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Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Esfandiari A, Azarpira N, Niknahad H. Dithiothreitol supplementation mitigates hepatic and renal injury in bile duct ligated mice: Potential application in the treatment of cholestasis-associated complications. Biomed Pharmacother 2018; 99:1022-1032. [DOI: 10.1016/j.biopha.2018.01.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 12/29/2017] [Accepted: 01/03/2018] [Indexed: 01/18/2023] Open
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Heidari R, Ghanbarinejad V, Mohammadi H, Ahmadi A, Ommati MM, Abdoli N, Aghaei F, Esfandiari A, Azarpira N, Niknahad H. Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice. Biomed Pharmacother 2018; 97:1086-1095. [DOI: 10.1016/j.biopha.2017.10.166] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 10/28/2017] [Accepted: 10/31/2017] [Indexed: 12/27/2022] Open
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Li YF, Wu JS, Li YY, Dai Y, Zheng M, Zeng JK, Wang GF, Wang TM, Li WK, Zhang XY, Gu M, Huang C, Yang L, Wang ZT, Ma YM. Chicken bile powder protects against α-naphthylisothiocyanate-induced cholestatic liver injury in mice. Oncotarget 2017; 8:97137-97152. [PMID: 29228599 PMCID: PMC5722551 DOI: 10.18632/oncotarget.21385] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2017] [Accepted: 07/26/2017] [Indexed: 12/19/2022] Open
Abstract
This study explored the effects of chicken bile powder (CBP), a 2000-year-old Chinese medicine, on α-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis in mice. CBP treatment for 14 days significantly ameliorated ANIT-induced changes in serum alanine aminotransferase, aspartate aminotransferase, bile acids, bilirubin, γ-glutamyl transpeptidase, alkaline phosphatase, and liver tissue morphology. Serum metabolomics showed changes in 24 metabolites in ANIT-exposed mice; 16 of these metabolites were reversed by CBP treatment via two main pathways (bile acid biosynthesis and arachidonic acid metabolism). Additionally, CBP administration markedly increased fecal and biliary bile acid excretion, and reduced total and hydrophobic bile acid levels in the livers of cholestatic mice. Moreover, CBP increased liver expression of bile acid efflux transporters and metabolic enzymes. It also attenuated ANIT-induced increases in hepatic nuclear factor-κB-mediated inflammatory signaling, and increased liver expression of the nuclear farnesoid X receptor (FXR) in cholestatic mice. CBP also activated FXR in vitro in HEK293T cells expressing mouse Na+-taurocholate cotransporting polypeptide. It did not ameliorate the ANIT-induced liver injuries in FXR-knockout mice. These results suggested that CBP provided protection from cholestatic liver injury by restoring bile acid homeostasis and reducing inflammation in a FXR-dependent manner.
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Affiliation(s)
- Yi-Fei Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jia-Sheng Wu
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuan-Yuan Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yan Dai
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Min Zheng
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jia-Kai Zeng
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guo-Feng Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tian-Ming Wang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wen-Kai Li
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xue-Yan Zhang
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ming Gu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- Research Centre for Traditional Chinese Medicine of Complexity Systems, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zheng-Tao Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue-Ming Ma
- Department of Pharmacology, School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.,Shanghai Key Laboratory of Compound Chinese Medicines, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Meng FY, Liu L, Liu J, Li CY, Wang JP, Yang FH, Chen ZS, Zhou P. Hepatocyte isolation from resected benign tissues: Results of a 5-year experience. World J Gastroenterol 2016; 22:8178-8186. [PMID: 27688659 PMCID: PMC5037086 DOI: 10.3748/wjg.v22.i36.8178] [Citation(s) in RCA: 3] [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: 07/21/2016] [Revised: 09/01/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze retrospectively a 5-year experience of human hepatocyte isolation from resected liver tissues with benign disease.
