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
- Wuxi Fisheries College, Nanjing Agricultural University, Wuxi, China
- Aquatic Animal Genome Center of Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
| | - Yinping Wang
- Scientific Observing and Experimental Station of Fishery Resources and Environment in the Lower Reaches of the Changjiang River, Ministry of Agriculture and Rural Affairs, Wuxi, China
| | - Zhixiang Zhu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, China
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21
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Bock KW. Aryl hydrocarbon receptor (AHR), integrating energy metabolism and microbial or obesity-mediated inflammation. Biochem Pharmacol 2020; 184:114346. [PMID: 33227291 DOI: 10.1016/j.bcp.2020.114346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023]
Abstract
Aryl hydrocarbon receptor (AHR) has been characterized as multifunctional sensor, integrator and ligand-activated transcription factor of the bHLH/PAS family. Regulation of inflammatory diseases and energy metabolism are among the putative functions of AHR. Challenges in AHR research include marked species differences, and cell, tissue and context dependence of AHR functions. The commentary is focused on AHR's role in the integration between energy expenditure and microbial and non-infectious inflammation, the latter exemplified by obesity-mediated nonalcoholic fatty liver disease. One of the mechanisms controlling energy-consuming inflammation is represented by a signalsome that is involved in retinoic acid-triggered neutrophil differentiation and regulation of the NADPH oxidase complex (NOX). Established signalsome components are AHR, CD38, multiple protein kinases and adaptors. To prevent chronic inflammatory diseases, the complex interplay between a range of inflammatory responses and energy expenditure must be precisely regulated. Surviving an infection requires both pathogen clearance and tissue protection from inflammatory damage. Defenses are energy-consuming anabolic programs. Therefore, anti-inflammatory, catabolic tolerance programs by metabolic reprogramming of macrophages have evolved. Therapeutic options of AHR agonists to reduce chronic inflammatory diseases are discussed.
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Affiliation(s)
- Karl Walter Bock
- Institute of Experimental and Clinical Pharmacology and Toxicology, Wilhelmstrasse 56, D-72074 Tübingen, Germany.
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22
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Landerer S, Kalthoff S, Paulusch S, Strassburg CP. A Gilbert syndrome-associated haplotype protects against fatty liver disease in humanized transgenic mice. Sci Rep 2020; 10:8689. [PMID: 32457304 PMCID: PMC7250928 DOI: 10.1038/s41598-020-65481-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 04/30/2020] [Indexed: 12/13/2022] Open
Abstract
UDP-glucuronosyltransferases 1 A (UGT1A) enzymes are capable of detoxifying a broad range of endo- and xenobiotic compounds, which contributes to antioxidative effects, modulation of inflammation and cytoprotection. In the presence of low-function genetic UGT1A variants fibrosis development is increased in various diseases. This study aimed to examine the role of common UGT1A polymorphisms in NASH. Therefore, htgUGT1A-WT mice and htgUGT1A-SNP mice (carrying a common human haplotype present in 10% of the white population) were fed a high-fat Paigen diet for 24 weeks. Serum aminotransferase activities, hepatic triglycerides, fibrosis development and UGT1A expression were assessed. Microscopic examination revealed higher hepatic fat deposition and a significant induction of UGT1A gene expression in htgUGT1A-WT mice. In agreement with these observations, lower serum aminotransferase activities and lower expression levels of fibrosis-related genes were measured in htgUGT1A-SNP mice. This was accompanied by reduced PPARα protein levels in htgUGT1A-WT but not in SNP mice. Our data demonstrate a protective effect of a UGT1A SNP haplotype, leading to milder hepatic steatosis and NASH. Higher PPARα protein levels in animals with impaired UGT1A activity are the likely result of reduced glucuronidation of ligands involved in PPARα-mediated fatty acid oxidation and may lead to the observed protection in htgUGT1A-SNP mice.
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Affiliation(s)
- Steffen Landerer
- Department of Internal Medicine I, University Hospital Bonn, 53127, Bonn, Germany
| | - Sandra Kalthoff
- Department of Internal Medicine I, University Hospital Bonn, 53127, Bonn, Germany
| | - Stefan Paulusch
- Department of Internal Medicine I, University Hospital Bonn, 53127, Bonn, Germany
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23
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Xu L, Zheng R, Xie P, Guo Q, Ji H, Li T. Dysregulation of UDP-glucuronosyltransferases in CCl 4 induced liver injury rats. Chem Biol Interact 2020; 325:109115. [PMID: 32380060 DOI: 10.1016/j.cbi.2020.109115] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 04/15/2020] [Accepted: 04/23/2020] [Indexed: 10/24/2022]
Abstract
UDP-glucuronosyltransferases (UGTs) are a family of phase II drug metabolizing enzymes that catalyze glucuronidation of numerous endogenous and exogenous substrates. Carbon tetrachloride (CCl4) is widely used to develop liver injuries mimicking human liver diseases. However, effects of CCl4 on the expression and activities of UGTs and the mechanism have not been fully elucidated. The present study aims to elucidate the dysregulation patterns of major UGTs induced by CCl4. Biochemical and histopathological results showed that CCl4 exerted hepatotoxicity in rats. The mRNA levels of UGTs were all significantly reduced in acute liver injury rats. However, mRNA levels of UGT1A1, 1A6, 2B1 and 2B2 were up-regulated while the UGT2B3, 2B6 and 2B12 levels were reduced in chronic CCl4-induced liver fibrosis rats. The protein expression of UGT1A1, 1A6 and 2B were decreased in acute liver injury rats. UGT1A1 and 1A6 proteins were increased, whereas UGT2B protein was reduced in liver fibrosis rats. In addition, CCl4 inhibited the enzyme activities of UGTs in rats. Moreover, the dysregulation of UGTs was accompanied by the decreased mRNA expression of Nrf2, CAR, FXR, PXR, PPAR-α and their corresponding target genes, except for Nrf2, HO-1, AhR and CYP1A1 in liver fibrosis rats. These findings suggest that dysregulation of UGTs under CCl4 exposure is isoform-specific, which could have a complex impact on drug efficacy and endogenous metabolism. Different exposure durations of CCl4 (single vs multiple doses) could have differential effects on rat hepatic UGTs expression.
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Affiliation(s)
- Lijie Xu
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
| | - Rongyao Zheng
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
| | - Peng Xie
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
| | - Qianqian Guo
- Department of Pharmacy, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, 450000, China
| | - Hui Ji
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
| | - Tingting Li
- School of Pharmacy, China Pharmaceutical University, Nanjing, 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, Jiangsu, China.
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24
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Case Report of Increased Exposure to Antiretrovirals following Sleeve Gastrectomy. Antimicrob Agents Chemother 2020; 64:AAC.02453-19. [PMID: 32015045 DOI: 10.1128/aac.02453-19] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 01/28/2020] [Indexed: 12/25/2022] Open
Abstract
Bariatric surgery is increasingly performed in morbidly obese HIV patients. Limited data exist regarding antiretroviral drug exposure after bariatric surgery. We report a case of a morbidly obese HIV patient who underwent sleeve gastrectomy. Abacavir, lamivudine, and dolutegravir therapeutic drug monitoring was performed at several time points pre- and postsurgery. Significantly increased levels were measured, particularly for abacavir, whose levels increased ∼12-fold. Several mechanistic explanations for these findings are discussed.
