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Zagorski JW, Kaminski NE. Utilization of a novel human hepatocyte-endothelial cell coculture model to determine differential toxicities of pyrrolizidine alkaloid food contaminants. Food Chem Toxicol 2024; 187:114584. [PMID: 38490353 DOI: 10.1016/j.fct.2024.114584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/04/2024] [Accepted: 03/07/2024] [Indexed: 03/17/2024]
Abstract
Pyrrolizidine alkaloids (PA) are comprised of a family of hundreds of metabolites, produced by plants as a mechanism to protect against herbivory. Upon ingestion and metabolism, dehydropyrrolizidine alkaloids are formed, which are known to generate DNA adducts and subsequently double-strand DNA breaks. Within the liver, the most sensitive cell type to PA exposure is the sinusoidal endothelial cell, as evidenced by the generation of veno-occlusive disease in the human population. PAs are a common crop contaminant and have been regulated by some agencies, using the precautionary principle; each equally potent and genotoxic. Therefore, as a proof of principle we have established a human in vitro coculture model system, utilizing the metabolically active HepaRG hepatocyte and the SK-Hep-1 endothelial cell, to determine differential potencies of different PAs commonly found in crops and food products, notably cell death, targeting of endothelial cells, and genotoxicity comparing the micronucleus assay versus γH2AX assay. Our results demonstrate differential potencies of the PAs used, which encompass three esterification states (monoester, cyclic diester, and open-chain diester). The results suggest that a more nuanced approach to the regulation of PAs may be more appropriate in the regulatory decision-making process.
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Affiliation(s)
- Joseph W Zagorski
- Center for Research on Ingredient Safety, Michigan State University, East Lansing, MI, 48824, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, USA
| | - Norbert E Kaminski
- Center for Research on Ingredient Safety, Michigan State University, East Lansing, MI, 48824, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, 48824, USA; Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, USA.
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Alhejji Y, Widjaja F, Tian S, Hoekstra T, Wesseling S, Rietjens IM. In vitro-in silico study on the influence of dose, fraction bioactivated and endpoint used on the relative potency value of pyrrolizidine alkaloid N-oxides compared to parent pyrrolizidine alkaloids. Curr Res Toxicol 2024; 6:100160. [PMID: 38469320 PMCID: PMC10926302 DOI: 10.1016/j.crtox.2024.100160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 02/22/2024] [Accepted: 02/27/2024] [Indexed: 03/13/2024] Open
Abstract
Pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) are phytotoxins found in food, feed and the environment. Yet, limited data exist from which the relative potency of a PA-N-oxide relative to its corresponding PA (REPPANO to PA) can be defined. This study aims to investigate the influence of dose, fraction bioactivated and endpoint on the REPPANO to PA of a series of pyrrolizidine N-oxides using in vitro-in silico data and physiologically based kinetic (PBK) modeling. The first endpoint used to calculate the REPPANO to PA was the ratio of the area under the concentration-time curve of PA resulting from an oral dose of PA-N-oxide divided by that from an equimolar dose of PA (Method 1). The second endpoint was the ratio of the amount of pyrrole-protein adducts formed under these conditions (Method 2). REPPANO to PA values appeared to decrease with increasing dose, with the decrease for Method 2 already starting at lower dose level than for Method 1. At dose levels as low as estimated daily human intakes, REPPANO to PA values amounted to 0.92, 0.81, 0.78, and 0.68 for retrorsine N-oxide, seneciphylline N-oxide, riddelliine N-oxide and senecivernine N-oxide, respectively, and became independent of the dose or fraction bioactivated, because no GSH depletion, saturation of PA clearance or PA-N-oxide reduction occurs. Overall, the results demonstrate the strength of using PBK modeling in defining REPPANO to PA values, thereby substantiating the use of the same approach for other PA-N-oxides for which in vivo data are lacking.
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Affiliation(s)
- Yasser Alhejji
- Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Frances Widjaja
- Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands
| | - Shenghan Tian
- Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands
| | - Thomas Hoekstra
- Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands
| | - Sebastiaan Wesseling
- Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands
| | - Ivonne M.C.M. Rietjens
- Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, the Netherlands
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Huang Z, Wu Z, Gu X, Ji L. Diagnosis, toxicological mechanism, and detoxification for hepatotoxicity induced by pyrrolizidine alkaloids from herbal medicines or other plants. Crit Rev Toxicol 2024; 54:123-133. [PMID: 38411492 DOI: 10.1080/10408444.2024.2310597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 01/18/2024] [Indexed: 02/28/2024]
Abstract
Pyrrolizidine alkaloids (PAs) are one type of phytotoxins distributed in various plants, including many medicinal herbs. Many organs might suffer injuries from the intake of PAs, and the liver is the most susceptible one. The diagnosis, toxicological mechanism, and detoxification of PAs-induced hepatotoxicity have been studied for several decades, which is of great significance for its prevention, diagnosis, and therapy. When the liver was exposed to PAs, liver sinusoidal endothelial cells (LSECs) loss, hemorrhage, liver parenchymal cells death, nodular regeneration, Kupffer cells activation, and fibrogenesis occurred. These pathological changes classified the PAs-induced liver injury as acute, sub-acute, and chronic type. PAs metabolic activation, mitochondria injury, glutathione (GSH) depletion, inflammation, and LSECs damage-induced activation of the coagulation system were well recognized to play critical roles in the pathological process of PAs-induced hepatotoxicity. A lot of natural compounds like glycyrrhizic acid, (-)-epicatechin, quercetin, baicalein, chlorogenic acid, and so on were demonstrated to be effective in alleviating PAs-induced liver injury, which rendered them huge potential to be developed into therapeutic drugs for PAs poisoning in clinics. This review presents updated information about the diagnosis, toxicological mechanism, and detoxification studies on PAs-induced hepatotoxicity.
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Affiliation(s)
- Zhenlin Huang
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zeqi Wu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xinnan Gu
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lili Ji
- The MOE Key Laboratory for Standardization of Chinese Medicines, Shanghai Key Laboratory of Compound Chinese Medicines and The SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Ren X, Xu K, Xu J, Mei Q. Melatonin attenuates monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats via activation of Sirtuin-3. J Biochem Mol Toxicol 2023; 37:e23422. [PMID: 37350538 DOI: 10.1002/jbt.23422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 01/03/2023] [Accepted: 06/09/2023] [Indexed: 06/24/2023]
Abstract
Melatonin possesses potent hepatoprotective properties, but it remains to be elucidated whether melatonin has a therapeutic effect on monocrotaline (MCT)-induced hepatic sinusoidal obstruction syndrome (HSOS). In this study, male Sprague Dawley rats were intraperitoneally injected with melatonin or the same volume of vehicle at 0 and 24 h after MCT intragastric administration. Next, hematoxylin-eosin staining and electron microscopy were performed to evaluate the hepatic sinusoidal injury of rats. Endothelial cell marker RECA-1 was observed by immunohistochemistry. Hepatic oxidative stress was analyzed by detecting malondialdehyde, glutathione S-transferase, and reactive oxygen species. Assessment of liver function was carried out by analysis of serum aspartate aminotransferase, alanine aminotransferase, total bilirubin, and albumin levels. Real-time polymerase chain reaction and Western blot analysis were used to identify liver Sirtuin-3 (SIRT3) and active matrix metallopeptidase 9 (MMP-9) expression. Besides, liver sinusoidal endothelial cells (LSECs) were used for the in vitro functional verification experiment. Specifically, liver histology of the melatonin-treated groups showed that the pathological damages caused by MCT were significantly attenuated, total HSOS scores were decreased, and the elevation of serum hyaluronic acid observed in the model group was also reduced. Moreover, melatonin treatment also improved the survival of rats after partial hepatectomy. Administration of melatonin ameliorated MCT-induced LSECs injury, hepatic oxidative stress, and hepatic dysfunction. Furthermore, melatonin treatment increased SIRT3 expression while attenuating MMP-9 activity in liver tissues. Cell experiment also demonstrated that SIRT3 might mediate the protective effect of melatonin on LSECs. Collectively, our study provided the potential rationale for the application of melatonin for the prevention of MCT-induced HSOS.
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Affiliation(s)
- Xiaofei Ren
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Kui Xu
- Department of Gastroenterology, Lu'an Hospital of Anhui Medical University, Lu'an People's Hospital of Anhui Province, Lu'an, Anhui, China
| | - Jianming Xu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qiao Mei
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Shang H, Huang C, Xiao Z, Yang P, Zhang S, Hou X, Zhang L. Gut microbiota-derived tryptophan metabolites alleviate liver injury via AhR/Nrf2 activation in pyrrolizidine alkaloids-induced sinusoidal obstruction syndrome. Cell Biosci 2023; 13:127. [PMID: 37422682 PMCID: PMC10329330 DOI: 10.1186/s13578-023-01078-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 06/26/2023] [Indexed: 07/10/2023] Open
Abstract
BACKGROUND AND AIMS Hepatic sinusoidal obstruction syndrome (HSOS) is caused by toxic injury, such as pyrrolizidine alkaloids, to the liver sinusoidal endothelial cells, and the gut microbiota may be involved. However, the specific role and underlying mechanism of gut microbiota in HSOS is unknown. METHODS HSOS model was established by gavage of monocrotaline (MCT) in rats. Fecal microbiota transplantation (FMT) with HSOS-derived or healthy gut flora was also conducted to validate the role of gut microflora in MCT-induced liver injury. The microbial 16 s rRNA analysis and untargeted metabolomics analysis in the faeces were performed to identify HSOS-related flora and metabolites. Finally, by supplementation with specific tryptophan metabolites, such as indole-3-acetaldehyde (IAAld) and indole acetic acid (IAA), we further confirmed the role of tryptophan metabolism in HSOS and the role of the AhR/Nrf2 pathway in MCT-induced liver injury. RESULTS MCT induced HSOS-like liver injury in rats with significantly altered gut microbiota. Particularly, some tryptophan-metabolizing bacteria reduced in MCT-treated rats, such as Bacteroides, Bifidobacterium, Lactobacillus and Clostridium, and accompanied by a decrease in microbial tryptophan metabolic activity and a series of tryptophan derivatives. Restoring the gut microbiota via FMT improved MCT-induced liver damage, while HSOS-derived gut microbiota aggravated the liver injury induced by MCT. Supplementation with microbial tryptophan derivatives (IAAld or IAA), or 6-formylindolo(3,2-b)carbazole (Ficz, an AhR agonist) could activate the AhR/Nrf2 signaling pathway, thereby attenuating the MCT-induced liver oxidative stress and liver sinusoidal endothelial cells injury. CONCLUSIONS Gut microbiota plays a critical role in MCT-induced HSOS, with inadequate microbial tryptophan metabolism in the gut and consequently a lower activity of the AhR/Nrf2 signaling pathway in the liver, which should be a potential target for the management of HSOS.