METHODS We established a method of modified four-step retrograde perfusion to isolate primary human hepatocytes. Samples were collected from the resected livers of patients with intrahepatic duct calculi (n = 7) and liver hemangioma (n = 17). Only the samples weighing ≥ 15 g were considered suitable for hepatocyte isolation. By using the standard trypan blue exclusion technique, hepatocyte viability and yield were immediately determined after isolation.
RESULTS Twenty-four liver specimens, weighing 15-42 g, were immediately taken from the margin of the removed samples and transferred to the laboratory for hepatocyte isolation. Warm ischemia time was 5-35 min and cold ischemia time was 15-45 min. For the 7 samples of intrahepatic duct calculi, the method resulted in a hepatocyte yield of 3.49 ± 2.31 × 106 hepatocytes/g liver, with 76.4% ± 10.7% viability. The 17 samples of liver hemangioma had significantly higher yield of cells (5.4 ± 1.71 × 106 cells/g vs 3.49 ± 2.31 × 106 cells/g, P < 0.05) than the samples of intrahepatic duct calculi. However, there seems to be no clear difference in cell viability (80.3% ± 9.67% vs 76.4% ± 10.7%, P > 0.05). We obtained a cell yield of 5.31 ± 1.87 × 106 hepatocytes/g liver when the samples weighed > 20 g. However, for the tissues weighing ≤ 20 g, a reduction in yield was found (3.08 ± 1.86 × 106 cells/g vs 5.31 ± 1.87 × 106 cells/g, P < 0.05).
CONCLUSION Benign diseased livers are valuable sources for large-number hepatocyte isolation. Our study represents the largest number of primary human hepatocytes isolated from resected specimens from patients with benign liver disease. We evaluated the effect of donor liver characteristics on cell isolation, and we found that samples of liver hemangioma can provide better results than intrahepatic duct calculi, in terms of cell yield. Furthermore, the size of the tissues can affect the outcome of hepatocyte isolation.
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Yang F, Tang X, Ding L, zhou Y, Yang Q, Gong J, Wang G, Wang Z, Yang L. Curcumin protects ANIT-induced cholestasis through signaling pathway of FXR-regulated bile acid and inflammation. Sci Rep 2016; 6:33052. [PMID: 27624003 PMCID: PMC5021964 DOI: 10.1038/srep33052] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/15/2016] [Indexed: 12/16/2022] Open
Abstract
Cholestasis is a clinically significant symptom and widely associated with liver diseases, however, there are very few effective therapies for cholestasis. Danning tablet (DNT, a Chinese patent medicine preparation) has been clinically used to treat human liver and gallbladder diseases for more than 20 years in China. However, which ingredients of DNT contributed to this beneficial effect and their mechanistic underpinnings have been largely unknown. In the present study, we discovered that DNT not only demonstrated greater benefits for cholecystitis patients after cholecystectomy surgery in clinic but also showed protective effect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis model in rodent. Curcumin, one major compound derived from DNT, exerted the protective effect against cholestasis through farnesoid X receptor (FXR), which has been focused as potential therapeutic targets for treating cholestasis. The underlying mechanism of curcumin against cholestasis was restoring bile acid homeostasis and antagonizing inflammatory responses in a FXR-dependent manner and in turn contributed to overall cholestasis attenuation. Collectively, curcumin can be served as a potential treatment option for liver injury with cholestasis.