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25
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Fujihira H, Masahara-Negishi Y, Akimoto Y, Hirayama H, Lee HC, Story BA, Mueller WF, Jakob P, Clauder-Münster S, Steinmetz LM, Radhakrishnan SK, Kawakami H, Kamada Y, Miyoshi E, Yokomizo T, Suzuki T. Liver-specific deletion of Ngly1 causes abnormal nuclear morphology and lipid metabolism under food stress. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165588. [PMID: 31733337 DOI: 10.1016/j.bbadis.2019.165588] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 09/09/2019] [Accepted: 10/09/2019] [Indexed: 12/14/2022]
Abstract
The cytoplasmic peptide:N-glycanase (Ngly1) is a de-N-glycosylating enzyme that cleaves N-glycans from misfolded glycoproteins and is involved in endoplasmic reticulum-associated degradation. The recent discovery of NGLY1-deficiency, which causes severe systemic symptoms, drew attention to the physiological function of Ngly1 in mammals. While several studies have been carried out to reveal the physiological necessity of Ngly1, the semi-lethal nature of Ngly1-deficient animals made it difficult to analyze its function in adults. In this study, we focus on the physiological function of Ngly1 in liver (hepatocyte)-specific Ngly1-deficient mice generated using the cre-loxP system. We found that hepatocyte-specific Ngly1-deficient mice showed abnormal hepatocyte nuclear size/morphology with aging but did not show other notable defects in unstressed conditions. This nuclear phenotype did not appear to be related to the function of the only gene currently reported to rescue Ngly1-deficient murine lethality so far, endo-β-N-acetylglucosaminidase. We also found that under a high fructose diet induced stress, the hepatocyte-specific Ngly1-deletion resulted in liver transaminases elevation and increased lipid droplet accumulation. We showed that the processing and localization of the transcription factor, nuclear factor erythroid 2-like 1 (Nfe2l1), was impaired in the Ngly1-deficient hepatocytes. Therefore, Nfe2l1, at least partially, contributes to the phenotypes observed in hepatocyte-specific Ngly1-deficient mice. Our results indicate that Ngly1 plays important roles in the adult liver impacting nuclear morphology and lipid metabolism. Hepatocyte-specific Ngly1-deficient mice could thus serve as a valuable animal model for assessing in vivo efficacy of drugs and/or treatment for NGLY1-deficiency.
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Affiliation(s)
- Haruhiko Fujihira
- Glycometabolic Biochemistry Laboratory, Cluster for Pioneering Research, RIKEN, Saitama 351-0198, Japan; Division of Glycobiologics, Intractable Disease Research Center, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Yuki Masahara-Negishi
- Glycometabolic Biochemistry Laboratory, Cluster for Pioneering Research, RIKEN, Saitama 351-0198, Japan
| | - Yoshihiro Akimoto
- Department of Anatomy, Kyorin University School of Medicine, Tokyo 181-8611, Japan
| | - Hiroto Hirayama
- Glycometabolic Biochemistry Laboratory, Cluster for Pioneering Research, RIKEN, Saitama 351-0198, Japan; Suzuki Project, T-CiRA Joint Program, Fujisawa, Kanagawa 251-8555, Japan
| | - Hyeon-Cheol Lee
- Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Benjamin A Story
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany
| | - William F Mueller
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany
| | - Petra Jakob
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany
| | - Sandra Clauder-Münster
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany
| | - Lars M Steinmetz
- Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Heidelberg 69117, Germany; Department of Genetics, School of Medicine, Stanford University, Stanford, CA 94305, United States
| | - Senthil K Radhakrishnan
- Department of Pathology, Virginia Commonwealth University, Richmond, VA 23298, United States
| | - Hayato Kawakami
- Department of Anatomy, Kyorin University School of Medicine, Tokyo 181-8611, Japan
| | - Yoshihiro Kamada
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Takehiko Yokomizo
- Department of Biochemistry, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Tadashi Suzuki
- Glycometabolic Biochemistry Laboratory, Cluster for Pioneering Research, RIKEN, Saitama 351-0198, Japan; Suzuki Project, T-CiRA Joint Program, Fujisawa, Kanagawa 251-8555, Japan.
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26
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Lammers LA, Achterbergh R, Mathôt RAA, Romijn JA. The effects of fasting on drug metabolism. Expert Opin Drug Metab Toxicol 2019; 16:79-85. [PMID: 31851534 DOI: 10.1080/17425255.2020.1706728] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Introduction: There is considerable variability in the rates and extent of drug metabolism between patients due to physiological, genetic, pharmacologic, environmental and nutritional factors such as fasting. This variability in drug metabolism may result in treatment failure or, conversely, in increased side effects or toxicity. Preclinical studies have shown that fasting alters drug metabolism by modulating the activity of drug metabolizing enzymes involved. However, until recently little was known about the effects of fasting on drug metabolism in humans.Areas covered: This review describes the effects of fasting on drug metabolism based on both preclinical studies and studies performed in humans.Expert opinion: A better understanding of the effects of fasting may improve the efficacy and safety of pharmacotherapy for individual patients. Fasting contributes to variability in human drug metabolism by differentially affecting drug metabolizing enzymes. Although the effects of fasting on drug metabolism appear to be small (between 10-20%), fasting may be relevant for drugs with a small therapeutic range and/or in combination with other factors that contribute to variability in drug metabolism such as physiological, genetic or pharmacological factors. Therefore, additional research on this topic is warranted.
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Affiliation(s)
- Laureen A Lammers
- Department of Hospital Pharmacy, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.,Department of Clinical Pharmacy, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Roos Achterbergh
- Department of Medicine, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Ron A A Mathôt
- Department of Hospital Pharmacy, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
| | - Johannes A Romijn
- Department of Medicine, Amsterdam UMC, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
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Zhou AL, Ward RE. Milk polar lipids modulate lipid metabolism, gut permeability, and systemic inflammation in high-fat-fed C57BL/6J ob/ob mice, a model of severe obesity. J Dairy Sci 2019; 102:4816-4831. [PMID: 30981495 DOI: 10.3168/jds.2018-15949] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 02/22/2019] [Indexed: 12/14/2022]
Abstract
Dynamic interactions between lipid metabolism, gut permeability, and systemic inflammation remain unclear in the context of obesity. Milk polar lipids, lipids derived from the milk fat globule membrane, could positively affect the aforementioned obesity-related endpoints. This study aimed to test the hypotheses that milk polar lipids will reduce gut permeability, systemic inflammation, and liver lipid levels, and differentially affect the hepatic expression of genes associated with fatty acid synthesis and cholesterol regulation in preexisting obesity. We fed 3 groups of C57BL/6J ob/ob mice (n = 6 per group) for 2 wk: (1) a modified AIN-93G diet (CO) with 34% fat by energy; (2) CO with milk gangliosides (GG) at 0.2 g/kg of diet; and (3) CO with milk phospholipids (PL) at 10 g/kg of diet. The GG and PL were provided as semi-purified concentrates and replaced 2.0% and 7.2% of dietary fat by energy. The GG and PL did not affect total food intake, weight gain, fasting glucose, or gut permeability. The PL decreased liver mass and the mesenteric fat depot compared with the CO. The GG increased tight junction protein occludin in colon mucosa compared with the CO. The GG and PL decreased tight junction protein zonula occludens-1 in jejunum mucosa compared with the CO. Plasma endotoxin increased during the study but was unaffected by the treatments. Compared with the CO and GG, the PL increased plasma sphingomyelin and plasma IL-6. The GG and PL differentially regulated genes associated with lipid metabolism in the liver compared with the CO. Regarding general effects on lipid metabolism, the GG and PL decreased lipid levels in the liver and the mesenteric depot, and increased lipid levels in the plasma. Diet consumption decreased significantly when the ob/ob mice were kept in metabolic cages, which were not big enough and resulted in unwanted animal deaths. Future studies may keep this in mind and use better metabolic equipment for ob/ob mice. In conclusion, dietary milk polar lipids may have limited beneficial effects on gut barrier integrity, systemic inflammation, and lipid metabolism in the context of severe obesity.
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Affiliation(s)
- A L Zhou
- Nutrition, Dietetics and Food Sciences, Utah State University, 8700 Old Main Hill, Logan 84322
| | - R E Ward
- Nutrition, Dietetics and Food Sciences, Utah State University, 8700 Old Main Hill, Logan 84322.