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Affiliation(s)
- Haitao Shang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Department of Gastroenterology, Qingdao Hospital, University of Health and Rehabilitation Sciences (Qingdao Municipal Hospital), Qingdao, 266071, China
| | - Chao Huang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Zhuanglong Xiao
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Pengcheng Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shengyan Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Lei Zhang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Widjaja F, Zheng L, Wesseling S, Rietjens IMCM. Physiologically based kinetic modeling of senecionine N-oxide in rats as a new approach methodology to define the effects of dose and endpoint used on relative potency values of pyrrolizidine alkaloid N-oxides. Front Pharmacol 2023; 14:1125146. [PMID: 36937884 PMCID: PMC10017778 DOI: 10.3389/fphar.2023.1125146] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/14/2023] [Indexed: 03/06/2023] Open
Abstract
Over 1,000 pyrrolizidine alkaloids (PAs) and their N-oxides (PA-N-oxides) occur in 3% of all flowering plants. PA-N-oxides are toxic when reduced to their parent PAs, which are bioactivated into pyrrole intermediates that generate protein- and DNA-adducts resulting in liver toxicity and carcinogenicity. Literature data for senecionine N-oxide in rats indicate that the relative potency (REP) value of this PA-N-oxide compared to its parent PA senecionine varies with the endpoint used. The first endpoint was the ratio between the area under the concentration-time curve (AUC) for senecionine upon dosing senecionine N-oxide or an equimolar dose of senecionine, while the second endpoint was the ratio between the amount for pyrrole-protein adducts formed under these conditions. This study aimed to investigate the mode of action underlying this endpoint dependent REP value for senecionine N-oxide with physiologically based kinetic (PBK) modeling. Results obtained reveal that limitation of 7-GS-DHP adduct formation due to GSH depletion, resulting in increased pyrrole-protein adduct formation, occurs more likely upon high dose oral PA administration than upon an equimolar dose of PA-N-oxide. At high dose levels, this results in a lower REP value when based on pyrrole-protein adduct levels than when based on PA concentrations. At low dose levels, the difference no longer exists. Altogether, the results of the study show how the REP value for senecionine N-oxide depends on dose and endpoint used, and that PBK modeling provides a way to characterize REP values for PA-N-oxides at realistic low dietary exposure levels, thus reducing the need for animal experiments.
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Affiliation(s)
- Frances Widjaja
- Division of Toxicology, Wageningen University, Wageningen, Netherlands
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Widjaja F, Alhejji Y, Yangchen J, Wesseling S, Rietjens IMCM. Physiologically-Based Kinetic Modeling Predicts Similar In Vivo Relative Potency of Senecionine N-Oxide for Rat and Human at Realistic Low Exposure Levels. Mol Nutr Food Res 2023; 67:e2200293. [PMID: 36478522 DOI: 10.1002/mnfr.202200293] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 10/30/2022] [Indexed: 12/12/2022]
Abstract
SCOPE This study aims to determine if previously developed physiologically-based kinetic (PBK) model in rat can be modified for senecionine (SEN) and its N-oxide (SENO), and be used to investigate potential species differences between rat and human in relative potency (REP) of the N-oxide relative to the parent pyrrolizidine alkaloid (PA). METHODS AND RESULTS In vitro derived kinetic parameters including the apparent maximum velocities (Vmax ) and Michaelis-Menten constants (Km ) for SENO reduction and SEN clearance are used to define the PBK models. The rat model is validated with published animal data, and the toxicokinetic profiles of SEN from either orally-administered SENO or SEN are simulated. REP values of SENO relative to SEN amount to 0.84 and 0.89 in rat and human, respectively. CONCLUSION The REP value can be dose- and species-dependent, with the values for rat and human being comparable at low realistic exposure scenarios. In summary, PBK modeling serves as a valuable New Approach Methodology (NAM) tool for predicting REP values of PA-N-oxides and may actually result in more accurate REP values for human risk assessment than what would be defined using in vivo animal experiments.
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Affiliation(s)
- Frances Widjaja
- Division of Toxicology, Wageningen University, PO Box 8000, Wageningen, 6700 EA, The Netherlands
| | - Yasser Alhejji
- Division of Toxicology, Wageningen University, PO Box 8000, Wageningen, 6700 EA, The Netherlands.,Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, 51452, Saudi Arabia
| | - Jamyang Yangchen
- Division of Toxicology, Wageningen University, PO Box 8000, Wageningen, 6700 EA, The Netherlands.,Bhutan Agriculture and Food Regulatory Authority, Ministry of Agriculture and Forests, Thimphu, 11002, Bhutan
| | - Sebastiaan Wesseling
- Division of Toxicology, Wageningen University, PO Box 8000, Wageningen, 6700 EA, The Netherlands
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University, PO Box 8000, Wageningen, 6700 EA, The Netherlands
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Singh H, Lonare MK, Sharma M, Udehiya R, Singla S, Saini SP, Dumka VK. Interactive effect of carbendazim and imidacloprid on buffalo bone marrow derived mesenchymal stem cells: oxidative stress, cytotoxicity and genotoxicity. Drug Chem Toxicol 2023; 46:35-49. [PMID: 34844488 DOI: 10.1080/01480545.2021.2007023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The effect of a combination of two pesticides, carbendazim (CBZ) and imidacloprid (IMI), was investigated on mesenchymal stem cells derived from the bone marrow of buffalo (bMSCs). The bMSCs were exposed to the CBZ (2.25 µM, 4.49 µM, and 8.98 µM) and IMI (0.81 mM, 1.61 mM, and 3.22 mM) alone as well as in combinations. The bMSCs were found to be positive for the stem cell markers, AP, CD73, and OCT4. The bMSCs showed a significant reduction (p ≤ 0.05) in cell viability, and status of anti-oxidants while a significant increase (p ≤ 0.05) in the level of LDH, ALP, and CK-MB in CBZ and IMI-treated groups. A significant increase (p ≤ 0.05) was noticed in LPO, O2─ radical, total ROS, loss of ΔΨm, apoptotic index, and DNA damage in CBZ and IMI-treated groups. A low-dose combination group showed an elevated effect compared to the groups treated with the single pesticide. The interaction index was calculated for CBZ-IMI combined treatment groups on various parameters that showed the majority of antagonist effects. Present findings confirmed that CBZ and IMI-induced cytotoxicity in bMSCs was mediated via ROS production, altered ΔΨm and LPO along with depressed antioxidant status which was responsible for cell apoptosis and cell damage. This study suggested that CBZ and IMI had a dose-dependent toxic effect when the pesticides were used alone, while, co-exposure to both the pesticides simultaneously had an antagonist or non-additive effect on buffalo bMSCs at lower dose combinations and they induced a potentiating effect at high-dose combination.
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Affiliation(s)
| | | | | | - Rahul Udehiya
- Department of Veterinary Surgery and Radiology, Guru Angad Dev Veterinary and Animal Sciences University, Ludhiana, Punjab, India
| | - Saloni Singla
- Department of Veterinary Pharmacology and Toxicology
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Inhibition of Vascular Endothelial Growth Factor Protects against the Development of Oxaliplatin-Induced Sinusoidal Obstruction Syndrome in Wild-Type but Not in CD39-Null Mice. Cancers (Basel) 2022; 14:cancers14235992. [PMID: 36497474 PMCID: PMC9739893 DOI: 10.3390/cancers14235992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/19/2022] [Accepted: 11/20/2022] [Indexed: 12/12/2022] Open
Abstract
(1) Background: Sinusoidal obstruction syndrome (SOS) after oxaliplatin-based chemotherapy is associated with unfavorable outcomes after partial hepatectomy for colorectal liver metastases (CLM). Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), may prevent SOS development. We investigated the impact of VEGF-inhibition on the development of SOS in a murine model. (2) Methods: Male wild-type and CD39-null mice received oxaliplatin, additional anti-VEGF (OxAV), or controls, and were sacrificed or subjected to major partial hepatectomy (MH). Specimen were used for histological analysis of SOS. Liver damage was assessed by plasma transaminases. The VEGF pathway was elucidated by quantitative PCR of liver tissue and protein analysis of plasma. (3) Results: Mice treated with oxaliplatin developed SOS. Concomitant anti-VEGF facilitated a reduced incidence of SOS, but not in CD39-null mice. SOS was associated with increased plasma VEGF-A and decreased hepatocyte growth factor (HGF). After OxAV treatment, VEGF-R2 was upregulated in wild-type but downregulated in CD39-null mice. Oxaliplatin alone was associated with higher liver damage after MH than in mice with concomitant VEGF-inhibition. (4) Conclusions: We established a murine model of oxaliplatin-induced SOS and provided novel evidence on the protective effect of VEGF-inhibition against the development of SOS that may be associated with changes in the pathway of VEGF and its receptor VEGF-R2.
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Huu Hoang T, Sato-Matsubara M, Yuasa H, Matsubara T, Thuy LTT, Ikenaga H, Phuong DM, Hanh NV, Hieu VN, Hoang DV, Hai H, Okina Y, Enomoto M, Tamori A, Daikoku A, Urushima H, Ikeda K, Dat NQ, Yasui Y, Shinkawa H, Kubo S, Yamagishi R, Ohtani N, Yoshizato K, Gracia-Sancho J, Kawada N. Cancer cells produce liver metastasis via gap formation in sinusoidal endothelial cells through proinflammatory paracrine mechanisms. SCIENCE ADVANCES 2022; 8:eabo5525. [PMID: 36170363 PMCID: PMC9519040 DOI: 10.1126/sciadv.abo5525] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 08/04/2022] [Indexed: 06/10/2023]
Abstract
Intracellular gap (iGap) formation in liver sinusoidal endothelial cells (LSECs) is caused by the destruction of fenestrae and appears under pathological conditions; nevertheless, their role in metastasis of cancer cells to the liver remained unexplored. We elucidated that hepatotoxin-damaged and fibrotic livers gave rise to LSECs-iGap formation, which was positively correlated with increased numbers of metastatic liver foci after intrasplenic injection of Hepa1-6 cells. Hepa1-6 cells induced interleukin-23-dependent tumor necrosis factor-α (TNF-α) secretion by LSECs and triggered LSECs-iGap formation, toward which their processes protruded to transmigrate into the liver parenchyma. TNF-α triggered depolymerization of F-actin and induced matrix metalloproteinase 9 (MMP9), intracellular adhesion molecule 1, and CXCL expression in LSECs. Blocking MMP9 activity by doxycycline or an MMP2/9 inhibitor eliminated LSECs-iGap formation and attenuated liver metastasis of Hepa1-6 cells. Overall, this study revealed that cancer cells induced LSEC-iGap formation via proinflammatory paracrine mechanisms and proposed MMP9 as a favorable target for blocking cancer cell metastasis to the liver.