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Affiliation(s)
- Fan Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaowen Tang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ding
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue zhou
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qiaoling Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junting Gong
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guangyun Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhengtao Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Arroyo-Salgado B, Olivero-Verbel J, Guerrero-Castilla A. Direct effect of p,p'- DDT on mice liver. BRAZ J PHARM SCI 2016. [DOI: 10.1590/s1984-82502016000200007] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
ABSTRACT Contact with the pesticide dichlorodiphenyltrichloroethane (p,p′-DDT) can be the cause of various harmful effects in humans, wildlife, and the environment. This pesticide is known to be persistent, lipophilic, resistant to degradation, and bioaccumulive in the environment and to be slowly released into bloodstream. Growing evidence shows that exposure to DDT is linked to type 2 diabetes mellitus. Individuals exposed to elevated levels of DDT and its metabolite have an increased prevalence of diabetes and insulin resistance. To evaluate these possible relationships, experiments were performed on eight-week-old female mice, divided into three groups (n = 10 per group): Group 1 received a vehicle-control intraperitoneal (i.p.) injection of sesame oil; Groups 2 and 3 received an i.p. dose of 50 and 100 µg/g p,p′-DDT respectively, dissolved in sesame oil. All groups were treated once daily for four days. Real-time PCR analysis of several genes was undertaken. Additionally, biochemical parameters and histopathological changes were measured. NQO1, HMOX1, NR1I3 and NR3C1 were up-regulated in DDT-exposed animals compared to the vehicle control group, while only SREBP1 was down-regulated in the 100 µg/g group. MTTP and FABP5, not previously reported for DDT exposure, but involved in regulation of fatty acid fluxes, could also function as biomarkers cross-talking between these signaling pathways. These results suggest that beyond epidemiological data, there is increasing molecular evidence that DDT may mimic different processes involved in diabetes and insulin resistance pathways.
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Kunne C, de Graaff M, Duijst S, de Waart DR, Oude Elferink RPJ, Paulusma CC. Hepatic cytochrome P450 deficiency in mouse models for intrahepatic cholestasis predispose to bile salt-induced cholestasis. J Transl Med 2014; 94:1103-13. [PMID: 25068656 DOI: 10.1038/labinvest.2014.102] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 06/19/2014] [Accepted: 06/29/2014] [Indexed: 11/09/2022] Open
Abstract
Progressive familial intrahepatic cholestasis (PFIC) types 1 and 3 are severe cholestatic liver diseases caused by deficiency of ATB8B1 and ABCB4, respectively. Mouse models for PFIC display mild phenotypes compared with human patients, and this can be explained by the difference in bile salt pool composition. Mice, unlike humans, have the ability to detoxify hydrophobic bile salts by cytochrome P450-mediated (re)hydroxylation and thus have a less toxic bile salt pool. We have crossed mouse models for PFIC1 and PFIC3 with Hrn mice that have a reduced capacity to (re)hydroxylate bile salts. Double transgenes were obtained by backcrossing Atp8b1(G308V/G308V) and Abcb4(-/-) mice with Hrn mice that have a liver-specific disruption of the cytochrome P450 reductase gene and therefore have markedly reduced P450 activity. In these mice, a more hydrophobic bile salt pool was instilled by cholic acid supplementation of the diet, and bile formation and liver pathology was studied. As opposed to single transgenes, Atp8b1(G308V/G308V)/Hrn and Abcb4(-/-)/Hrn mice rapidly developed strong cholestasis that was evidenced by increased plasma bilirubin and bile salt levels. The bile salt pool was more toxic in both models; Atp8b1(G308V/G308V)/Hrn mice had a more hydrophobic plasma pool compared with the single transgene, whereas Abcb4(-/-)/Hrn mice had a more hydrophobic biliary pool compared with the single transgene. In line with these findings, liver damage was not aggravated in Atp8b1(G308V/G308V)/Hrn but was more severe in Abcb4(-/-)/Hrn mice. These data indicate that bile salt pool composition is a critical determinant in the initiation and progression of cholestasis and liver pathology in PFIC1 and PFIC3. Most importantly, our data suggest that the hydrophobicity of the plasma bile salt pool is an important determinant of the severity of cholestasis, whereas the hydrophobicity of the biliary bile salt pool is an important determinant of the severity of liver pathology.