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28
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Lammers LA, Achterbergh R, Romijn JA, Mathôt RAA. Nutritional Status Differentially Alters Cytochrome P450 3A4 (CYP3A4) and Uridine 5'-Diphospho-Glucuronosyltransferase (UGT) Mediated Drug Metabolism: Effect of Short-Term Fasting and High Fat Diet on Midazolam Metabolism. Eur J Drug Metab Pharmacokinet 2019; 43:751-767. [PMID: 29876844 PMCID: PMC6244726 DOI: 10.1007/s13318-018-0487-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND OBJECTIVES Previous studies have shown that nutritional status can alter drug metabolism which may result in treatment failure or untoward side effects. This study assesses the effect of two nutritional conditions, short-term fasting, and a short-term high fat diet (HFD) on cytochrome P450 3A4 (CYP3A4) and uridine 5'-diphospho-glucuronosyltransferase (UGT) mediated drug metabolism by studying the pharmacokinetics of midazolam and its main metabolites. METHODS In a randomized-controlled cross-over trial, nine healthy subjects received a single intravenous administration of 0.015 mg/kg midazolam after: (1) an overnight fast (control); (2) 36 h of fasting; and (3) an overnight fast after 3 days of a HFD consisting of 500 ml of cream supplemented to their regular diet. Pharmacokinetic parameters were analyzed simultaneously using non-linear mixed-effects modeling. RESULTS Short-term fasting increased CYP3A4-mediated midazolam clearance by 12% (p < 0.01) and decreased UGT-mediated metabolism apparent 1-OH-midazolam clearance by 13% (p < 0.01) by decreasing the ratio of clearance and the fraction metabolite formed (ΔCL1-OH-MDZ/f1-OH-MDZ). Furthermore, short-term fasting decreased apparent clearance of 1-OH-midazolam-O-glucuronide (CL1-OH-MDZ-glucuronide/(f1-OH-MDZ-glucuronide × f1-OH-MDZ)) by 20% (p < 0.01). The HFD did not affect systemic clearance of midazolam or metabolites. CONCLUSIONS Short-term fasting differentially alters midazolam metabolism by increasing CYP3A4-mediated metabolism but by decreasing UGT-mediated metabolism. In contrast, a short-term HFD did not affect systemic clearance of midazolam.
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Affiliation(s)
- Laureen A Lammers
- Department of Hospital Pharmacy, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - Roos Achterbergh
- Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Johannes A Romijn
- Department of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Ron A A Mathôt
- Department of Hospital Pharmacy, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands
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Santos A, Giráldez F, Frutos J, Andrés S. Liver transcriptomic and proteomic profiles of preweaning lambs are modified by milk replacer restriction. J Dairy Sci 2019; 102:1194-1204. [DOI: 10.3168/jds.2018-15110] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Accepted: 10/15/2018] [Indexed: 01/03/2023]
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30
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Wu Z, Yang F, Jiang S, Sun X, Xu J. Induction of Liver Steatosis in BAP31-Deficient Mice Burdened with Tunicamycin-Induced Endoplasmic Reticulum Stress. Int J Mol Sci 2018; 19:ijms19082291. [PMID: 30081561 PMCID: PMC6121476 DOI: 10.3390/ijms19082291] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 07/24/2018] [Accepted: 08/02/2018] [Indexed: 12/12/2022] Open
Abstract
Endoplasmic reticulum (ER) stress is highly associated with liver steatosis. B-cell receptor-associated protein 31 (BAP31) has been reported to be involved in ER homeostasis, and plays key roles in hepatic lipid metabolism in high-fat diet-induced obese mice. However, whether BAP31 modulates hepatic lipid metabolism via regulating ER stress is still uncertain. In this study, wild-type and liver-specific BAP31-depleted mice were administrated with ER stress activator of Tunicamycin, the markers of ER stress, liver steatosis, and the underlying molecular mechanisms were determined. BAP31 deficiency increased Tunicamycin-induced hepatic lipid accumulation, aggravated liver dysfunction, and increased the mRNA levels of ER stress markers, including glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), inositol-requiring protein-1α (IRE1α) and C/EBP homologous protein (CHOP), thus promoting ER stress in vivo and in vitro. Hepatic lipid export via very low-density lipoprotein (VLDL) secretion was impaired in BAP31-depleted mice, accompanied by reduced Apolipoprotein B (APOB) and microsomal triglyceride transfer protein (MTTP) expression. Exogenous lipid clearance was also inhibited, along with impaired gene expression related to fatty acid transportation and fatty acid β-oxidation. Finally, BAP31 deficiency increased Tunicamycin-induced hepatic inflammatory response. These results demonstrate that BAP31 deficiency increased Tunicamycin-induced ER stress, impaired VLDL secretion and exogenous lipid clearance, and reduced fatty acid β-oxidation, which eventually resulted in liver steatosis.
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Affiliation(s)
- Zhenhua Wu
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
| | - Fan Yang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
| | - Shan Jiang
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
| | - Xiaoyu Sun
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
| | - Jialin Xu
- Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110169, China.
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Annalora AJ, O'Neil S, Bushman JD, Summerton JE, Marcus CB, Iversen PL. A k-mer based transcriptomics approach for antisense drug discovery targeting the Ewing's family of tumors. Oncotarget 2018; 9:30568-30586. [PMID: 30093970 PMCID: PMC6078127 DOI: 10.18632/oncotarget.25736] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 06/19/2018] [Indexed: 12/22/2022] Open
Abstract
Ewing’s sarcoma treatment failures are associated with high mortality indicating a need for new therapeutic approaches. We used a k-mer counting approach to identify cancer-specific mRNA transcripts in 3 Ewing’s Family Tumor (EFT) cell lines not found in the normal human transcriptome. Phosphorodiamidate morpholino oligomers targeting six EFT-specific transcripts were evaluated for cytotoxicity in TC-32 and CHLA-10 EFT lines and in HEK293 renal epithelial control cells. Average morpholino efficacy (EC50) was 0.66 ± 0.13 in TC-32, 0.25 ± 0.14 in CHLA-10 and 3.07 ± 5.02 µM in HEK293 control cells (ANOVA p < 0.01). Synergy was observed for a cocktail of 12 morpholinos at low dose (0.3 µM) in TC-32 cells, but not in CHLA-10 cells. Paired synergy was also observed in both EFT cell lines when the PHGDH pre-mRNA transcript was targeted in combination with XAGE1B or CYP4F22 transcripts. Antagonism was observed when CCND1 was targeted with XAGE1B or CYP4F22, or when IGFBP-2 was targeted with CCND1 or RBM11. This transcriptome profiling approach is highly effective for cancer drug discovery, as it identified new EWS-specific target genes (e.g. CYP4F22, RBM11 and IGBP-2), and predicted effective antisense agents (EC50 < 1 µM) that demonstrate both synergy and antagonism in combination therapy.
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Affiliation(s)
- Andrew J Annalora
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
| | - Shawn O'Neil
- Center for Genome Research and Biocomputing, Oregon State University, Corvallis, OR 97331, USA
| | | | | | - Craig B Marcus
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA
| | - Patrick L Iversen
- Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR 97331, USA.,LS Pharma, LLC, Grand Junction, CO 81507, USA
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32
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Setayesh T, Nersesyan A, Mišík M, Ferk F, Langie S, Andrade VM, Haslberger A, Knasmüller S. Impact of obesity and overweight on DNA stability: Few facts and many hypotheses. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2018; 777:64-91. [PMID: 30115431 DOI: 10.1016/j.mrrev.2018.07.001] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 05/03/2018] [Accepted: 07/06/2018] [Indexed: 12/18/2022]
Abstract
Health authorities are alarmed worldwide about the increase of obesity and overweight in the last decades which lead to adverse health effects including inflammation, cancer, accelerated aging and infertility. We evaluated the state of knowledge concerning the impact of elevated body mass on genomic instability. Results of investigations with humans (39 studies) in which DNA damage was monitored in lymphocytes and sperm cells, are conflicting and probably as a consequence of heterogeneous study designs and confounding factors (e.g. uncontrolled intake of vitamins and minerals and consumption of different food types). Results of animal studies with defined diets (23 studies) are more consistent and show that excess body fat causes DNA damage in multiple organs including brain, liver, colon and testes. Different molecular mechanisms may cause genetic instability in overweight/obese individuals. ROS formation and lipid peroxidation were found in several investigations and may be caused by increased insulin, fatty acid and glucose levels or indirectly via inflammation. Also reduced DNA repair and formation of advanced glycation end products may play a role but more data are required to draw firm conclusions. Reduction of telomere lengths and hormonal imbalances are characteristic for overweight/obesity but the former effects are delayed and moderate and hormonal effects were not investigated in regard to genomic instability in obese individuals. Increased BMI values affect also the activities of drug metabolizing enzymes which activate/detoxify genotoxic carcinogens, but no studies concerning the impact of these alterations of DNA damage in obese individuals are available. Overall, the knowledge concerning the impact of increased body weight and DNA damage is poor and further research is warranted to shed light on this important issue.