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Affiliation(s)
- Truong Huu Hoang
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Department of Pain Medicine and Palliative Care, Cancer Institute, 108 Military Central Hospital, Hanoi, Vietnam
| | - Misako Sato-Matsubara
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hideto Yuasa
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Le Thi Thanh Thuy
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hiroko Ikenaga
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Dong Minh Phuong
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Ngo Vinh Hanh
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Vu Ngoc Hieu
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Dinh Viet Hoang
- Department of Anesthesiology, Cho Ray Hospital, Ho Chi Minh City, Vietnam
| | - Hoang Hai
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Yoshinori Okina
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Masaru Enomoto
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Akihiro Tamori
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Atsuko Daikoku
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Hayato Urushima
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Kazuo Ikeda
- Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Ninh Quoc Dat
- Department of Pediatrics, Hanoi Medical University, Hanoi, Vietnam
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Hiroji Shinkawa
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Shoji Kubo
- Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Ryota Yamagishi
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Naoko Ohtani
- Department of Pathophysiology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Katsutoshi Yoshizato
- Endowed Laboratory of Synthetic Biology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
- BioIntegrence Co. Ltd., Osaka, Japan
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, CIBEREHD, Barcelona, Spain
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
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11
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Ajisebiola BS, Adeniji OB, James AS, Ajayi BO, Adeyi AO. Naja nigricollis venom altered reproductive and neurological functions via modulation of pro-inflammatory cytokines and oxidative damage in male rats. Metabol Open 2022; 14:100188. [PMID: 35633732 PMCID: PMC9130106 DOI: 10.1016/j.metop.2022.100188] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/30/2022] [Accepted: 05/12/2022] [Indexed: 01/03/2023] Open
Abstract
Reproductive and neurological anomalies are often characterized by malfunctioning of reproductive and nervous organs sometimes attributed to systemic toxins. However, limited information is available on the impact of snake venom toxins on male reproductive and nervous system. This study investigated the toxicological effects of Naja nigricollis venom on male reproductive and neural functions in rat model. Twenty male Wistar rats weighing between 195 and 230 g were divided randomly into two groups of ten rats each. Group 1 served as normal control while rats in group 2 were envenomed with a single intraperitoneal injection of 0.25 mg/kg-1 (LD12.5) of N. nigricollis venom on first and twenty fifth day within the period of fifty days experiment. The venom significantly decreased sperm counts, motile cells and volume combined with increased sperm abnormalities. The venom induced hormonal imbalances in the envenomed group as levels of testosterone, luteinizing and follicle stimulating hormones depreciated compared to the control. Oxidative stress biomarkers: malondialdehyde significantly increased parallels with depletion of glutathione level and catalase activities in testis, epididymis and brain of envenomed rats. Furthermore, N. nigricollis venom up-regulated tumor necrosis factor-alpha (TNF-α) and interleukin1-beta (IL-1β) production in testis, epididymis and brain of envenomed rats compared to the control. Also, various histological alterations were noticed in tissues of testis, epididymis and brain of envenomed rats. Findings indicated that N. nigricollis venom is capable of inducing reproductive and neurological dysfunction in envenomed victims.
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Affiliation(s)
| | | | - Adewale Segun James
- Department of Chemical Sciences (Biochemistry Program), Augustine University, Lagos, Nigeria
| | - Babajide O. Ajayi
- Onco-preventives and Systems Oncology Research Laboratory, Biochemistry Unit, Department of Chemical Sciences, Ajayi Crowther University, Oyo, Nigeria
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12
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Zhang Z, Zou H, Dai Z, Shang J, Sure S, Lai C, Shi Y, Yang Q, Xiang G, Yao Y, Feng T, Zhong D, Huang X. Gynura segetum-induced liver injury leading to acute liver failure: a case report and literature review. BMC Complement Med Ther 2022; 22:61. [PMID: 35260147 PMCID: PMC8905811 DOI: 10.1186/s12906-022-03549-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 03/02/2022] [Indexed: 12/27/2022] Open
Abstract
Background Gynura segetum (GS) is widely used in medical care and in community settings in China as the herbal remedy. It is widely thought to have antiphlogistic properties and pain relief in traditional Chinese medicine. It has been reported that GS can cause chronic drug-induced liver injury (DILI), manifested as hepatic sinusoid obstruction syndrome (HOSO). But case reports of acute DILI developing acute liver failure (ALF) due to GS are extremely rare. Case presentation We report a case of a 63-year-old female patient with hepatolithiasis for more than 6 years. There were no deterioration of liver function and no history of viral liver disease, autoimmune liver disease, blood transfusion or surgical allergy before operation. ALF and grade II liver encephalopathy occurred after partial hepatectomy. To follow up the medical history, the patient has been taking GS (Tusanqi) for a year and a half. The causality assessment was done by the updated Roussel Uclaf Causality Assessment Method, and the possibility of DILI caused by GS as highly probable for the score was 6 points. Excluding other causes, a diagnosis of DILI-associated ALF was established. After symptomatic support and artificial liver support system (ALSS) treatment, the clinical symptoms and signs of the patients were significantly improved. After discharge, the liver function of the patients returned to normal. Conclusions Based on this rare case of severe liver injury, we recommend that timely prevention, identification, and appropriate management of DILI is essential for patients with a history of taking GS and other hepatotoxic drugs, and careful monitoring of liver function for patients with DILI could avoid ALF as far as possible.
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Affiliation(s)
- Zilong Zhang
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Haibo Zou
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Zonglin Dai
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Jin Shang
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Shining Sure
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.,Department of Pathology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Chunyou Lai
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ying Shi
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Qinyan Yang
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Guangming Xiang
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Yutong Yao
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Tianhang Feng
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Deyuan Zhong
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Xiaolun Huang
- Department of Hepatobiliary-Pancreatic Surgery, Cell Transplantation Center, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. .,Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China.
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13
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Edgar JA, Molyneux RJ, Colegate SM. 1,2-Dehydropyrrolizidine Alkaloids: Their Potential as a Dietary Cause of Sporadic Motor Neuron Diseases. Chem Res Toxicol 2022; 35:340-354. [PMID: 35238548 DOI: 10.1021/acs.chemrestox.1c00384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Sporadic motor neuron diseases (MNDs), such as amyotrophic lateral sclerosis (ALS), can be caused by spontaneous genetic mutations. However, many sporadic cases of ALS and other debilitating neurodegenerative diseases (NDDs) are believed to be caused by environmental factors, subject to considerable debate and requiring intensive research. A common pathology associated with MND development involves progressive mitochondrial dysfunction and oxidative stress in motor neurons and glial cells of the central nervous system (CNS), leading to apoptosis. Consequent degeneration of skeletal and respiratory muscle cells can lead to death from respiratory failure. A significant number of MND cases present with cancers and liver and lung pathology. This Perspective explores the possibility that MNDs could be caused by intermittent, low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids (1,2-dehydroPAs) that are increasingly recognized as contaminants of many foods consumed throughout the world. Nontoxic, per se, 1,2-dehydroPAs are metabolized, by particular cytochrome P450 (CYP450) isoforms, to 6,7-dihydropyrrolizines that react with nucleophilic groups (-NH, -SH, -OH) on DNA, proteins, and other vital biochemicals, such as glutathione. Many factors, including aging, gender, smoking, and alcohol consumption, influence CYP450 isoform activity in a range of tissues, including glial cells and neurons of the CNS. Activation of 1,2-dehydroPAs in CNS cells can be expected to cause gene mutations and oxidative stress, potentially leading to the development of MNDs and other NDDs. While relatively high dietary exposure to 1,2-dehydroPAs causes hepatic sinusoidal obstruction syndrome, pulmonary venoocclusive disease, neurotoxicity, and diverse cancers, this Perspective suggests that, at current intermittent, low levels of dietary exposure, neurotoxicity could become the primary pathology that develops over time in susceptible individuals, along with a tendency for some of them to also display liver and lung pathology and diverse cancers co-occurring with some MND/NDD cases. Targeted research is recommended to investigate this proposal.
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Affiliation(s)
- John A Edgar
- CSIRO Agriculture and Food, 11 Julius Avenue, North Ryde, New South Wales 2113, Australia
| | - Russell J Molyneux
- Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo, 200 West Kawili Street, Hilo, Hawaii 96720, United States
| | - Steven M Colegate
- Poisonous Plant Research Laboratory, ARS/USDA, 1150 East 1400 North, Logan, Utah 84341, United States
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14
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Kupffer cells play a crucial role in monocrotaline-induced liver injury by producing TNF-α. Toxicology 2022; 468:153101. [DOI: 10.1016/j.tox.2022.153101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 11/17/2022]
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15
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He Y, Zhu L, Ma J, Lin G. Metabolism-mediated cytotoxicity and genotoxicity of pyrrolizidine alkaloids. Arch Toxicol 2021; 95:1917-1942. [PMID: 34003343 DOI: 10.1007/s00204-021-03060-w] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023]
Abstract
Pyrrolizidine alkaloids (PAs) and PA N-oxides are common phytotoxins produced by over 6000 plant species. Humans are frequently exposed to PAs via ingestion of PA-containing herbal products or PA-contaminated foods. PAs require metabolic activation to form pyrrole-protein adducts and pyrrole-DNA adducts which lead to cytotoxicity and genotoxicity. Individual PAs differ in their metabolic activation patterns, which may cause significant difference in toxic potency of different PAs. This review discusses the current knowledge and recent advances of metabolic pathways of different PAs, especially the metabolic activation and metabolism-mediated cytotoxicity and genotoxicity, and the risk evaluation methods of PA exposure. In addition, this review provides perspectives of precision toxicity assessment strategies and biomarker development for the risk control and translational investigations of human intoxication by PAs.
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Affiliation(s)
- Yisheng He
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Lin Zhu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Jiang Ma
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China
| | - Ge Lin
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR, China.
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16
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Cen P, Ding J, Jin J. Hepatic sinusoidal obstruction syndrome caused by the ingestion of Gynura segetum in a patient with alcoholic cirrhosis: a case report. J Int Med Res 2021; 49:300060520980649. [PMID: 33845617 PMCID: PMC8047090 DOI: 10.1177/0300060520980649] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Hepatic sinusoidal obstruction syndrome (HSOS) is a rare hepatic vascular disorder characterized by intrahepatic congestion, liver injury, and post-sinusoidal portal hypertension, and it is frequently associated with hematopoietic stem cell transplantation. In this study, we observed a case of HSOS associated with the ingestion of Gynura segetum, a pyrrolizidine alkaloid (PA)-containing Chinese herb, in a patient with alcoholic cirrhosis. The patient was a 43-year-old man with chief complaints of physical asthenia and a loss of appetite for more than a month. The diagnosis of HSOS combined with alcoholic cirrhosis was confirmed via the histopathological examination of liver tissues. With proper supportive and symptomatic care and anticoagulation therapy using low-molecular-weight heparin, the patient’s condition was stabilized. Because of its nonspecific symptoms in the early stage and a lack of information about PA consumption, PA-induced HSOS (PA-HSOS) has been long neglected, especially in patients with underlying liver diseases. Early identification and intervention are critical for optimizing outcomes. Further efforts are needed to supervise the use of PA-containing herbal medicines and identify accurate biomarkers for PA-HSOS.