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Affiliation(s)
- Cindy Kunne
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Marijke de Graaff
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Suzanne Duijst
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Dirk R de Waart
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Ronald P J Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
| | - Coen C Paulusma
- Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
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La Merrill M, Karey E, Moshier E, Lindtner C, La Frano MR, Newman JW, Buettner C. Perinatal exposure of mice to the pesticide DDT impairs energy expenditure and metabolism in adult female offspring. PLoS One 2014; 9:e103337. [PMID: 25076055 PMCID: PMC4116186 DOI: 10.1371/journal.pone.0103337] [Citation(s) in RCA: 133] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Accepted: 06/25/2014] [Indexed: 12/16/2022] Open
Abstract
Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Its use in malaria control continues in some countries according to recommendation by the World Health Organization. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) have an increased prevalence of diabetes and insulin resistance. Here we hypothesize that perinatal exposure to DDT disrupts metabolic programming leading to impaired metabolism in adult offspring. To test this, we administered DDT to C57BL/6J mice from gestational day 11.5 to postnatal day 5 and studied their metabolic phenotype at several ages up to nine months. Perinatal DDT exposure reduced core body temperature, impaired cold tolerance, decreased energy expenditure, and produced a transient early-life increase in body fat in female offspring. When challenged with a high fat diet for 12 weeks in adulthood, female offspring perinatally exposed to DDT developed glucose intolerance, hyperinsulinemia, dyslipidemia, and altered bile acid metabolism. Perinatal DDT exposure combined with high fat feeding in adulthood further impaired thermogenesis as evidenced by reductions in core temperature and in the expression of numerous RNA that promote thermogenesis and substrate utilization in the brown adipose tissue of adult female mice. These observations suggest that perinatal DDT exposure impairs thermogenesis and the metabolism of carbohydrates and lipids which may increase susceptibility to the metabolic syndrome in adult female offspring.
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Affiliation(s)
- Michele La Merrill
- Department of Environmental Toxicology, University of California Davis, Davis, California, United States of America
- Department of Preventive Medicine, Mount Sinai School of Medicine, New York, New York, United States of America
- Metabolism Institute, Mount Sinai School of Medicine, New York, New York, United States of America
- * E-mail:
| | - Emma Karey
- Department of Environmental Toxicology, University of California Davis, Davis, California, United States of America
| | - Erin Moshier
- Department of Preventive Medicine, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Claudia Lindtner
- Metabolism Institute, Mount Sinai School of Medicine, New York, New York, United States of America
- Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York, United States of America
| | - Michael R. La Frano
- West Coast Metabolomic Center, University of California Davis, Davis, California, United States of America
- Department of Nutrition, University of California Davis, Davis, California, United States of America
| | - John W. Newman
- West Coast Metabolomic Center, University of California Davis, Davis, California, United States of America
- Department of Nutrition, University of California Davis, Davis, California, United States of America
- Obesity and Metabolism Research Unit, USDA-ARS-Western Human Nutrition Research Center, Davis, California, United States of America
| | - Christoph Buettner
- Metabolism Institute, Mount Sinai School of Medicine, New York, New York, United States of America
- Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York, United States of America
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Mechanistic Modeling Reveals the Critical Knowledge Gaps in Bile Acid-Mediated DILI. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2014; 3:e123. [PMID: 25006780 PMCID: PMC4120015 DOI: 10.1038/psp.2014.21] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023]
Abstract
Bile salt export pump (BSEP) inhibition has been proposed to be an important mechanism for drug-induced liver injury (DILI). Modeling can prioritize knowledge gaps concerning bile acid (BA) homeostasis and thus help guide experimentation. A submodel of BA homeostasis in rats and humans was constructed within DILIsym, a mechanistic model of DILI. In vivo experiments in rats with glibenclamide were conducted, and data from these experiments were used to validate the model. The behavior of DILIsym was analyzed in the presence of a simulated theoretical BSEP inhibitor. BSEP inhibition in humans is predicted to increase liver concentrations of conjugated chenodeoxycholic acid (CDCA) and sulfate-conjugated lithocholic acid (LCA) while the concentration of other liver BAs remains constant or decreases. On the basis of a sensitivity analysis, the most important unknowns are the level of BSEP expression, the amount of intestinal synthesis of LCA, and the magnitude of farnesoid-X nuclear receptor (FXR)-mediated regulation.