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Affiliation(s)
- Tahereh Setayesh
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Armen Nersesyan
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Miroslav Mišík
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Franziska Ferk
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Sabine Langie
- Environmental Risk and Health Unit, Flemish Institute for Technological Research (VITO), Mol, Belgium
| | - Vanessa M Andrade
- Laboratório de Biologia Celulare Molecular, Programa de Pós-Graduação em Ciências da Saúde, Unidade Acadêmica de Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Brazil
| | | | - Siegfried Knasmüller
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
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Achterbergh R, Lammers LA, Kuijsten L, Klümpen HJ, Mathôt RAA, Romijn JA. Effects of nutritional status on acetaminophen measurement and exposure. Clin Toxicol (Phila) 2018; 57:42-49. [DOI: 10.1080/15563650.2018.1487563] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- R. Achterbergh
- Departments of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - L. A. Lammers
- Hospital Pharmacy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - L. Kuijsten
- Hospital Pharmacy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - H. J. Klümpen
- Department of Medical Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Cancer Center Amsterdam, Amsterdam, The Netherlands
| | - R. A. A. Mathôt
- Hospital Pharmacy, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - J. A. Romijn
- Departments of Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
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Morales-Prieto N, Ruiz-Laguna J, Sheehan D, Abril N. Transcriptome signatures of p,p´-DDE-induced liver damage in Mus spretus mice. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2018; 238:150-167. [PMID: 29554563 DOI: 10.1016/j.envpol.2018.03.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 02/19/2018] [Accepted: 03/04/2018] [Indexed: 06/08/2023]
Abstract
The use of DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl) ethane) in some countries, although regulated, is contributing to an increased worldwide risk of exposure to this organochlorine pesticide or its derivative p,p'-DDE [1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene]. Many studies have associated p,p'-DDE exposure to type 2 diabetes, obesity and alterations of the reproductive system, but their molecular mechanisms of toxicity remain poorly understood. We have addressed this issue by using commercial microarrays based on probes for the entire Mus musculus genome to determine the hepatic transcriptional signatures of p,p'-DDE in the phylogenetically close mouse species Mus spretus. High-stringency hybridization conditions and analysis assured reliable results, which were also verified, in part, by qRT-PCR, immunoblotting and/or enzymatic activity. Our data linked 198 deregulated genes to mitochondrial dysfunction and perturbations of central signaling pathways (kinases, lipids, and retinoic acid) leading to enhanced lipogenesis and aerobic glycolysis, inflammation, cell proliferation and testosterone catabolism and excretion. Alterations of transcript levels of genes encoding enzymes involved in testosterone catabolism and excretion would explain the relationships established between p,p´-DDE exposure and reproductive disorders, obesity and diabetes. Further studies will help to fully understand the molecular basis of p,p´-DDE molecular toxicity in liver and reproductive organs, to identify effective exposure biomarkers and perhaps to design efficient p,p'-DDE exposure counteractive strategies.
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Affiliation(s)
- Noelia Morales-Prieto
- Departamento de Bioquímica y Biología Molecular, Campus de Excelencia Internacional Agroalimentario CeiA3, Universidad de Córdoba, Campus de Rabanales, Edificio Severo Ochoa, E-14071, Córdoba, Spain
| | - Julia Ruiz-Laguna
- Departamento de Bioquímica y Biología Molecular, Campus de Excelencia Internacional Agroalimentario CeiA3, Universidad de Córdoba, Campus de Rabanales, Edificio Severo Ochoa, E-14071, Córdoba, Spain
| | - David Sheehan
- College of Arts and Science, Khalifa University of Science and Technology, PO Box 127788, Abu Dhabi, United Arab Emirates
| | - Nieves Abril
- Departamento de Bioquímica y Biología Molecular, Campus de Excelencia Internacional Agroalimentario CeiA3, Universidad de Córdoba, Campus de Rabanales, Edificio Severo Ochoa, E-14071, Córdoba, Spain.
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35
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Beaumont M, Neyrinck AM, Olivares M, Rodriguez J, de Rocca Serra A, Roumain M, Bindels LB, Cani PD, Evenepoel P, Muccioli GG, Demoulin JB, Delzenne NM. The gut microbiota metabolite indole alleviates liver inflammation in mice. FASEB J 2018; 32:fj201800544. [PMID: 29906245 PMCID: PMC6219839 DOI: 10.1096/fj.201800544] [Citation(s) in RCA: 125] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 05/29/2018] [Indexed: 12/20/2022]
Abstract
The gut microbiota regulates key hepatic functions, notably through the production of bacterial metabolites that are transported via the portal circulation. We evaluated the effects of metabolites produced by the gut microbiota from aromatic amino acids (phenylacetate, benzoate, p-cresol, and indole) on liver inflammation induced by bacterial endotoxin. Precision-cut liver slices prepared from control mice, Kupffer cell (KC)-depleted mice, and obese mice ( ob/ ob) were treated with or without LPS and bacterial metabolites. We observed beneficial effects of indole that dose-dependently reduced the LPS-induced up-regulation of proinflammatory mediators at both mRNA and protein levels in precision-cut liver slices prepared from control or ob/ ob mice. KC depletion partly prevented the antiinflammatory effects of indole, notably through a reduction of nucleotide-binding domain and leucine-rich repeat containing (NLR) family pyrin domain-containing 3 (NLRP3) pathway activation. In vivo, the oral administration of indole before an LPS injection reduced the expression of key proteins of the NF-κB pathway and downstream proinflammatory gene up-regulation. Indole also prevented LPS-induced alterations of cholesterol metabolism through a transcriptional regulation associated with increased 4β-hydroxycholesterol hepatic levels. In summary, indole appears as a bacterial metabolite produced from tryptophan that is able to counteract the detrimental effects of LPS in the liver. Indole could be a new target to develop innovative strategies to decrease hepatic inflammation.-Beaumont, M., Neyrinck, A. M., Olivares, M., Rodriguez, J., de Rocca Serra, A., Roumain, M., Bindels, L. B., Cani, P. D., Evenepoel, P., Muccioli, G. G., Demoulin, J.-B., Delzenne, N. M. The gut microbiota metabolite indole alleviates liver inflammation in mice.
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Affiliation(s)
- Martin Beaumont
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Audrey M. Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Marta Olivares
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Julie Rodriguez
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Audrey de Rocca Serra
- Pole of Experimental Medicine, De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Martin Roumain
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Laure B. Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Patrice D. Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
- Walloon Excellence in Life Sciences and Biotechnology (WELBIO), Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Pieter Evenepoel
- Department of Immunology and Microbiology, Laboratory of Nephrology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Giulio G. Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Jean-Baptiste Demoulin
- Pole of Experimental Medicine, De Duve Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Nathalie M. Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
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36
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Nobutani K, Miyoshi J, Musch MW, Nishiyama M, Watanabe J, Kaneko A, Yamamoto M, Yoshida M, Kono T, Jeong H, Chang EB. Daikenchuto (TU-100) alters murine hepatic and intestinal drug metabolizing enzymes in an in vivo dietary model: effects of gender and withdrawal. Pharmacol Res Perspect 2018; 5. [PMID: 28971602 PMCID: PMC5625165 DOI: 10.1002/prp2.361] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Revised: 08/15/2017] [Accepted: 08/21/2017] [Indexed: 12/16/2022] Open
Abstract
Herbal medicines and natural products used for maintenance of health or treatment of diseases have many biological effects, including altering the pharmacokinetics and metabolism of other medications. Daikenchuto (TU‐100), an aqueous extract of ginger, ginseng, and Japanese green pepper fruit, is a commonly prescribed Kampo (Japanese herbal medicine) for postoperative ileus or bloating. The effects of TU‐100 on drug metabolism have not been investigated. In this study, we analyzed the effect of TU‐100 on expression of key drug‐metabolizing enzymes (DMEs) and drug transporters (DTs) in murine liver and gastrointestinal tract using a dietary model. Liver, jejunum, and proximal colon were analyzed for phase I and II DMEs and DT mRNA expression by reverse transcription (RT) first by nonquantitative and followed by quantitative polymerase chain reaction (PCR) and protein expression. Liver, jejunum, and proximal colon expressed some identical but also unique DMEs and DTs. TU‐100 increased the greatest changes in cytochrome (Cyp) 2b10 and Cyp3a11 and Mdr1a. Basal and TU‐100 stimulated levels of DME and DT expression were gender‐dependent, dose‐dependent and reversible after cessation of TU‐100 supplementation, except for some changes in the intestine. Quantitative Western blot analysis of protein extracts confirmed the quantitative PCR results.