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Affiliation(s)
- Panpan Cen
- Department of Infectious Diseases, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Jiexia Ding
- Department of Infectious Diseases, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
| | - Jie Jin
- Department of Infectious Diseases, Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China
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17
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Ramzi M, Namdari N, Haghighat S, Haghighinejad H. Evaluation of Reversed Administration Order of Busulfan (BU) and Cyclophosphamide (CY) as Conditioning on Liver Toxicity in Allogenic Hematopoietic Stem Cell Transplantation (ALL-HSCT). Int J Hematol Oncol Stem Cell Res 2020; 14:171-176. [PMID: 33024523 PMCID: PMC7521389 DOI: 10.18502/ijhoscr.v14i3.3725] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Background: Busulfan (BU) in combination with cyclophosphamide (CY) is used as an effective conditioning regimen in hematopoietic SCT. Busulfan, depletes glutathione level in liver and causes elevated levels of CY metabolites. Cyclophosphamide metabolites are highly toxic for sinusoidal endothelial cells and cause VOD/ SOS with high mortality rate. Materials and Methods: Between September 2013 and September 2015, all adult patients with acute leukemia who were candidates for myeloablative allogenic SCT and were admitted to Stem Cell Transplantation center were enrolled in this prospective randomized clinical trial. We tested the hypothesis that reverse administration from BU-CY (n=28) to CY-BU group (n=27) would reduce liver toxicity. Results: Liver function tests were significantly higher in the BU-CY group between day -1 and +4 (p<0.05), but VOD/SOS was not diagnosed in both groups. The incidence and severity of acute GVHD was higher in the BU-CY group, but not statistically significant. Engraftment and mortality rate were not different. Conclusion: These data support the concept that CY-BU is associated with less liver toxicity, suggesting CY-BU is superior to BU-CY as conditioning.
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Affiliation(s)
- Mani Ramzi
- Hematology and Bone Marrow Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Nasrin Namdari
- Department of Hematology and Medical Oncology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Shirin Haghighat
- Department of Hematology, Hematology Research Center, Medical Oncology and Stem Cell Transplantation, Shiraz University of Medical Sciences, Shiraz, Iran
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18
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Hessel-Pras S, Braeuning A, Guenther G, Adawy A, Enge AM, Ebmeyer J, Henderson CJ, Hengstler JG, Lampen A, Reif R. The pyrrolizidine alkaloid senecionine induces CYP-dependent destruction of sinusoidal endothelial cells and cholestasis in mice. Arch Toxicol 2020; 94:219-229. [PMID: 31606820 DOI: 10.1007/s00204-019-02582-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 09/18/2019] [Indexed: 02/07/2023]
Abstract
Pyrrolizidine alkaloids (PAs) are widely occurring phytotoxins which can induce severe liver damage in humans and other mammalian species by mechanisms that are not fully understood. Therefore, we investigated the development of PA hepatotoxicity in vivo, using an acutely toxic dose of the PA senecionine in mice, in combination with intravital two-photon microscopy, histology, clinical chemistry, and in vitro experiments with primary mouse hepatocytes and liver sinusoidal endothelial cells (LSECs). We observed pericentral LSEC necrosis together with elevated sinusoidal marker proteins in the serum of senecionine-treated mice and increased sinusoidal platelet aggregation in the damaged tissue regions. In vitro experiments showed no cytotoxicity to freshly isolated LSECs up to 500 µM senecionine. However, metabolic activation of senecionine by preincubation with primary mouse hepatocytes increased the cytotoxicity to cultivated LSECs with an EC50 of approximately 22 µM. The cytochrome P450 (CYP)-dependency of senecionine bioactivation was confirmed in CYP reductase-deficient mice where no PA-induced hepatotoxicity was observed. Therefore, toxic metabolites of senecionine are generated by hepatic CYPs, and may be partially released from hepatocytes leading to destruction of LSECs in the pericentral region of the liver lobules. Analysis of hepatic bile salt transport by intravital two-photon imaging revealed a delayed uptake of a fluorescent bile salt analogue from the hepatic sinusoids into hepatocytes and delayed elimination. This was accompanied by transcriptional deregulation of hepatic bile salt transporters like Abcb11 or Abcc1. In conclusion, senecionine destroys LSECs although the toxic metabolite is formed in a CYP-dependent manner in the adjacent pericentral hepatocytes.
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Affiliation(s)
- Stefanie Hessel-Pras
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany.
| | - Albert Braeuning
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany
| | - Georgia Guenther
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystraße 67, Dortmund, Germany
| | - Alshaimaa Adawy
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystraße 67, Dortmund, Germany
| | - Anne-Margarethe Enge
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany
| | - Johanna Ebmeyer
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany
| | - Colin J Henderson
- Systems Medicine, Jacqui Wood Cancer Centre, University of Dundee, School of Medicine, James Arrott Drive, Ninewells Hospital, Dundee, UK
| | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystraße 67, Dortmund, Germany
| | - Alfonso Lampen
- Department Food Safety, German Federal Institute for Risk Assessment, Max-Dohrn-Str. 8-10, Berlin, Germany
| | - Raymond Reif
- Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystraße 67, Dortmund, Germany
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19
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Xu J, Wang W, Yang X, Xiong A, Yang L, Wang Z. Pyrrolizidine alkaloids: An update on their metabolism and hepatotoxicity mechanism. LIVER RESEARCH 2019. [DOI: 10.1016/j.livres.2019.11.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/15/2023]
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20
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Fujii Y, Doi M, Tsukiyama N, Hattori Y, Ohya K, Shiroma N, Morio K, Morioka T, Aikata H, Shinozaki K, Chayama K. Sinusoidal obstruction syndrome post-treatment with trastuzumab emtansine (T-DM1) in advanced breast cancer. Int Cancer Conf J 2019; 9:18-23. [PMID: 31950012 DOI: 10.1007/s13691-019-00392-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 10/08/2019] [Indexed: 12/21/2022] Open
Abstract
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for use in the treatment of human epidermal growth factor receptor 2-positive metastatic breast cancer. Here, we present the cases of two patients with metastatic breast cancer who received T-DM1 monotherapy and developed noncirrhotic portal hypertension (NCPH). Patient 1 presented with ruptured gastric varices at 2 years and 5 months after T-DM1 treatment. Patient 2 presented with intrahepatic portal-hepatic venous shunt at 2 years and 6 months and portal-systemic shunt encephalopathy at 4 years and 11 months after T-DM1 treatment. In both the patients, liver biopsies revealed sinusoidal obstruction syndrome (SOS). T-DM1-induced hepatotoxicity can result from SOS. In long-term administration of T-DM1 the unfavorable events associated with chronic liver circulatory disorder due to SOS, such as NCPH, are concerning.
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Affiliation(s)
- Yasutoshi Fujii
- 1Division of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima, 734-8530 Japan
| | - Mihoko Doi
- 1Division of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima, 734-8530 Japan
| | - Naofumi Tsukiyama
- 1Division of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima, 734-8530 Japan
| | - Yui Hattori
- 2Department of Pathology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima, 734-8530 Japan
| | - Kazuki Ohya
- 3Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Noriyuki Shiroma
- 4Department of Pathology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Kei Morio
- 3Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Takehiko Morioka
- 1Division of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima, 734-8530 Japan
| | - Hiroshi Aikata
- 3Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Katsunori Shinozaki
- 1Division of Clinical Oncology, Hiroshima Prefectural Hospital, 1-5-54 Ujinakanda, Minami-ku, Hiroshima, 734-8530 Japan
| | - Kazuaki Chayama
- 3Department of Gastroenterology and Metabolism, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
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21
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Hong EK, Joo I, Park J, Lee K. Assessment of hepatic sinusoidal obstruction syndrome with intravoxel incoherent motion diffusion-weighted imaging: An experimental study in a rat model. J Magn Reson Imaging 2019; 51:81-89. [PMID: 31094055 DOI: 10.1002/jmri.26790] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Revised: 04/29/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) parameters may reflect perfusion and diffusion changes in hepatic sinusoidal obstruction syndrome (SOS). PURPOSE To investigate the feasibility of IVIM-DWI in the noninvasive assessment of hepatic SOS in an experimental rat model. STUDY TYPE Animal study. POPULATION/SUBJECTS Forty-four rats were administered different doses (90 or 160 mg/kg) of monocrotaline by gavage either 48 or 72 hours before MRI to induce different degrees of hepatic SOS, and another 10 rats served as controls. FIELD STRENGTH/SEQUENCE 3T scanner, IVIM-DWI using nine b values (0-800 sec/mm2 ). ASSESSMENT Histologically, rats were classified as having none (n = 10), mild (n = 8), moderate (n = 19), or severe SOS (n = 17). The apparent diffusion coefficient (ADC) and IVIM-derived parameters (D: true diffusion coefficient, D*: pseudo-diffusion coefficient, and f: perfusion fraction) of the liver parenchyma were measured. STATISTICAL TESTS IVIM-DWI parameters were compared according to histologic grades of SOS (none, mild, moderate, and severe), and receiver operating characteristic (ROC) curve analysis was performed to determine the diagnostic accuracy. RESULTS ADC, D, and f of the liver parenchyma were significantly different according to SOS severity groups (Ps < 0.01) and significantly decreased as SOS severity increased (rho = -0.323, -0.313, and -0.700; P = 0.017, 0.021, and <0.001, respectively). Means of f in none, mild, moderate, and severe SOS were 17.2%, 13.3%, 12.3%, and 11.1%, respectively. Among ADC and IVIM-derived parameters, f provided the highest area under the ROC curves for detecting ≥mild, ≥moderate, and severe SOS (0.991, 0.890, and 0.803, respectively). DATA CONCLUSION IVIM-DWI may be useful in the diagnosis and severity assessment of hepatic SOS. LEVEL OF EVIDENCE 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;51:81-89.
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Affiliation(s)
- Eun Kyoung Hong
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Ijin Joo
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Juil Park
- Department of Radiology, Seoul National University Hospital, Seoul, Korea.,Department of Radiology, Seoul National University College of Medicine, Seoul, Korea
| | - Kyoungbun Lee
- Department of Pathology, Seoul National University Hospital, Seoul, Korea
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22
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Lu Y, Ma J, Lin G. Development of a two-layer transwell co-culture model for the in vitro investigation of pyrrolizidine alkaloid-induced hepatic sinusoidal damage. Food Chem Toxicol 2019; 129:391-398. [PMID: 31054999 DOI: 10.1016/j.fct.2019.04.057] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 04/26/2019] [Accepted: 04/29/2019] [Indexed: 12/01/2022]
Abstract
Pyrrolizidine alkaloids (PAs) are hepatotoxic and specifically damage hepatic sinusoidal endothelial cells (HSECs) via cytochrome P450 enzymes (CYPs)-mediated metabolic activation. Due to the lack of CYPs in HSECs, currently there is no suitable cell model for investigating PA-induced HSEC injury. This study aimed to establish a two-layer transwell co-culture model that mimics hepatic environment by including HepaRG hepatocytes and HSECs to evaluate cytotoxicity of PAs on their major target HSECs. In this model, PAs were metabolically activated by CYPs in HepaRG hepatocytes to generate reactive pyrrolic metabolites, which react with co-cultured HSECs leading to HSEC damage. Three representative PAs, namely retrorsine, monocrotaline, and clivorine, induced significant concentration-dependent cytotoxicity in HSECs in the co-culture model, but did no cause obvious cytotoxicity directly in HSECs. Using the developed co-cultured model, further mechanism studies of retrorsine-induced HSEC damage demonstrated that the reactive pyrrolic metabolite generated by CYP-mediated bioactivation in HepaRG hepatocytes caused formation of pyrrole-protein adducts, reduction of GSH content, and generation of reactive oxygen species in HSECs, leading to cell apoptosis. The established co-culture model is reliable and applicable for cytotoxic assessment of PA-induced HSEC damage and offers a novel platform for screening toxicity of different PAs on their target cells.