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Chatterjee S, Bijsmans IT, van Mil SW, Augustijns P, Annaert P. Toxicity and intracellular accumulation of bile acids in sandwich-cultured rat hepatocytes: Role of glycine conjugates. Toxicol In Vitro 2014; 28:218-30. [DOI: 10.1016/j.tiv.2013.10.020] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2013] [Revised: 10/24/2013] [Accepted: 10/30/2013] [Indexed: 02/06/2023]
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Shoda LKM, Woodhead JL, Siler SQ, Watkins PB, Howell BA. Linking physiology to toxicity using DILIsym®, a mechanistic mathematical model of drug-induced liver injury. Biopharm Drug Dispos 2013; 35:33-49. [DOI: 10.1002/bdd.1878] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Revised: 10/10/2013] [Accepted: 11/01/2013] [Indexed: 12/22/2022]
Affiliation(s)
- Lisl K. M. Shoda
- The Hamner-UNC Institute for Drug Safety Sciences; The Hamner Institutes; Research Triangle Park NC 27709 USA
| | - Jeffrey L. Woodhead
- The Hamner-UNC Institute for Drug Safety Sciences; The Hamner Institutes; Research Triangle Park NC 27709 USA
| | - Scott Q. Siler
- The Hamner-UNC Institute for Drug Safety Sciences; The Hamner Institutes; Research Triangle Park NC 27709 USA
| | - Paul B. Watkins
- The Hamner-UNC Institute for Drug Safety Sciences; The Hamner Institutes; Research Triangle Park NC 27709 USA
| | - Brett A. Howell
- The Hamner-UNC Institute for Drug Safety Sciences; The Hamner Institutes; Research Triangle Park NC 27709 USA
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Abstract
Determining the biliary clearance of drugs in humans is very challenging because bile is not readily accessible due to the anatomy of the hepatobiliary tract. The collection of bile usually is limited to postsurgical patients with underlying hepatobiliary disease. In healthy subjects, feces typically are used as a surrogate to quantify the amount of drug excreted via nonurinary pathways. Nevertheless, it is very important to characterize hepatobiliary elimination because this is a potential site of drug interactions that might result in significant alterations in systemic or hepatic exposure. In addition to the determination of in vivo biliary clearance values of drugs, the availability of in vitro models that can predict the extent of biliary excretion of drugs in humans may be a powerful tool in the preclinical stages of drug development. In this review, recent advances in the most commonly used in vivo methods to estimate biliary excretion of drugs in humans are outlined. Additionally, in vitro models that can be employed to investigate the molecular processes involved in biliary excretion are discussed to present an updated picture of the new tools and techniques that are available to study the complex processes involved in hepatic drug transport.
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Utanohara S, Tsuji M, Momma S, Morio Y, Oguchi K. The effect of ursodeoxycholic acid on glycochenodeoxycholic acid-induced apoptosis in rat hepatocytes. Toxicology 2005; 214:77-86. [PMID: 16023280 DOI: 10.1016/j.tox.2005.05.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2005] [Revised: 05/30/2005] [Accepted: 05/31/2005] [Indexed: 10/25/2022]
Abstract
Ursodeoxycholic acid (UDCA) has been widely used for treating cholestatic liver diseases. However, in a recent review of clinical trial articles, its therapeutic benefits were not proven. Therefore, we investigated whether UDCA prevents or potentiates glycochenodeoxycholic acid (GCDCA)-induced apoptosis in isolated rat hepatocytes. Hepatocellular cytotoxicity was assessed by lactate dehydrogenase (LDH) release, and apoptosis evaluated by DNA fragmentation, caspase activities, release of cytochrome C from mitochondria, and mitochondrial membrane potential change (Deltapsi). When hepatocytes were co-incubated with GCDCA and UDCA for a short time (2-6 h), GCDCA-induced LDH release was significantly reduced, while prolonged co-incubation (12-20 h) increased it. Similarly, the same co-incubation for a short time resulted in the inhibition of caspase activities and cytochrome C release, while prolonged incubation enhanced them compared with the incubation with GCDCA alone. Furthermore, UDCA significantly promoted the GCDCA-induced Deltapsi decline after 4h of incubation. These results demonstrated that UDCA reduced GCDCA-induced apoptosis in short incubation, but potentiated it in prolonged incubation. Based on these, we propose a hypothesis that induction of Deltapsi decrease from earlier stage of incubation may be responsible for the aggravation of GCDCA-induced apoptosis in long-term exposure, and would like to raise caution about clinical long-term use of UDCA.