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Affiliation(s)
- Kentaro Nobutani
- Department of Medicine, Knapp Center for Biomedical Center, The University of Chicago, Chicago, Illinois
| | - Jun Miyoshi
- Department of Medicine, Knapp Center for Biomedical Center, The University of Chicago, Chicago, Illinois
| | - Mark W Musch
- Department of Medicine, Knapp Center for Biomedical Center, The University of Chicago, Chicago, Illinois
| | - Mitsue Nishiyama
- Tsumura Research Laboratories, Tsumura & Co., Ami, Ibaraki, Japan
| | - Junko Watanabe
- Tsumura Research Laboratories, Tsumura & Co., Ami, Ibaraki, Japan
| | - Atsushi Kaneko
- Tsumura Research Laboratories, Tsumura & Co., Ami, Ibaraki, Japan
| | | | - Masaru Yoshida
- Division of Gastroenterology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan
| | - Toru Kono
- Center for Clinical and Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Hokkaido, Japan.,Division of Gastroenterologic and General Surgery, Department of Surgery, Asahikawa Medical University, Asahikawa, Hokkaido, Japan
| | - Hyunyoung Jeong
- Departments of Pharmacy Practice and Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, Illinois
| | - Eugene B Chang
- Department of Medicine, Knapp Center for Biomedical Center, The University of Chicago, Chicago, Illinois
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37
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Yang N, Li S, Yan C, Sun R, He J, Xie Y, Peng Y, Wang G, Aa J. Inhibitory Effects of Endogenous Linoleic Acid and Glutaric Acid on the Renal Glucuronidation of Berberrubine in Mice and on Recombinant Human UGT1A7, 1A8, and 1A9. Mol Pharmacol 2018; 93:216-227. [PMID: 29351921 DOI: 10.1124/mol.117.110668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2017] [Accepted: 01/08/2018] [Indexed: 12/22/2022] Open
Abstract
Berberrubine (BRB) has a strong lipid-lowering effect and can be extensively metabolized into berberrubine-9-O-β-d-glucuronide (BRBG) in vivo. Recently, pharmacokinetics studies showed that the production of BRBG was significantly decreased in the urine of mice fed with a high-fat diet (HFD), indicating a decreased glucuronidation capacity. Based on the UDP-glucuronosyltransferase (UGT) isoform identification, hepatic and renal microsomal incubation, glucuronidation was examined to suggest the metabolism of BRB in liver and kidneys. The results showed that the renal UGT activity for metabolizing BRB markedly decreased, which may be highly related to the decreased expression and activity of renal Ugt1a7c. Surprisingly, in vitro studies revealed neither BRB nor BRBG inhibited the renal UGT activity. By employing an integrated strategy of metabolomics and pharmacokinetics, we identified and confirmed for the first time the inhibitory effect of some potential endogenous molecules on the renal glucuronidation of C57BL/6J mice, such as glutaric acid (GA) and linoleic acid (LA). By employing recombinant human UGTs, we found that GA and LA efficiently affect the activity of recombinant human UGT1A7, 1A9, and 1A8 at their normal or abnormal physiologic levels in vivo. GA (2 mM) markedly inhibited the activity of UGT1A7 by 89.4% and UGT1A9 by 32.8%. The inhibition rates reached 99.3% for UGT1A9, 48.3% for UGT1A7, and 46.8% for UGT1A8 with LA at 200 μM. It has been suggested that the endogenous molecules have the potential to affect the efficiency of glucuronidation, which might be a key factor contributing to individual differences in drug metabolism.
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Affiliation(s)
- Na Yang
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Sijia Li
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Caixia Yan
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Runbin Sun
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jun He
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Yuan Xie
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Ying Peng
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Guangji Wang
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Jiye Aa
- Jiangsu Province Key Laboratory of Drug Metabolism and Pharmacokinetics, State Key Laboratory of Natural Medicines, Jiangsu Province Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China
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Xu JL, Li LY, Wang YQ, Li YQ, Shan M, Sun SZ, Yu Y, Wang B. Hepatocyte-specific deletion of BAP31 promotes SREBP1C activation, promotes hepatic lipid accumulation, and worsens IR in mice. J Lipid Res 2017; 59:35-47. [PMID: 29113994 DOI: 10.1194/jlr.m077016] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 10/20/2017] [Indexed: 01/14/2023] Open
Abstract
Conditional knockout mice with targeted disruption of B-cell associated protein (BAP)31 in adult mouse liver were generated and challenged with a high-fat diet (HFD) for 36 or 96 days and markers of obesity, diabetes, and hepatic steatosis were determined. Mutant mice were indistinguishable from WT littermates, but exhibited increased HFD-induced obesity. BAP31-deletion in hepatocytes increased the expression of SREBP1C and the target genes, including acetyl-CoA carboxylase 1 and stearoyl-CoA desaturase-1, and increased hepatic lipid accumulation and HFD-induced liver steatosis. Immunoprecipitation assay showed that BAP31 interacts with SREBP1C and insulin-induced gene 1 (INSIG1), and BAP31-deletion reduces INSIG1 expression, suggesting that BAP31 may regulate SREBP1C activity by modulating INSIG1 protein levels. Additionally, BAP31-deletion induced glucose and insulin intolerance, decreased Akt and glycogen synthase kinase 3β phosphorylation, and enhanced hepatic glucose production in mice. Expression of endoplasmic reticulum (ER) stress markers was significantly induced in BAP31-mutant mice. HFD-induced inflammation was aggravated in mutant mice, along with increased c-Jun N-terminal kinase and nuclear factor-κB activation. These findings demonstrate that BAP31-deletion induces SREBP activation and promotes hepatic lipid accumulation, reduces insulin signaling, impairs glucose/insulin tolerance, and increases ER stress and hepatic inflammation, explaining the protective roles of BAP31 in the development of liver steatosis and insulin resistance in HFD-induced obesity in animal models.
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Affiliation(s)
- Jia-Lin Xu
- Institutes of Biochemistry and Molecular Biology Northeastern University, Shenyang 110169, People's Republic of China
| | - Li-Ya Li
- Microbial Pharmaceuticals, College of Life and Health Sciences, Northeastern University, Shenyang 110169, People's Republic of China
| | - Yan-Qing Wang
- Institutes of Biochemistry and Molecular Biology Northeastern University, Shenyang 110169, People's Republic of China
| | - Ya-Qi Li
- Institutes of Biochemistry and Molecular Biology Northeastern University, Shenyang 110169, People's Republic of China
| | - Mu Shan
- Institutes of Biochemistry and Molecular Biology Northeastern University, Shenyang 110169, People's Republic of China
| | - Shi-Zhuo Sun
- Institutes of Biochemistry and Molecular Biology Northeastern University, Shenyang 110169, People's Republic of China
| | - Yang Yu
- Institutes of Biochemistry and Molecular Biology Northeastern University, Shenyang 110169, People's Republic of China
| | - Bing Wang
- Institutes of Biochemistry and Molecular Biology Northeastern University, Shenyang 110169, People's Republic of China
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Yang N, Sun R, Liao X, Aa J, Wang G. UDP-glucuronosyltransferases (UGTs) and their related metabolic cross-talk with internal homeostasis: A systematic review of UGT isoforms for precision medicine. Pharmacol Res 2017; 121:169-183. [PMID: 28479371 DOI: 10.1016/j.phrs.2017.05.001] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 05/03/2017] [Accepted: 05/03/2017] [Indexed: 12/11/2022]
Abstract
UDP-glucuronosyltransferases (UGTs) are the primary phase II enzymes catalyzing the conjugation of glucuronic acid to the xenobiotics with polar groups for facilitating their clearance. The UGTs belong to a superfamily that consists of diverse isoforms possessing distinct but overlapping metabolic activity. The abnormality or deficiency of UGTs in vivo is highly associated with some diseases, efficacy and toxicity of drugs, and precisely therapeutic personality. Despite the great effects and fruitful results achieved, to date, the expression and functions of individual UGTs have not been well clarified, the inconsistency of UGTs is often observed in human and experimental animals, and the complex regulation factors affecting UGTs have not been systematically summarized. This article gives an overview of updated reports on UGTs involving the various regulatory factors in terms of the genetic, environmental, pathological, and physiological effects on the functioning of individual UGTs, in turn, the dysfunction of UGTs induced disease risk and endo- or xenobiotic metabolism-related toxicity. The complex cross-talk effect of UGTs with internal homeostasis is systematically summarized and discussed in detail, which would be of great importance for personalized precision medicine.