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Affiliation(s)
- Yao Lu
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Jiang Ma
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
| | - Ge Lin
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.
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Sinusoidal obstruction syndrome in a paediatric patient with acute lymphoblastic leukaemia after completion of reinduction therapy according to ALL Intercontinental Berlin-Frankfurt-Münster 2009. Contemp Oncol (Pozn) 2019; 22:266-269. [PMID: 30783392 PMCID: PMC6377418 DOI: 10.5114/wo.2018.82646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Accepted: 11/23/2018] [Indexed: 12/23/2022] Open
Abstract
Sinusoidal obstruction syndrome (SOS), also termed veno-occlusive disease (VOD) of the liver, is a well-known complication of haematopoietic stem cell transplantation (HSCT) both in children and adults. In the medical literature there are occasional reports of SOS in patients receiving conventional chemotherapy. In children with solid tumours this entity occurs during treatment of nephroblastoma, rhabdomyosarcoma, and medulloblastoma. In the late 1990s SOS was quite often observed as the complication of oral 6-thioguanine (6-TG) in patients suffering from acute lymphoblastic leukaemia (ALL), who received 6-TG throughout maintenance. In current protocols, the syndrome has become uncommon because treatment with 6-TG is limited to two weeks of oral therapy. Here, we report a case of a nine-year-old boy with ALL, who developed sinusoidal obstruction syndrome shortly after completing the reinduction block of chemotherapy (cyclophosphamide, cytarabine, thioguanine) according to the ALL Intercontinental Berlin-Frankfurt-Münster 2009 (ALL IC BFM 2009) treatment protocol.
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McDonald GB, Freston JW, Boyer JL, DeLeve LD. Liver Complications Following Treatment of Hematologic Malignancy With Anti-CD22-Calicheamicin (Inotuzumab Ozogamicin). Hepatology 2019; 69:831-844. [PMID: 30120894 PMCID: PMC6351187 DOI: 10.1002/hep.30222] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Accepted: 08/14/2018] [Indexed: 02/06/2023]
Abstract
Treatment of hematological malignancy with antibody-drug conjugates (ADCs) may cause liver injury. ADCs deliver a toxic moiety into antigen-expressing tumor cells, but may also injure hepatic sinusoids (sinusoidal obstruction syndrome; SOS). We studied patients who received an anti-CD22/calicheamicin conjugate (inotuzumab ozogamicin; InO) to gain insight into mechanisms of sinusoidal injury, given that there are no CD22+ cells in the normal liver, but nonspecific uptake of ADCs by liver sinusoidal endothelial cells (LSECs). Six hundred thirty-eight patients (307 with acute lymphocytic leukemia [ALL], 311 with non-Hodgkin's lymphoma [NHL]) were randomized to either InO or standard chemotherapy (controls). While blinded to treatment assignment, we reviewed all cases with hepatobiliary complications to adjudicate the causes. Frequency of SOS among patients who received InO was 5 of 328 (1.5%), compared to no cases among 310 control patients. Drug-induced liver injury (DILI) developed in 26 (7.9%) InO recipients and 3 (1%) controls. Intrahepatic cholestasis (IHC) was observed in 4.9% of InO recipients and in 5.5% of controls. Subsequent to the randomization study, 113 patients with ALL underwent allogeneic hematopoietic cell transplantation (HCT); frequency of SOS in those previously exposed to InO was 21 of 79 (27%) versus 3 of 34 (9%) in controls. An exploratory multivariate model identified a past history of liver disease and thrombocytopenia before conditioning therapy as dominant risk factors for SOS after transplant. Conclusion: Frequencies of SOS and DILI after inotuzumab ozogamicin treatment were 1.5% and 7.9%, respectively, compared to none and 1% among controls who received standard chemotherapy. These data suggest that ADCs that do not target antigens present in the normal liver have a relatively low frequency of SOS, but a relatively high frequency of DILI.
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Kumar A, Palek R, Liska V. A Critical Analysis of Experimental Animal Models of Sinusoidal Obstruction Syndrome. J Clin Exp Hepatol 2019; 9:345-353. [PMID: 31360027 PMCID: PMC6637067 DOI: 10.1016/j.jceh.2018.07.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/07/2018] [Indexed: 02/08/2023] Open
Abstract
Given the high mortality rate and clinical impact associated with sinusoidal obstruction syndrome (SOS), many studies have attempted to better characterize the disease and potential treatment strategies. However, the unpredictability of SOS onset represents a major obstacle when developing reproducible and controlled clinical trials in humans. Similarly, although in vitro studies have elucidated many of the molecular and cellular mechanisms of SOS, they often lack clinical relevance and translatability, highlighting the importance of experimental in vivo research. Animal models have greatly varied in the approach used to induce SOS in accordance with the numerous causes of human disease. Thus far, the most common and prevalent model is the monocrotaline-induced model in rats, which has served as the basis for both new diagnostic and treatment studies and has been revised over the last 20 years to optimize its use. Furthermore, radiotherapy, oxaliplatin-based chemotherapy, and even hematopoietic stem cell transplantation have been recently used to better replicate human SOS in animals. Nevertheless, because of the novelty of such research, further studies should be conducted to better understand the reproducibility and applicability of these newer models. Thus, this review seeks to summarize the methods and results of experimental in vivo models of SOS and compare the efficacy of these various adaptations.
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Key Words
- BM SPC, Bone Marrow Endothelial Progenitor Cell
- CRLM, Colorectal Liver Metastases
- CV, Central Vein
- HSCT, Hematopoietic Stem Cell Transplantation
- HVOD, Hepatic Veno-Occlusive Disease
- MCT, Monocrotaline
- MMP-9, Matrix Metalloproteinase-9
- NO, Nitric Oxide
- PA, Pyrrolizidine Alkaloid
- RILD, Radiation-Induced Liver Disease
- SEC, Sinusoidal Endothelial Cell
- SOS, Sinusoidal Obstruction Syndrome
- blue liver disease
- in vivo
- monocrotaline
- oxaliplatin
- veno-occlusive disease
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Affiliation(s)
- Arvind Kumar
- Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Pilsen, Czech Republic,Department of Surgery, Charles University, Faculty of Medicine in Pilsen, Teaching Hospital Pilsen, Pilsen, Czech Republic
| | - Richard Palek
- Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Pilsen, Czech Republic,Department of Surgery, Charles University, Faculty of Medicine in Pilsen, Teaching Hospital Pilsen, Pilsen, Czech Republic
| | - Vaclav Liska
- Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Pilsen, Czech Republic,Department of Surgery, Charles University, Faculty of Medicine in Pilsen, Teaching Hospital Pilsen, Pilsen, Czech Republic,Address for correspondence: Vaclav Liska, Biomedical Center, Charles University, Faculty of Medicine in Pilsen, Alej Svobody 1655/76 323 00, Pilsen, Czech Republic.
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El-Serafi I, Remberger M, El-Serafi A, Benkessou F, Zheng W, Martell E, Ljungman P, Mattsson J, Hassan M. The effect of N-acetyl-l-cysteine (NAC) on liver toxicity and clinical outcome after hematopoietic stem cell transplantation. Sci Rep 2018; 8:8293. [PMID: 29844459 PMCID: PMC5974141 DOI: 10.1038/s41598-018-26033-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 05/03/2018] [Indexed: 02/06/2023] Open
Abstract
UNLABELLED Busulphan (Bu) is a myeloablative drug used for conditioning prior to hematopoietic stem cell transplantation. Bu is predominantly metabolized through glutathione conjugation, a reaction that consumes the hepatic glutathione. N-acetyl-l-cysteine (NAC) is a glutathione precursor used in the treatment of acetaminophen hepatotoxicity. NAC does not interfere with the busulphan myeloablative effect. We investigated the effect of NAC concomitant treatment during busulphan conditioning on the liver enzymes as well as the clinical outcome. Prophylactic NAC treatment was given to 54 patients upon the start of busulphan conditioning. These patients were compared with 54 historical matched controls who did not receive NAC treatment. In patients treated with NAC, aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were significantly (P < 0.05) decreased after conditioning compared to their start values. Within the NAC-group, liver enzymes were normalized in those patients (30%) who had significantly high start values. No significant decrease in enzyme levels was observed in the control group. Furthermore, NAC affected neither Bu kinetics nor clinical outcome (sinusoidal obstruction syndrome incidence, graft-versus-host disease and/or graft failure). IN CONCLUSION NAC is a potential prophylactic treatment for hepatotoxicity during busulphan conditioning. NAC therapy did not alter busulphan kinetics or affect clinical outcome.
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Affiliation(s)
- Ibrahim El-Serafi
- ECM, KFC, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
| | - Mats Remberger
- Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Ahmed El-Serafi
- ECM, KFC, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
- College of Medicine, University of Sharjah, Sharjah, UAE
| | - Fadwa Benkessou
- ECM, KFC, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Wenyi Zheng
- ECM, KFC, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Eva Martell
- Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - Per Ljungman
- Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
| | - Jonas Mattsson
- Center for Allogeneic Stem Cell Transplantation, Karolinska University Hospital, Stockholm, Sweden
- Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Moustapha Hassan
- ECM, KFC, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
- Experimental Cancer Medicine, Clinical Research Center, Karolinska University Hospital, Huddinge, Sweden.
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Jing X, Zhang J, Huang Z, Sheng Y, Ji L. The involvement of Nrf2 antioxidant signalling pathway in the protection of monocrotaline-induced hepatic sinusoidal obstruction syndrome in rats by (+)-catechin hydrate. Free Radic Res 2018; 52:402-414. [DOI: 10.1080/10715762.2018.1437914] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Xiaoqi Jing
- MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiaqi Zhang
- MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zhenlin Huang
- MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuchen Sheng
- Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lili Ji
- MOE Key Laboratory for Standardization of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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DeLeve LD. Hepatic Venoocclusive Disease: A Major Complication of Hematopoietic Stem Cell Transplantation in Cancer Patients. TUMORI JOURNAL 2018. [DOI: 10.1177/030089160108700224] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Laurie D DeLeve
- University of Southern California, Keck School of Medicine, Division of Gastrointestinal and Liver Diseases, Los Angeles, USA
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Li YH, Tai WCS, Khan I, Lu C, Lu Y, Wong WY, Chan WY, Wendy Hsiao WL, Lin G. Toxicoproteomic assessment of liver responses to acute pyrrolizidine alkaloid intoxication in rats. JOURNAL OF ENVIRONMENTAL SCIENCE AND HEALTH. PART C, ENVIRONMENTAL CARCINOGENESIS & ECOTOXICOLOGY REVIEWS 2018; 36:65-83. [PMID: 29667502 DOI: 10.1080/10590501.2018.1450186] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
A toxicoproteomic study was performed on liver of rats treated with retrorsine (RTS), a representative hepatotoxic pyrrolizidine alkaloid at a toxic dose (140 mg/kg) known to cause severe acute hepatotoxicity. By comparing current data with our previous findings in mild liver lesions of rats treated with a lower dose of RTS, seven proteins and three toxicity pathways of vascular endothelial cell death, which was further verified by observed sinusoidal endothelial cell losses, were found uniquely associated with retrorsine-induced hepatotoxicity. This toxicoproteomic study of acute pyrrolizidine alkaloid intoxication lays a foundation for future investigation to delineate molecular mechanisms of pyrrolizidine alkaloid-induced hepatotoxicity.