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Affiliation(s)
- Shinichi Utanohara
- Department of Pharmacology, School of Medicine, Showa University, Hatanodai 1-5-8, Tokyo 142-8555, Japan
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Campana G, Pasini P, Roda A, Spampinato S. Regulation of ileal bile acid-binding protein expression in Caco-2 cells by ursodeoxycholic acid: Role of the farnesoid X receptor. Biochem Pharmacol 2005; 69:1755-63. [PMID: 15935148 DOI: 10.1016/j.bcp.2005.03.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2004] [Accepted: 03/23/2005] [Indexed: 12/21/2022]
Abstract
Ursodeoxycholic acid (UDCA) is beneficial in cholestatic diseases but its molecular mechanisms of action remain to be clearly elucidated. Other bile acids, such as chenodeoxycholic (CDCA), are agonists for the nuclear farnesoid X receptor (FXR) and regulate the expression of genes relevant for bile acid and cholesterol homeostasis. In ileal cells CDCA, through the FXR, up-regulates the expression of the ileal bile acid-binding protein (IBABP), implicated in the enterohepatic circulation of bile acids. We report that UDCA (100 and 200 microM) induced a moderate increase of IBABP mRNA (approximately 10% of the effect elicited by 50 microM CDCA) in enterocyte-like Caco-2 cells and approximately halved the potent effect of CDCA (50 microM). On the contrary, UDCA reduced by 80-90% CDCA-induced IBABP transcription in hepatocarcinoma derived HepG2 cells. We confirmed that these effects on IBABP transcription required the FXR by employing a cell-based transactivation assay. Finally, in a receptor binding assay, we found that UDCA binds to FXR expressed in CHO-K1 cells (K(d)=37.7 microM). Thus, UDCA may regulate IBABP in Caco-2 cells, which express it constitutively, by acting as a partial agonist through a FXR mediated mechanism. The observation that in HepG2 cells, which do not express constitutively IBABP, UDCA was able to almost completely prevent CDCA-induced activation of IBABP promoter, suggests that tissue-specific factors, other than FXR, may be required for bile acid regulation of FXR target genes.
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Affiliation(s)
- Gabriele Campana
- Department of Pharmacology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy
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Castelli M, Reiners JJ, Kessel D. A mechanism for the proapoptotic activity of ursodeoxycholic acid: effects on Bcl-2 conformation. Cell Death Differ 2005; 11:906-14. [PMID: 15258617 DOI: 10.1038/sj.cdd.4401433] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Ursodeoxycholic acid (UDCA), a relatively nontoxic bile acid, enhanced the apoptotic response of tumor cells to both photosensitizers that cause photodamage to Bcl-2 and to the nonpeptidic Bcl-2/Bcl-x(L) antagonist HA14-1. The latter agent binds to the surface pocket formed by the BH1, BH2 and BH3 domains of Bcl-2 and Bcl-x(L). Fluorescence polarization studies indicated that affinity of HA14-1 for Bcl-2 was enhanced in the presence of UDCA. Moreover, Bcl-2 photodamage was promoted by UDCA using a photosensitizing agent with affinity for the endoplasmic reticulum, a site of Bcl-2 localization. Fluorescence resonance energy transfer (FRET) studies revealed that the proximity of Bcl-2 to a hydrophobic photosensitizing agent embedded in liposomes was enhanced by UDCA. Since photodamage will occur only if a protein is in close contact with a photosensitizing agent, we propose that these findings support the hypothesis that UDCA causes a conformational change in Bcl-2, promoting HA14-1 binding and enhancing affinity for certain membrane-bound photosensitizers.