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Affiliation(s)
- Na Yang
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Runbin Sun
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Xiaoying Liao
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
| | - Jiye Aa
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China.
| | - Guangji Wang
- Key Lab of Drug Metabolism and Pharmacokinetics, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
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40
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Lloret-Linares C, Luo H, Rouquette A, Labat L, Poitou C, Tordjman J, Bouillot JL, Mouly S, Scherrmann JM, Bergmann JF, Declèves X. The effect of morbid obesity on morphine glucuronidation. Pharmacol Res 2017; 118:64-70. [DOI: 10.1016/j.phrs.2016.08.031] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 08/29/2016] [Accepted: 08/29/2016] [Indexed: 01/28/2023]
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41
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Tanemura K, Ohtaki T, Kuwahara Y, Tsumagari S. Association between liver failure and hepatic UDP-glucuronosyltransferase activity in dairy cows with follicular cysts. J Vet Med Sci 2017; 79:86-91. [PMID: 27666462 PMCID: PMC5289243 DOI: 10.1292/jvms.15-0674] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Uridine 5’-diphospho-glucuronosyltransferase (UGT) liver activity was measured using estradiol-17β as a substrate in dairy cows with follicular cysts. The activity was significantly lower than that in dairy cows with normal estrous cycles (P<0.01). Liver disorders, such as fatty liver and hepatitis, were observed in half cows with follicular cysts, and liver UGT activity was lower than that in cows with normal estrus cycles. In addition, the liver UGT activity was significantly lower in dairy cows with follicular cysts without liver disorders than in dairy cows with normal estrous cycles. Therefore, the cows were divided into those with low, middle and high liver UGT activities, and liver disorder complication rates were investigated. The complication rate was significantly higher in the low- (78.1%) than in the middle- (22.2%) and high-level (8.3%) groups, suggesting that liver disorders are closely associated with the development of follicular cysts in dairy cows and that steroid hormone metabolism is delayed because of reduced liver UGT activity, resulting in follicular cyst formation. We conclude that reduced estradiol-17β glucuronidation in the liver and liver disorders are associated with follicular cyst occurrence in dairy cows.
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Affiliation(s)
- Kouichi Tanemura
- Laboratory of Theriogenology, College of Bioresouce Sciences, Nihon University, 1866 Kameino, Fujisawa, Kanagawa 252-0880, Japan
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Redan BW, Buhman KK, Novotny JA, Ferruzzi MG. Altered Transport and Metabolism of Phenolic Compounds in Obesity and Diabetes: Implications for Functional Food Development and Assessment. Adv Nutr 2016; 7:1090-1104. [PMID: 28140326 PMCID: PMC5105043 DOI: 10.3945/an.116.013029] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Interest in the application of phenolic compounds from the diet or supplements for the prevention of chronic diseases has grown substantially, but the efficacy of such approaches in humans is largely dependent on the bioavailability and metabolism of these compounds. Although food and dietary factors have been the focus of intense investigation, the impact of disease states such as obesity or diabetes on their absorption, metabolism, and eventual efficacy is important to consider. These factors must be understood in order to develop effective strategies that leverage bioactive phenolic compounds for the prevention of chronic disease. The goal of this review is to discuss the inducible metabolic systems that may be influenced by disease states and how these effects impact the bioavailability and metabolism of dietary phenolic compounds. Because current studies generally report that obesity and/or diabetes alter the absorption and excretion of these compounds, this review includes a description of the absorption, conjugation, and excretion pathways for phenolic compounds and how they are potentially altered in disease states. A possible mechanism that will be discussed related to the modulation of phenolic bioavailability and metabolism may be linked to increased inflammatory status from increased amounts of adipose tissue or elevated plasma glucose concentrations. Although more studies are needed, the translation of benefits derived from dietary phenolic compounds to individuals with obesity or diabetes may require the consideration of dosing strategies or be accompanied by adjunct therapies to improve the bioavailability of these compounds.
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Affiliation(s)
- Benjamin W Redan
- Interdepartmental Nutrition Program, Department of Nutrition Science, and
| | - Kimberly K Buhman
- Interdepartmental Nutrition Program, Department of Nutrition Science, and
| | - Janet A Novotny
- USDA–Agricultural Research Service Food Components and Health Laboratory, Beltsville, MD
| | - Mario G Ferruzzi
- Interdepartmental Nutrition Program, Department of Nutrition Science, and .,Department of Food Science, Purdue University, West Lafayette, IN; and
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43
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Guo Y, Cui JY, Lu H, Klaassen CD. Effect of nine diets on mRNAs of phase-II conjugation enzymes in livers of mice. Xenobiotica 2016; 47:645-654. [PMID: 27686132 DOI: 10.1080/00498254.2016.1213926] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
1. Phase-II enzymes are important in metabolizing many xenobiotics including prescription drugs and chemical carcinogens. Whereas it is known that diet can alter the expression of phase-II conjugation enzymes, the previous studies are limited in using only two or three diets and examining only a few enzymes. 2. Adult male C57BL6 mice were fed one of nine diets for 3 weeks. Of the 87 genes encoding major hepatic phase-II enzymes, approximately one-half (43) were altered by at least one diet. Diet restriction altered the hepatic expression of the most genes encoding phase-II enzymes (27), followed by lab chow (15), atherogenic diet (13), high-fat diet (10), western diet (7), high-fructose diet (5), and essential fatty acid-deficient diet (3), whereas the low n-3 fatty acid diet had no effect on the hepatic expression of these phase-II enzymes. 3. This comprehensive study provides detailed information on which conjugation enzymes are changed by these diets, and these data can be used to further investigate the mechanism for these changes in messenger RNAs, and whether these changes result in alterations in enzyme activity and drug action.