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Affiliation(s)
- Yan-Hong Li
- a School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR, China
- b School of Medicine , South China University of Technology , Guangzhou , China
| | - William Chi-Shing Tai
- c Department of Applied Biology and Chemical Technology , The Hong Kong Polytechnic University , Hong Kong SAR, China
| | - Imran Khan
- d State Key Laboratory of Quality Research in Chinese Medicines , Macau University of Science and Technology , Macau SAR, China
| | - Cheng Lu
- e Institute of Basic Research in Clinical Medicine , China Academic of Chinese Medical Sciences , Beijing , China
| | - Yao Lu
- a School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR, China
| | - Wing-Yan Wong
- c Department of Applied Biology and Chemical Technology , The Hong Kong Polytechnic University , Hong Kong SAR, China
| | - Wood-Yee Chan
- a School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR, China
| | - Wen-Luan Wendy Hsiao
- d State Key Laboratory of Quality Research in Chinese Medicines , Macau University of Science and Technology , Macau SAR, China
| | - Ge Lin
- a School of Biomedical Sciences, Faculty of Medicine , The Chinese University of Hong Kong , Hong Kong SAR, China
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Mansour SA, Abbassy MA, Shaldam HA. Zinc Ameliorate Oxidative Stress and Hormonal Disturbance Induced by Methomyl, Abamectin, and Their Mixture in Male Rats. TOXICS 2017; 5:toxics5040037. [PMID: 29207507 PMCID: PMC5750565 DOI: 10.3390/toxics5040037] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Revised: 11/28/2017] [Accepted: 11/30/2017] [Indexed: 12/31/2022]
Abstract
Exposure to mixtures of toxicants (e.g., pesticides) is common in real life and a subject of current concern. The present investigation was undertaken to assess some toxicological effects in male rats following exposure to methomyl (MET), abamectin (ABM), and their combination (MET+ABM), and to evaluate the ameliorative effect of zinc co-administration. Three groups of rats were designated for MET, ABM, and the mixture treatments. Three other groups were designated for zinc in conjunction with the pesticides. Additionally, one group received water only (control), and the other represented a positive zinc treatment. The obtained results revealed that MET was acutely more toxic than ABM. The tested pesticides induced significant elevation in lipid peroxidation and catalase levels, while declined the levels of the other tested parameters e.g., Superoxide dismutase (SOD), Glutathione-S-transferase (GST), Glutathione peroxidase (GPx), Glutathione reductase (GR), Cytochrome P450 (CYP450), testosterone, and thyroxine). Biochemical alterations induced by the mixture were greater than those recorded for each of the individual insecticides. The joint action analysis, based on the obtained biochemical data, revealed the dominance of antagonistic action among MET and ABM. Zinc supplementation achieved noticeable ameliorative effects. It was concluded that zinc may act as a powerful antioxidant, especially in individuals who are occupationally exposed daily to low doses of such pesticides.
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Affiliation(s)
- Sameeh A Mansour
- Environmental Toxicology Research Unit (ETRU), Pesticide Chemistry Department, National Research Centre, Dokki, Giza 12311, Egypt.
| | - Mostafa A Abbassy
- Department of Pest Control and Environmental Protection, Faculty of Agriculture, Damanhour University, Behira, Egypt.
| | - Hassan A Shaldam
- Department of Pest Control and Environmental Protection, Faculty of Agriculture, Damanhour University, Behira, Egypt.
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31
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Huang Z, Chen M, Zhang J, Sheng Y, Ji L. Integrative analysis of hepatic microRNA and mRNA to identify potential biological pathways associated with monocrotaline-induced liver injury in mice. Toxicol Appl Pharmacol 2017; 333:35-42. [PMID: 28818515 DOI: 10.1016/j.taap.2017.08.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Revised: 08/05/2017] [Accepted: 08/11/2017] [Indexed: 01/22/2023]
Abstract
Pyrrolizidine alkaloids (PAs) are a type of natural hepatotoxic compounds. Monocrotaline (MCT), belongs to PAs, is a main compound distributed in medicinal herb Crotalaria ferruginea Grah. ex Benth. This study aims to identify the potential biological signaling pathway associated with MCT-induced liver injury by analyzing the integrative altered hepatic microRNA (miRNA) and mRNA expression profile. C57BL/6 mice were orally given with MCT (270, 330mg/kg). Serum alanine/aspartate aminotransferase (ALT/AST) activity, total bilirubin (TBil) amount and liver histological evaluation showed the liver injury induced by MCT. Results of miRNA chip analysis showed that the hepatic expression of 15 miRNAs (whose signal intensity>200) was significantly altered in MCT-treated mice, and among them total 11 miRNAs passed further validation by using Real-time PCR assay. Results of mRNA chip analysis demonstrated that the hepatic expression of 569 genes was up-regulated and of other 417 genes was down-regulated in MCT-treated mice. There are total 426 predicted target genes of those above altered 11 miRNAs, and among them total 10 genes were also altered in mice treated with both MCT (270mg/kg) and MCT (330mg/kg) from the results of mRNA chip. Among these above 10 genes, total 8 genes passed further validation by using Real-time PCR assay. Only 1 biological signaling pathway was annotated by using those above 8 genes, which is phagosome. In conclusion, this study demonstrated the integrative altered expression profile of liver miRNA and mRNA, and identified that innate immunity may be critically involved in MCT-induced liver injury in mice.
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Affiliation(s)
- Zhenlin Huang
- Shanghai Key Laboratory for Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Minwei Chen
- Shanghai Key Laboratory for Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jiaqi Zhang
- Shanghai Key Laboratory for Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yuchen Sheng
- Center for Drug Safety Evaluation and Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ji
- Shanghai Key Laboratory for Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines, and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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López-Gil S, Nuño-Lámbarri N, Chávez-Tapia N, Uribe M, Barbero-Becerra VJ. Liver toxicity mechanisms of herbs commonly used in Latin America. Drug Metab Rev 2017; 49:338-356. [PMID: 28571502 DOI: 10.1080/03602532.2017.1335750] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mexico owns approximately 4500 medicinal plants species, a great diversity that position it at the second place after China. According to the Mexican health department, 90% of common population consumes them to treat various diseases. Additionally, herbal remedies in Latin America (LA) are considered a common practice, but the frequency of use and the liver damage related to its consumption is still unknown. Despite the high prevalence and indiscriminate herbal consumption, the exact mechanism of hepatotoxicity and adverse effects is not fully clarified and is still questioned. Some herb products associated with herb induced liver injury (HILI) are characterized by presenting a different chemical composition that may vary from batch to batch, also the biological activity of many medicinal plants and other natural products are directly related to their most active component and its concentration. There are two main biological components that are associated with liver damage, alkaloids, and flavonoids, which are frequent constituents of commonly used herbs. The interaction with the different cytochrome P-450 isoforms, inflammatory, and oxidative activities seem to be the main damage pathway involved in the liver. It is important to know the herbal adverse effects and mechanisms involved; therefore, this article is focused on the beneficial and deleterious effects as well as the possible toxicity mechanisms and interactions of the herbs that are frequently used in LA, since the herb-host interaction may not always be the expected or desired depending on the clinical context in which it is administered.
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Affiliation(s)
- Sofía López-Gil
- a Translational Research Unit , Medica Sur Clinic & Foundation , Mexico City , Mexico.,b Universidad Popular Autónoma del Estado de Puebla , Puebla , Mexico
| | - Natalia Nuño-Lámbarri
- a Translational Research Unit , Medica Sur Clinic & Foundation , Mexico City , Mexico
| | - Norberto Chávez-Tapia
- a Translational Research Unit , Medica Sur Clinic & Foundation , Mexico City , Mexico.,c Obesity and Digestive Diseases Unit , Medica Sur Clinic & Foundation , Mexico City , Mexico
| | - Misael Uribe
- c Obesity and Digestive Diseases Unit , Medica Sur Clinic & Foundation , Mexico City , Mexico
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Von Willebrand Factor Deposition and ADAMTS-13 Consumption in Allograft Tissue of Thrombotic Microangiopathy-like Disorder After Living Donor Liver Transplantation: A Case Report. Transplant Proc 2017; 49:1596-1603. [PMID: 28651806 DOI: 10.1016/j.transproceed.2017.02.047] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Revised: 02/03/2017] [Accepted: 02/20/2017] [Indexed: 01/06/2023]
Abstract
BACKGROUND Thrombotic microangiopathy (TMA) pathogenesis after living donor liver transplantation (LDLT) is thought to be caused by release of unusually large von Willebrand factor multimers (UL-vWFMs) resulting from sinusoidal endothelial cell damage and induction of platelet adhesion and aggregation. A decrease in a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13 (ADAMTS-13) that cleave UL-vWFMs might cause excessive UL-vWFMs activity and result in platelet thrombus formation. However, this phenomenon has not undergone a full pathologic assessment. PROCEDURES A 60-year-old man was diagnosed with hepatitis C-related end-stage cirrhosis. His son was the donor, and he underwent LDLT. On postoperative day 44, his laboratory findings met most TMA diagnostic criteria, and he was diagnosed with TMA-like disorder (TMALD). Localization of CD42b as a platelet marker, vWF, and ADAMTS-13 in allograft tissue of this patient were evaluated using immunohistochemistry. RESULTS CD42b expression was observed as platelet aggregates attached to hepatocytes or within the hepatocyte cytoplasm, a morphology called extravasated platelet aggregation (EPA). vWF expression was observed mainly as deposited compact clusters, and ADAMTS-13 expression resembled distinct dots throughout the liver tissue. CONCLUSION These findings suggest that EPA indicated sinusoidal endothelial cell damage followed by detachment, and vWF deposition resulted from UL-vWFM oversynthesis. ADAMTS-13 might be consumed in the allograft tissue to cleave UL-vWFMs, but ADAMTS-13 levels might be insufficient to cleave all the deposited UL-vWFMs. We present the case of an LDLT recipient diagnosed with TMALD using blood tests, which showed the presence of TMA pathogenesis in the allograft.
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Hepatic Issues and Complications Associated With Inflammatory Bowel Disease: A Clinical Report From the NASPGHAN Inflammatory Bowel Disease and Hepatology Committees. J Pediatr Gastroenterol Nutr 2017; 64:639-652. [PMID: 27984347 DOI: 10.1097/mpg.0000000000001492] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Hepatobiliary disorders are common in patients with inflammatory bowel disease (IBD), and persistent abnormal liver function tests are found in approximately 20% to 30% of individuals with IBD. In most cases, the cause of these elevations will fall into 1 of 3 main categories. They can be as a result of extraintestinal manifestations of the disease process, related to medication toxicity, or the result of an underlying primary hepatic disorder unrelated to IBD. This latter possibility is beyond the scope of this review article, but does need to be considered in anyone with elevated liver function tests. This review is provided as a clinical summary of some of the major hepatic issues that may occur in patients with IBD.