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Affiliation(s)
- M Castelli
- Cancer Biology Program, Wayne State University School of Medicine, Detroit, MI 48201, USA
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Palmeira CM, Rolo AP. Mitochondrially-mediated toxicity of bile acids. Toxicology 2004; 203:1-15. [PMID: 15363577 DOI: 10.1016/j.tox.2004.06.001] [Citation(s) in RCA: 152] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2004] [Revised: 05/26/2004] [Accepted: 06/02/2004] [Indexed: 01/14/2023]
Abstract
In the healthy hepatocyte, uptake of bile acids across the basolateral membrane and export via the canalicular export pump, are tightly coupled. Impairment of bile formation or excretion results in cholestasis, characterized by accumulation of bile acids in systemic blood and within the hepatocyte. When the concentration of bile acids exceeds the binding capacity of the binding protein located in the cytosol of the hepatocyte, bile acids induce apoptosis and necrosis, by damage to mitochondria. Mitochondria play a central role on the toxicity of bile acids. In this article, we review the published literature regarding bile acid effects on cell function, especially at the mitochondrial level. In patients with cholestatic liver disease, the extent of hepatocyte damage caused by intracellular accumulation of bile acids appears to be delayed by ingesting a hydrophilic bile acid. However, its effects on disease progression are not completely clarified. Therefore, identification of the mechanisms of cell injury will be of clinical utility, helping in the development of new therapeutic strategies. The goal of this review is to include a fresh consideration of all possible targets and integrating pathways that are involved in cholestasis, as well as in the benefits of bile acid therapy.
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Affiliation(s)
- Carlos M Palmeira
- Department of Zoology, Center for Neurosciences and Cell Biology of Coimbra, University of Coimbra, 3004-517, Portugal.
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17
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Solaas K, Kase BF, Pham V, Bamberg K, Hunt MC, Alexson SEH. Differential regulation of cytosolic and peroxisomal bile acid amidation by PPARα activation favors the formation of unconjugated bile acids. J Lipid Res 2004; 45:1051-60. [PMID: 15026425 DOI: 10.1194/jlr.m300291-jlr200] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
In human liver, unconjugated bile acids can be formed by the action of bile acid-CoA thioesterases (BACTEs), whereas bile acid conjugation with taurine or glycine (amidation) is catalyzed by bile acid-CoA:amino acid N-acyltransferases (BACATs). Both pathways exist in peroxisomes and cytosol. Bile acid amidation facilitates biliary excretion, whereas the accumulation of unconjugated bile acids may become hepatotoxic. We hypothesized that the formation of unconjugated and conjugated bile acids from their common substrate bile acid-CoA thioesters by BACTE and BACAT is regulated via the peroxisome proliferator-activated receptor alpha (PPARalpha). Livers from wild-type and PPARalpha-null mice either untreated or treated with the PPARalpha activator WY-14,643 were analyzed for BACTE and BACAT expression. The total liver capacity of taurochenodeoxycholate and taurocholate formation was decreased in WY-14,643-treated wild-type mice by 60% and 40%, respectively, but not in PPARalpha-null mice. Suppression of the peroxisomal BACAT activity was responsible for the decrease in liver capacity, whereas cytosolic BACAT activity was essentially unchanged by the treatment. In both cytosol and peroxisomes, the BACTE activities and protein levels were upregulated 5- to 10-fold by the treatment. These effects caused by WY-14,643 treatment were abolished in PPARalpha-null mice. The results from this study suggest that an increased formation of unconjugated bile acids occurs during PPARalpha activation.
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Affiliation(s)
- Karianne Solaas
- Division of Clinical Chemistry, Karolinska Institutet, Karolinska University Hospital at Huddinge, SE-141 86 Stockholm, Sweden.