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Affiliation(s)
- Ying Guo
- a Department of Internal Medicine , University of Kansas Medical Center , Kansas City, KS , USA.,b Department of Clinical Pharmacology , Xiangya Hospital, Central South University , Changsha , P.R. China , and
| | - Julia Yue Cui
- a Department of Internal Medicine , University of Kansas Medical Center , Kansas City, KS , USA
| | - Hong Lu
- a Department of Internal Medicine , University of Kansas Medical Center , Kansas City, KS , USA.,c Department of Pharmacology , SUNY Upstate Medical University , Syracuse, NY , USA
| | - Curtis D Klaassen
- a Department of Internal Medicine , University of Kansas Medical Center , Kansas City, KS , USA
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44
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Du J, Leung A, Trac C, Lee M, Parks BW, Lusis AJ, Natarajan R, Schones DE. Chromatin variation associated with liver metabolism is mediated by transposable elements. Epigenetics Chromatin 2016; 9:28. [PMID: 27398095 PMCID: PMC4939004 DOI: 10.1186/s13072-016-0078-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 06/29/2016] [Indexed: 01/23/2023] Open
Abstract
Background Functional regulatory regions in eukaryotic genomes are characterized by the disruption of nucleosomes leading to accessible chromatin. The modulation of chromatin accessibility is one of the key mediators of transcriptional regulation, and variation in chromatin accessibility across individuals has been linked to complex traits and disease susceptibility. While mechanisms responsible for chromatin variation across individuals have been investigated, the overwhelming majority of chromatin variation remains unexplained. Furthermore, the processes through which the variation of chromatin accessibility contributes to phenotypic diversity remain poorly understood. Results We profiled chromatin accessibility in liver from seven strains of mice with phenotypic diversity in response to a high-fat/high-sucrose (HF/HS) diet and identified reproducible chromatin variation across the individuals. We found that sites of variable chromatin accessibility were more likely to coincide with particular classes of transposable elements (TEs) than sites with common chromatin signatures. Evolutionarily younger long interspersed nuclear elements (LINEs) are particularly likely to harbor variable chromatin sites. These younger LINEs are enriched for binding sites of immune-associated transcription factors, whereas older LINEs are enriched for liver-specific transcription factors. Genomic region enrichment analysis indicates that variable chromatin sites at TEs may function to regulate liver metabolic pathways. CRISPR-Cas9 deletion of a number of variable chromatin sites at TEs altered expression of nearby metabolic genes. Finally, we show that polymorphism of TEs and differential DNA methylation at TEs can both influence chromatin variation. Conclusions Our results demonstrate that specific classes of TEs show variable chromatin accessibility across strains of mice that display phenotypic diversity in response to a HF/HS diet. These results indicate that chromatin variation at TEs is an important contributor to phenotypic variation among populations. Electronic supplementary material The online version of this article (doi:10.1186/s13072-016-0078-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Juan Du
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA USA ; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA USA
| | - Amy Leung
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA USA
| | - Candi Trac
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA USA
| | - Michael Lee
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA USA ; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA USA
| | - Brian W Parks
- Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI USA
| | - Aldons J Lusis
- Department of Medicine, University of California, Los Angeles, CA USA
| | - Rama Natarajan
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA USA ; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA USA
| | - Dustin E Schones
- Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope, Duarte, CA USA ; Irell & Manella Graduate School of Biological Sciences, City of Hope, Duarte, CA USA
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45
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Donepudi AC, Cheng Q, Lu ZJ, Cherrington NJ, Slitt AL. Hepatic Transporter Expression in Metabolic Syndrome: Phenotype, Serum Metabolic Hormones, and Transcription Factor Expression. Drug Metab Dispos 2016; 44:518-26. [PMID: 26847773 PMCID: PMC4810770 DOI: 10.1124/dmd.115.066779] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 01/16/2016] [Indexed: 12/15/2022] Open
Abstract
Metabolic syndrome is a multifactorial disease associated with obesity, insulin resistance, diabetes, and the alteration of multiple metabolic hormones. Obesity rates have been rising worldwide, which increases our need to understand how this population will respond to drugs and exposure to other chemicals. The purpose of this study was to determine in lean and obese mice the ontogeny of clinical biomarkers such as serum hormone and blood glucose levels as well as the physiologic markers that correlate with nuclear receptor- and transporter-related pathways. Livers from male and female wild-type (WT) (C57BL/6) and ob/ob mice littermates were collected before, during, and after the onset of obesity. Serum hormone and mRNA levels were analyzed. Physiologic changes and gene expression during maturation and progression to obesity were performed and correlation analysis was performed using canonical correlations. Significant ontogenic changes in both WT and ob/ob mice were observed and these ontogenic changes differ in ob/ob mice with the development of obesity. In males and females, the ontogenic pattern of the expression of genes such as Abcc3, 4, Abcg2, Cyp2b10, and 4a14 started to differ from week 3, and became significant at weeks 4 and 8 in ob/ob mice compared with WT mice. In obese males, serum resistin, glucagon, and glucose levels correlated with the expression of most hepatic ATP-binding cassette (Abc) transporters, whereas in obese females, serum glucagon-like peptide 1 levels were correlated with most hepatic uptake transporters and P450 enzymes. Overall, the correlation between physiologic changes and gene expression indicate that metabolism-related hormones may play a role in regulating the genes involved in drug metabolism and transport.
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Affiliation(s)
- Ajay C Donepudi
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.C.D., Q.C, A.L.S); Arizona Statistical Consulting Laboratory, The Bio5 Institute (Z.J.L.) and Department of Pharmacology and Toxicology, College of Pharmacy (N.J.C.), University of Arizona, Tucson, Arizona
| | - Qiuqiong Cheng
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.C.D., Q.C, A.L.S); Arizona Statistical Consulting Laboratory, The Bio5 Institute (Z.J.L.) and Department of Pharmacology and Toxicology, College of Pharmacy (N.J.C.), University of Arizona, Tucson, Arizona
| | - Zhenqiang James Lu
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.C.D., Q.C, A.L.S); Arizona Statistical Consulting Laboratory, The Bio5 Institute (Z.J.L.) and Department of Pharmacology and Toxicology, College of Pharmacy (N.J.C.), University of Arizona, Tucson, Arizona
| | - Nathan J Cherrington
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.C.D., Q.C, A.L.S); Arizona Statistical Consulting Laboratory, The Bio5 Institute (Z.J.L.) and Department of Pharmacology and Toxicology, College of Pharmacy (N.J.C.), University of Arizona, Tucson, Arizona
| | - Angela L Slitt
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, Rhode Island (A.C.D., Q.C, A.L.S); Arizona Statistical Consulting Laboratory, The Bio5 Institute (Z.J.L.) and Department of Pharmacology and Toxicology, College of Pharmacy (N.J.C.), University of Arizona, Tucson, Arizona
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46
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Zhan YT, Su HY, An W. Glycosyltransferases and non-alcoholic fatty liver disease. World J Gastroenterol 2016; 22:2483-2493. [PMID: 26937136 PMCID: PMC4768194 DOI: 10.3748/wjg.v22.i8.2483] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 10/22/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease and its incidence is increasing worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. Glycosyltransferases (GTs) are a diverse class of enzymes involved in catalyzing the transfer of one or multiple sugar residues to a wide range of acceptor molecules. GTs mediate a wide range of functions from structure and storage to signaling, and play a key role in many fundamental biological processes. Therefore, it is anticipated that GTs have a role in the pathogenesis of NAFLD. In this article, we present an overview of the basic information on NAFLD, particularly GTs and glycosylation modification of certain molecules and their association with NAFLD pathogenesis. In addition, the effects and mechanisms of some GTs in the development of NAFLD are summarized.
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47
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Wada T, Sunaga H, Miyata K, Shirasaki H, Uchiyama Y, Shimba S. Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression. J Biol Chem 2016; 291:7004-16. [PMID: 26865635 DOI: 10.1074/jbc.m115.693655] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Indexed: 11/06/2022] Open
Abstract
Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating the expression of genes involved in xenobiotic response. Recent studies have suggested that AhR plays essential roles not only in xenobiotic detoxification but also energy metabolism. Thus, in this study, we studied the roles of AhR in lipid metabolism. Under high fat diet (HFD) challenge, liver-specific AhR knock-out (AhR LKO) mice exhibited severe steatosis, inflammation, and injury in the liver. Gene expression analysis and biochemical study revealed thatde novolipogenesis activity was significantly increased in AhR LKO mice. In contrast, induction of suppressor of cytokine signal 3 (Socs3) expression by HFD was attenuated in the livers of AhR LKO mice. Rescue of theSocs3gene in the liver of AhR LKO mice cancelled the HFD-induced hepatic lipotoxicities. Promoter analysis established Socs3 as novel transcriptional target of AhR. These results indicated that AhR plays a protective role against HFD-induced hepatic steatosis and the subsequent lipotoxicity effects, such as inflammation, and that the mechanism of protection involves the direct transcriptional regulation ofSocs3expression by AhR.