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Restellini S, Chazouillères O, Frossard JL. Hepatic manifestations of inflammatory bowel diseases. Liver Int 2017; 37:475-489. [PMID: 27712010 DOI: 10.1111/liv.13265] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 09/27/2016] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel diseases are associated with various hepatobiliary disorders, reported both in Crohn's disease and ulcerative colitis. They may occur at any moment in the natural course of the disease. The prevalence of liver dysfunction rises from 3% to 50% accordingly to definitions used in different studies. Fatty liver is considered as the most common hepatobiliary complication in inflammatory bowel diseases while primary sclerosing cholangitis is the most specific one. Less frequently, inflammatory bowel diseases-associated hepatobiliary disorders include: autoimmune hepatitis/ primary sclerosing cholangitis overlap syndrome, IgG4-associated cholangiopathy, primary biliary cholangitis, hepatic amyloidosis, granulomatous hepatitis, cholelithiasis, portal vein thrombosis and liver abscess. The spectrum of these manifestations varies according to the type of inflammatory bowel diseases. Treatments of inflammatory bowel diseases may cause liver toxicity, although incidence of serious complications remains low. However, early diagnosis of drug-induced liver injury is of major importance as it affects future clinical management. When facing abnormal liver tests, clinicians should undertake a full diagnostic work-up in order to determine whether the hepatic abnormalities are related to the inflammatory bowel diseases or not. Management of hepatic manifestations in inflammatory bowel diseases usually involves both hepatologists and gastroenterologists because of the complexity of some situations.
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Affiliation(s)
- Sophie Restellini
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
| | - Olivier Chazouillères
- Division d'Hépatologie, Centre de Référence des Maladies Inflammatoires des Voies Biliaires, et Université de Sorbonne, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Paris, France
| | - Jean-Louis Frossard
- Service de Gastroentérologie et Hépatologie, Hôpitaux Universitaires de Genève, Genève, Suisse
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Abstract
Sinusoidal obstruction syndrome (SOS) is characterized by damage to small hepatic vessels affecting particularly sinusoidal endothelium. Damaged sinusoids can be associated with a partial or complete occlusion of small hepatic veins, hence the previous denomination of hepatic veno-occlusive disease (VOD). Exposure to certain exogenous toxins appears to be specific to this condition and is frequently included in its definition. Typical histopathological features of SOS in a liver biopsy specimen are presented in the text. The purpose of this article is to provide an overview on the different entities corresponding to this general definition. Such entities include: (i) liver disease related to pyrrolizidine alcaloids; (ii) liver injury related to conditioning for hematopoietic stem cell transplantation; (iii) vascular liver disease occurring in patients treated with chemotherapy for liver metastasis of colorectal cancer; and (iv) other liver diseases related to toxic agents.
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van Mierlo KM, Zhao J, Kleijnen J, Rensen SS, Schaap FG, Dejong CH, Olde Damink SW. The influence of chemotherapy-associated sinusoidal dilatation on short-term outcome after partial hepatectomy for colorectal liver metastases: A systematic review with meta-analysis. Surg Oncol 2016; 25:298-307. [DOI: 10.1016/j.suronc.2016.05.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Accepted: 05/30/2016] [Indexed: 12/14/2022]
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Glutathione Transferase Gene Variants Influence Busulfan Pharmacokinetics and Outcome After Myeloablative Conditioning. Ther Drug Monit 2016; 37:493-500. [PMID: 25565670 PMCID: PMC4505914 DOI: 10.1097/ftd.0000000000000180] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Supplemental Digital Content is Available in the Text. Background: Busulfan (Bu) and cyclophosphamide (Cy) are frequently included in conditioning regimens before hematopoietic stem cell transplantation (HSCT). Both drugs are detoxified by glutathione transferases (GST), and GST gene variants may explain some of the interindividual variability in pharmacokinetics and drug toxicity. Methods: The study investigated adult patients (n = 114) receiving oral Bu pre-HSCT. Bu doses were adjusted to obtain an average steady-state concentration (Css) of 900 mcg/L. Results: Median first dose Bu Css was 1000 mcg/L (600–1780 mcg/L). Patients carrying 1 and 2 GSTA1*B (rs3957357) alleles demonstrated median 12% and 16% higher Bu Css (P ≤ 0.05). Bu exposure (average Css; odds ratio = 1.009, 95% confidence interval = 1.002–1.017, P = 0.013) and GSTM1 gene copy number (odds ratio = 17.1, 95% confidence interval = 1.46–201, P = 0.024) were significant predictors of mortality ≤30 days. The mortality was 25% versus 2% among carriers of 2 versus no GSTM1 copies (P = 0.021). Mortality ≤3 months was associated with higher first dose Bu exposure (1090 versus 980 mcg/L, P = 0.021). GSTM1 expression and high Bu exposure may increase Cy toxicity by reducing intracellular glutathione. Conclusions: GST genotyping before HSCT may allow better prediction of Bu pharmacokinetics and drug toxicity, and thereby improve outcome after BuCy conditioning.
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Koo SX, Chan SH, Ngeow J. Genetic predisposition resulting in sinusoidal obstruction syndrome in a patient with resected sigmoid cancer on adjuvant oxaliplatin. BMJ Case Rep 2016; 2016:bcr-2015-212978. [PMID: 26729828 DOI: 10.1136/bcr-2015-212978] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
A Chinese man who had undergone a curative high anterior resection for sigmoid cancer was administrated XELOX (capecitabine and oxaliplatin) as postoperative adjuvant chemotherapy. He subsequently developed sinusoidal obstruction syndrome (SOS) that resolved on discontinuation of XELOX treatment. Genetic evaluation determined that he had the GSTT1-null and GSTM1-null genotype, known to be an independent risk factor for developing oxaliplatin-induced SOS.
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Affiliation(s)
- Si Xuan Koo
- Department of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore
| | | | - Joanne Ngeow
- National Cancer Centre Singapore, Singapore, Singapore
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EXP CLIN TRANSPLANTExp Clin Transplant 2015; 13. [DOI: 10.6002/ect.2015.0063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Sørensen KK, Simon‐Santamaria J, McCuskey RS, Smedsrød B. Liver Sinusoidal Endothelial Cells. Compr Physiol 2015; 5:1751-74. [DOI: 10.1002/cphy.c140078] [Citation(s) in RCA: 156] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Yang M, Ruan J, Fu PP, Lin G. Cytotoxicity of pyrrolizidine alkaloid in human hepatic parenchymal and sinusoidal endothelial cells: Firm evidence for the reactive metabolites mediated pyrrolizidine alkaloid-induced hepatotoxicity. Chem Biol Interact 2015; 243:119-26. [PMID: 26365561 DOI: 10.1016/j.cbi.2015.09.011] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Revised: 08/20/2015] [Accepted: 09/08/2015] [Indexed: 02/07/2023]
Abstract
Pyrrolizidine alkaloids (PAs) widely distribute in plants and can cause hepatic sinusoidal obstruction syndrome (HSOS), which typically presents as a primary sinusoidal endothelial cell damage. It is well-recognized that after ingestion, PAs undergo hepatic cytochromes P450 (CYPs)-mediated metabolic activation to generate dehydropyrrolizidine alkaloids (DHPAs), which are hydrolyzed to dehydroretronecine (DHR). DHPAs and DHR are reactive metabolites having same core pyrrole moiety, and can bind proteins to form pyrrole-protein adducts, which are believed as the primary cause for PA-induced HSOS. However, to date, the direct evidences supporting the toxicity of DHPAs and DHR in the liver, in particular in the sinusoidal endothelial cells, are lacking. Using human hepatic sinusoidal endothelial cells (HSEC) and HepG2 (representing hepatic parenchymal cells), cells that lack CYPs activity, this study determined the direct cytotoxicity of dehydromonocrotaline, a representative DHPA, and DHR, but no cytotoxicity of the intact PA (monocrotaline) in both cell lines, confirming that reactive metabolites mediate PA intoxication. Comparing with HepG2, HSEC had significantly lower basal glutathione (GSH) level, and was significantly more susceptible to the reactive metabolites with severer GSH depletion and pyrrole-protein adducts formation. The toxic potency of two reactive metabolites was also compared. DHPA was more reactive than DHR, leading to severer toxicity. In conclusion, our results unambiguously provided the first direct evidence for the critical role of DHPA and DHR in the reactive metabolites-mediated PA-induced hepatotoxicity, which occurs predominantly in HSEC due to severe GSH depletion and the significant formation of pyrrole-protein adducts in HSEC.
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Affiliation(s)
- Mengbi Yang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines Between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China
| | - Jianqing Ruan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines Between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China
| | - Peter P Fu
- National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
| | - Ge Lin
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region; Joint Research Laboratory for Promoting Globalization of Traditional Chinese Medicines Between The Chinese University of Hong Kong and Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China.
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Al-Johany AM, Al-Sadoon MK, Abdel Moneim AE, Bauomy AA, Diab MS. Histological, molecular and biochemical detection of renal injury after Echis pyramidum snake envenomation in rats. Saudi J Biol Sci 2015; 22:302-11. [PMID: 25972751 PMCID: PMC4423722 DOI: 10.1016/j.sjbs.2014.10.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 10/13/2014] [Accepted: 10/14/2014] [Indexed: 01/24/2023] Open
Abstract
Nephrotoxicity is a common sign of snake envenomation. The present work aimed to clarify the effect of intraperitoneal injection of 1/8 LD50 and 1/4 LD50 doses of Echis pyramidum snake venom on the renal tissue of rats after 2, 4 and 6 h from envenomation. Histopathological examination showed intense dose and time dependent abnormalities, including swelling glomerulus and tubular necrosis and damage as well as signs of intertubular medullary hemorrhage at early stages of envenomation. However, at late stages of envenomation by any of the doses under investigation, no intact renal corpuscles were recorded and complete lysis in renal corpuscles with ruptured Bowman's capsules was observed. Immunohistochemistry by immunohistochemical staining was used to test the protein expression of Bax in renal tissue of rats. The result showed that the expression of Bax in renal tissue sections of envenomated rats was increased according to dose and time-dependant manner. The isolation of DNA from the renal cells of envenomed rats pointed out to the occurrence of DNA fragmentation, which is another indicator for renal tissue injury especially after 6 h of 1/4 LD50 of E. pyramidum envenomation. Oxidative stress biomarkers malondialdehyde and nitrite/nitrate levels, antioxidant parameters; glutathione, total antioxidant capacity and catalase were assayed in renal tissue homogenates. The venom induced significant increase in the levels of malondialdehyde and nitrite/nitrate while the levels of glutathione, total antioxidant capacity and catalase were significantly decreased, especially after 6 h of envenomation. The results revealed that the E. pyramidum induced dose and time-dependant significant disturbances in the physiological parameters in the kidney. We conclude that the use of the immunohistochemical techniques, the detection of DNA integrity and oxidative stress marker estimations are more specific tools that can clarify cellular injury and could point out to the defense activity of the renal tissue at envenomation.