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18
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Barbier O, Duran-Sandoval D, Pineda-Torra I, Kosykh V, Fruchart JC, Staels B. Peroxisome proliferator-activated receptor alpha induces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme. J Biol Chem 2003; 278:32852-60. [PMID: 12810707 DOI: 10.1074/jbc.m305361200] [Citation(s) in RCA: 105] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Glucuronidation, a major metabolic pathway for a large variety of endobiotics and xenobiotics, is catalyzed by enzymes belonging to the UDP-glucuronosyltransferase (UGT) family. Among UGT enzymes, UGT2B4 conjugates a large variety of endogenous and exogenous molecules and is considered to be the major bile acid conjugating UGT enzyme in human liver. In the present study, we identify UGT2B4 as a novel target gene of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha), which mediates the hypolipidemic action of fibrates. Incubation of human hepatocytes or hepatoblastoma HepG2 and Huh7 cells with synthetic PPAR alpha agonists, fenofibric acid, or Wy 14643 resulted in an increase of UGT2B4 mRNA levels. Furthermore, treatment of HepG2 cells with Wy 14643 induced the glucuronidation of hyodeoxycholic acid, a specific bile acid UGT2B4 substrate. Analysis of UGT2B mRNA and protein levels in PPAR alpha wild type and null mice revealed that PPAR alpha regulates both basal and fibrate-induced expression of these enzymes in rodents also. Finally, a PPAR response element was identified in the UGT2B4 promoter by site-directed mutagenesis and electromobility shift assays. These results demonstrate that PPAR alpha agonists may control the catabolism of cytotoxic bile acids and reinforce recent data indicating that PPAR alpha, which has been largely implicated in the control of lipid and cholesterol metabolism, is also an important modulator of the metabolism of endobiotics and xenobiotics in human hepatocytes.
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MESH Headings
- Animals
- Bile Acids and Salts/metabolism
- Blotting, Northern
- Blotting, Western
- Cell Line
- Cells, Cultured
- Cholesterol/metabolism
- DNA, Complementary/metabolism
- Dose-Response Relationship, Drug
- Gene Expression Regulation
- Glucuronosyltransferase/metabolism
- Hepatocytes/metabolism
- Homozygote
- Humans
- Lipid Metabolism
- Liver/enzymology
- Liver/metabolism
- Luciferases/metabolism
- Mice
- Microsomes, Liver/metabolism
- Models, Biological
- Mutagenesis, Site-Directed
- Peroxisome Proliferators/pharmacology
- Plasmids/metabolism
- Promoter Regions, Genetic
- Pyrimidines/pharmacology
- RNA/metabolism
- RNA, Messenger/metabolism
- Receptors, Cytoplasmic and Nuclear/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Time Factors
- Transcription Factors/metabolism
- Transfection
- Tumor Cells, Cultured
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Affiliation(s)
- Olivier Barbier
- Unité de Recherche 545, Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, 59019 Lille, France
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19
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Rolo AP, Palmeira CM, Wallace KB. Mitochondrially mediated synergistic cell killing by bile acids. BIOCHIMICA ET BIOPHYSICA ACTA 2003; 1637:127-32. [PMID: 12527417 DOI: 10.1016/s0925-4439(02)00224-7] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The accumulation of endogenous bile acids contributes to hepatocellular damage during cholestatic liver disease. To examine the controversy regarding the therapeutic use of ursodeoxycholate (UDCA) in cholestatic patients, we investigated the possible cytoprotection or synergistic effects of UDCA against chenodeoxycholate (CDCA)-induced injury to isolated rat hepatocytes. Our aim was to investigate the role of the mitochondrial permeability transition (MPT) in the mechanism of cytotoxicity caused by UDCA plus CDCA. Although not toxic by itself, UDCA potentiated the mitochondrial depolarization, ATP depletion and cell killing caused by CDCA. Fructose maintained ATP levels and prevented bile acid-induced cell killing. Cyclosporine A (CyA), a potent inhibitor of the MPT, substantially reduced mitochondrial depolarization, ATP depletion and cell killing caused by CDCA. Our results demonstrate that the synergistic cytotoxicity by UDCA plus CDCA is mediated by impairment of mitochondrial function, an event that is expressed via induction of the MPT.
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Affiliation(s)
- Anabela P Rolo
- Center for Neurosciences and Cell Biology of Coimbra, Department of Zoology, University of Coimbra, 3004-517, Coimbra, Portugal
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