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Affiliation(s)
- Taira Wada
- From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan
| | - Hiroshi Sunaga
- From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan
| | - Kazuki Miyata
- From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan
| | - Haruno Shirasaki
- From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan
| | - Yuki Uchiyama
- From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan
| | - Shigeki Shimba
- From the Department of Health Science, School of Pharmacy, Nihon University, Funabashi, Chiba 274-8555, Japan
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48
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Yalcin EB, Kulkarni SR, Slitt AL, King R. Bisphenol A sulfonation is impaired in metabolic and liver disease. Toxicol Appl Pharmacol 2016; 292:75-84. [PMID: 26712468 PMCID: PMC4724572 DOI: 10.1016/j.taap.2015.12.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 12/11/2015] [Accepted: 12/16/2015] [Indexed: 01/22/2023]
Abstract
BACKGROUND Bisphenol A (BPA) is a widely used industrial chemical and suspected endocrine disruptor to which humans are ubiquitously exposed. The liver metabolizes and facilitates BPA excretion through glucuronidation and sulfonation. The sulfotransferase enzymes contributing to BPA sulfonation (detected in human and rodents) is poorly understood. OBJECTIVES To determine the impact of metabolic and liver disease on BPA sulfonation in human and mouse livers. METHODS The capacity for BPA sulfonation was determined in human liver samples that were categorized into different stages of metabolic and liver disease (including obesity, diabetes, steatosis, and cirrhosis) and in livers from ob/ob mice. RESULTS In human liver tissues, BPA sulfonation was substantially lower in livers from subjects with steatosis (23%), diabetes cirrhosis (16%), and cirrhosis (18%), relative to healthy individuals with non-fatty livers (100%). In livers of obese mice (ob/ob), BPA sulfonation was lower (23%) than in livers from lean wild-type controls (100%). In addition to BPA sulfonation activity, Sult1a1 protein expression decreased by 97% in obese mouse livers. CONCLUSION Taken together these findings establish a profoundly reduced capacity of BPA elimination via sulfonation in obese or diabetic individuals and in those with fatty or cirrhotic livers versus individuals with healthy livers.
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Affiliation(s)
- Emine B Yalcin
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, United States
| | - Supriya R Kulkarni
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, United States
| | - Angela L Slitt
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, United States.
| | - Roberta King
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, United States.
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49
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Lloret-Linares C, Miyauchi E, Luo H, Labat L, Bouillot JL, Poitou C, Oppert JM, Laplanche JL, Mouly S, Scherrmann JM, Uchida Y, Tachikawa M, Terasaki T, Bergmann JF, Declèves X. Oral Morphine Pharmacokinetic in Obesity: The Role of P-Glycoprotein, MRP2, MRP3, UGT2B7, and CYP3A4 Jejunal Contents and Obesity-Associated Biomarkers. Mol Pharm 2016; 13:766-73. [DOI: 10.1021/acs.molpharmaceut.5b00656] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Célia Lloret-Linares
- Inserm, UMR-S
1144 Université Paris Descartes-Paris Diderot, Variabilité
de réponse aux psychotropes, Paris F-75010, France
- Assistance Publique-Hôpitaux
de Paris, Hôpital Lariboisière, Therapeutic Research
Unit, Department of Internal Medicine, Paris F-75010, France
| | - Eisuke Miyauchi
- Membrane
Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical
Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Huilong Luo
- Inserm, UMR-S
1144 Université Paris Descartes-Paris Diderot, Variabilité
de réponse aux psychotropes, Paris F-75010, France
- Assistance Publique-Hôpitaux
de Paris, Hôpital Cochin, Pharmacokinetics and Pharmacochemistry
Unit, Paris F-75014, France
| | - Laurence Labat
- Inserm, UMR-S
1144 Université Paris Descartes-Paris Diderot, Variabilité
de réponse aux psychotropes, Paris F-75010, France
- Assistance Publique-Hôpitaux
de Paris, Hôpital Cochin, Pharmacokinetics and Pharmacochemistry
Unit, Paris F-75014, France
| | - Jean-Luc Bouillot
- Assistance Publique-Hôpitaux
de Paris, Hôpital Ambroise Paré, Université Versailles
Saint Quentin, Department of Surgery, Boulogne 92100, France
| | - Christine Poitou
- Assistance Publique-Hôpitaux
de Paris, Groupe Hospitalier Pitié-Salpêtrière,
Service de Nutrition, Université Pierre et Marie Curie, Institut
cardiométabolisme et nutrition (ICAN), Paris F-75013, France
| | - Jean-Michel Oppert
- Assistance Publique-Hôpitaux
de Paris, Groupe Hospitalier Pitié-Salpêtrière,
Service de Nutrition, Université Pierre et Marie Curie, Institut
cardiométabolisme et nutrition (ICAN), Paris F-75013, France
| | - Jean-Louis Laplanche
- Inserm, UMR-S
1144 Université Paris Descartes-Paris Diderot, Variabilité
de réponse aux psychotropes, Paris F-75010, France
| | - Stéphane Mouly
- Inserm, UMR-S
1144 Université Paris Descartes-Paris Diderot, Variabilité
de réponse aux psychotropes, Paris F-75010, France
- Assistance Publique-Hôpitaux
de Paris, Hôpital Lariboisière, Therapeutic Research
Unit, Department of Internal Medicine, Paris F-75010, France
| | - Jean-Michel Scherrmann
- Inserm, UMR-S
1144 Université Paris Descartes-Paris Diderot, Variabilité
de réponse aux psychotropes, Paris F-75010, France
| | - Yasuo Uchida
- Membrane
Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical
Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Masanori Tachikawa
- Membrane
Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical
Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Tetsuya Terasaki
- Membrane
Transport and Drug Targeting Laboratory, Graduate School of Pharmaceutical
Sciences, Tohoku University, Sendai 980-8578, Japan
| | - Jean-François Bergmann
- Inserm, UMR-S
1144 Université Paris Descartes-Paris Diderot, Variabilité
de réponse aux psychotropes, Paris F-75010, France
- Assistance Publique-Hôpitaux
de Paris, Hôpital Lariboisière, Therapeutic Research
Unit, Department of Internal Medicine, Paris F-75010, France
| | - Xavier Declèves
- Inserm, UMR-S
1144 Université Paris Descartes-Paris Diderot, Variabilité
de réponse aux psychotropes, Paris F-75010, France
- Assistance Publique-Hôpitaux
de Paris, Hôpital Cochin, Pharmacokinetics and Pharmacochemistry
Unit, Paris F-75014, France
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50
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Mallick P, Shah P, Gandhi A, Ghose R. Impact of obesity on accumulation of the toxic irinotecan metabolite, SN-38, in mice. Life Sci 2015; 139:132-8. [PMID: 26334566 DOI: 10.1016/j.lfs.2015.08.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Revised: 08/19/2015] [Accepted: 08/22/2015] [Indexed: 01/21/2023]
Abstract
AIM Our aim is to investigate the impact of high fat diet-induced obesity on plasma concentrations of the toxic irinotecan metabolite, SN-38, in mice. MAIN METHODS Diet-induced obese (DIO, 60% kcal fed) and lean mice (10% kcal fed) were treated orally with a single dose of 10mg/kg irinotecan to determine pharmacokinetic (PK) parameters. Feces and livers were collected for quantification of irinotecan and its metabolites (SN-38 & SN-38G). SN-38G formation by Ugt1a1 enzyme was analyzed in liver S9 fractions. Expression of the pro-inflammatory cytokine, TNF-α was determined in liver and plasma. Hepatic β-glucuronidase and carboxylesterase enzymes (CES) were also determined. KEY FINDINGS AUC0-8 and Cmax of SN-38 increased by 2-fold in DIO mice compared to their lean controls. This was accompanied by a~2-fold reduction in AUC0-8 and Cmax of SN-38G in DIO mice. There were no differences in the PK parameters of irinotecan in DIO or lean mice. Conversion of SN-38 to SN-38G by Ugt1a1 enzyme was reduced by ~2-fold in liver S9 fractions in DIO mice. Furthermore, in DIO mice, β-glucuronidase activity increased by 2-fold, whereas there was no change in CES activity. TNF-α mRNA expression was 3 fold higher in DIO mice. SIGNIFICANCE Our study demonstrates that reduced hepatic Ugt1a activity during obesity likely contributes to reduced glucuronidation, and results in higher levels of the toxic metabolite, SN-38. Thus, irinotecan dosage should be closely monitored for effective and safe chemotherapy in obese cancer patients who are at a higher risk of developing liver toxicity.
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Affiliation(s)
- Pankajini Mallick
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA
| | - Pranav Shah
- Division of Pre-Clinical Innovation, National Center for Advancing Translational Sciences, Rockville, MD, USA
| | - Adarsh Gandhi
- Department of Bioanalysis and Physiology, Lundbeck Research Inc. USA, Paramus, NJ, USA
| | - Romi Ghose
- Department of Pharmacological and Pharmaceutical Sciences, University of Houston, Houston, TX, USA.
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