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Affiliation(s)
- Awadh M. Al-Johany
- Department of Zoology, College of Science, King Saud University, Saudi Arabia
| | | | - Ahmed E. Abdel Moneim
- Department of Zoology & Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Amira A. Bauomy
- Department of Zoology & Entomology, Faculty of Science, Helwan University, Cairo, Egypt
| | - Marwa S.M. Diab
- Department of Zoology & Entomology, Faculty of Science, Helwan University, Cairo, Egypt
- Molecular Drug Evaluation Department, National Organization for Drug Control & Research (NODCAR), Giza, Egypt
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Kumaran D, Rupa D, Haresh K, Gupta S, Sharma D, Rath G. Oxaliplatin induced pulmonary toxicity—a rare phenomenon. ACTA ACUST UNITED AC 2015. [DOI: 10.1016/j.ctrc.2015.11.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Edgar JA, Molyneux RJ, Colegate SM. Pyrrolizidine Alkaloids: Potential Role in the Etiology of Cancers, Pulmonary Hypertension, Congenital Anomalies, and Liver Disease. Chem Res Toxicol 2014; 28:4-20. [PMID: 25483859 DOI: 10.1021/tx500403t] [Citation(s) in RCA: 155] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Large outbreaks of acute food-related poisoning, characterized by hepatic sinusoidal obstruction syndrome, hemorrhagic necrosis, and rapid liver failure, occur on a regular basis in some countries. They are caused by 1,2-dehydropyrrolizidine alkaloids contaminating locally grown grain. Similar acute poisoning can also result from deliberate or accidental consumption of 1,2-dehydropyrrolizidine alkaloid-containing herbal medicines, teas, and spices. In recent years, it has been confirmed that there is also significant, low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids in many countries due to consumption of common foods such as honey, milk, eggs, salads, and meat. The level of 1,2-dehydropyrrolizidine alkaloids in these foods is generally too low and too intermittent to cause acute toxicity. However, these alkaloids are genotoxic and can cause slowly developing chronic diseases such as pulmonary arterial hypertension, cancers, cirrhosis, and congenital anomalies, conditions unlikely to be easily linked with dietary exposure to 1,2-dehydropyrrolizidine alkaloids, especially if clinicians are unaware that such dietary exposure is occurring. This Perspective provides a comprehensive review of the acute and chronic toxicity of 1,2-dehydropyrrolizidine alkaloids and their potential to initiate certain chronic diseases, and suggests some associative considerations or indicators to assist in recognizing specific cases of diseases that may have resulted from dietary exposure to these hazardous natural substances. If it can be established that low-level dietary exposure to 1,2-dehydropyrrolizidine alkaloids is a significant cause of some of these costly and debilitating diseases, then this should lead to initiatives to reduce the level of these alkaloids in the food chain.
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Affiliation(s)
- John A Edgar
- CSIRO Food and Nutrition , 11 Julius Avenue, North Ryde, NSW 2113, Australia
| | - Russell J Molyneux
- Daniel K. Inouye College of Pharmacy, University of Hawaii at Hilo , 34 Rainbow Drive, Hilo, Hawaii 96720, United States
| | - Steven M Colegate
- Poisonous Plant Research Laboratory, ARS/USDA , 1150 East 1400 North, Logan, Utah 84341, United States
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Fashe MM, Juvonen RO, Petsalo A, Rahnasto-Rilla M, Auriola S, Soininen P, Vepsäläinen J, Pasanen M. Identification of a New Reactive Metabolite of Pyrrolizidine Alkaloid Retrorsine: (3H-Pyrrolizin-7-yl)methanol. Chem Res Toxicol 2014; 27:1950-7. [DOI: 10.1021/tx5002964] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Muluneh M. Fashe
- School
of Pharmacy, Faculty
of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Risto O. Juvonen
- School
of Pharmacy, Faculty
of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Aleksanteri Petsalo
- School
of Pharmacy, Faculty
of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Minna Rahnasto-Rilla
- School
of Pharmacy, Faculty
of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Seppo Auriola
- School
of Pharmacy, Faculty
of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Pasi Soininen
- School
of Pharmacy, Faculty
of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Jouko Vepsäläinen
- School
of Pharmacy, Faculty
of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | - Markku Pasanen
- School
of Pharmacy, Faculty
of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
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Liu X, Zhong F, Tang XL, Lian FL, Zhou Q, Guo SM, Liu JF, Sun P, Hao X, Lu Y, Wang WM, Chen N, Zhang NX. Cordyceps sinensis protects against liver and heart injuries in a rat model of chronic kidney disease: a metabolomic analysis. Acta Pharmacol Sin 2014; 35:697-706. [PMID: 24632844 DOI: 10.1038/aps.2013.186] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 12/06/2013] [Indexed: 12/17/2022]
Abstract
AIM To test the hypothesis that the traditional Chinese medicine Cordyceps sinensis could improve the metabolic function of extrarenal organs to achieve its anti-chronic kidney disease (CKD) effects. METHODS Male SD rats were divided into CKD rats (with 5/6-nephrectomy), CKD rats treated with Cordyceps sinensis (4 mg•kg-1•d-1, po), and sham-operated rats. After an 8-week treatment, metabolites were extracted from the hearts and livers of the rats, and then subjected to (1)H-NMR-based metabolomic analysis. RESULTS Oxidative stress, energy metabolism, amino acid and protein metabolism and choline metabolism were considered as links between CKD and extrarenal organ dysfunction. Within the experimental period of 8 weeks, the metabolic disorders in the liver were more pronounced than in the heart, suggesting that CKD-related extrarenal organ dysfunctions occurred sequentially rather than simultaneously. Oral administration of Cordyceps sinensis exerted statistically significant rescue effects on the liver and heart by reversely regulating levels of those metabolites that are typically perturbed in CKD. CONCLUSION Oral administration of Cordyceps sinensis significantly attenuates the liver and heart injuries in CKD rats. The (1)H NMR-based metabolomic approach has provided a systematic view for understanding of CKD and the drug treatment, which can also be used to elucidate the mechanisms of action of other traditional Chinese medicines.
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Yao J, Li CG, Gong LK, Feng CC, Li CZ, Gao M, Luan Y, Qi XM, Ren J. Hepatic cytochrome P450s play a major role in monocrotaline-induced renal toxicity in mice. Acta Pharmacol Sin 2014; 35:292-300. [PMID: 24362331 DOI: 10.1038/aps.2013.145] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2013] [Accepted: 09/09/2013] [Indexed: 12/13/2022]
Abstract
AIM Monocrotaline (MCT) in plants of the genus Crotalaria induces significant toxicity in multiple organs including the liver, lung and kidney. Metabolic activation of MCT is required for MCT-induced toxicity. In this study, we attempted to determine whether the toxicity of MCT in kidney was a consequence of the metabolic activation of MCT in the liver. METHODS Liver-specific cytochrome P450 reductase-null (Null) mice, wild-type (WT) mice and CYP3A inhibitor ketoconazole-pretreated WT (KET-WT) mice were examined. The mice were injected with MCT (300, 400, or 500 mg/kg, ip), and hepatotoxicity and nephrotoxicity were examined 24 h after MCT treatment. The levels of MCT and its metabolites in the blood, liver, lung, kidney and bile were determined using LC-MS analysis. RESULTS Treatment of WT mice with MCT increased the serum levels of alanine aminotransferase, hyaluronic acid, urea nitrogen and creatinine in a dose-dependent manner. Histological examination revealed that MCT (500 mg/kg) caused severe liver injury and moderate kidney injury. In contrast, these pathological abnormalities were absent in Null and KET-WT mice. After injection of MCT (400 and 500 mg/kg), the plasma, liver, kidney and lung of WT mice had significantly lower MCT levels and much higher N-oxide metabolites contents in compared with those of Null and KET-WT mice. Furthermore, WT mice had considerably higher levels of tissue-bound pyrroles and bile GSH-conjugated MCT metabolites compared with Null and KET-WT mice. CONCLUSION Cytochrome P450s in mouse liver play a major role in the metabolic activation of MCT and thus contribute to MCT-induced renal toxicity.
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Li YH, Kan WLT, Li N, Lin G. Assessment of pyrrolizidine alkaloid-induced toxicity in an in vitro screening model. JOURNAL OF ETHNOPHARMACOLOGY 2013; 150:560-567. [PMID: 24045176 DOI: 10.1016/j.jep.2013.09.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/08/2013] [Revised: 05/30/2013] [Accepted: 09/05/2013] [Indexed: 06/02/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Pyrrolizidine alkaloids (PAs) are a group of heterocyclic phytotoxins present in a wide range of plants. The consumption of PA-containing medicinal herbs or PA-contaminated foodstuffs has long been reported to cause human hepatotoxicity. However, the degrees of hepatotoxicity of different PAs are unknown, which makes it difficult to determine a universal threshold of toxic dose of individual PAs for safe regulation of PA-containing natural products. The aim of the present study is to develop a simple and convenient in vitro model to assess the hepatotoxicity of different PAs. MATERIAL AND METHODS Six common cytotoxicity assays were used to evaluate the hepatotoxicity of different PAs in human hepatocellular carcinoma HepG2 cells. RESULTS The combination of MTT and bromodeoxyuridine incorporation (BrdU) assays demonstrated to be a suitable method to evaluate the toxic potencies of various PAs in HepG2 cells, and the results indicated that otonecine-type PA (clivorine: IC₂₀=0.013 ± 0.004 mM (MTT), 0.066 ± 0.031 mM (BrdU)) exhibited significantly higher cytotoxic and anti-proliferative effects than retronecine-type PA (retrorsine: IC₂₀=0.27 ± 0.07 mM (MTT), 0.19 ± 0.03 mM (BrdU)). While as expected, the known less toxic platyphylline-type PA (platyphylline: IC₂₀=0.85 ± 0.11 mM (MTT), 1.01 ± 0.40 mM (BrdU)) exhibited significantly less toxicity. The different cytotoxic and anti-proliferative potencies of various PAs in the same retronecine-type could also be discriminated by using the combined MTT and BrdU assays. In addition, the developed assays were further utilized to test alkaloid extract of Gynura segetum, a senecionine and seneciphylline-containing herb, the overall cytotoxicity of two PAs in the extract was comparable to that of these two PAs tested individually. CONCLUSION Using the developed in vitro model, the cytotoxicity of different PAs and the extract of a PA-containing herb were investigated in parallel in one system, and their different hepatotoxic potencies were determined and directly compared for the first time. The results suggested that the developed model has a great potential to be applied for the quick screening of the toxicity of PAs and PA-containing natural products.
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Affiliation(s)
- Yan Hong Li
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong SAR, China.
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The potential contribution of tumour-related factors to the development of FOLFOX-induced sinusoidal obstruction syndrome. Br J Cancer 2013; 109:2396-403. [PMID: 24113143 PMCID: PMC3817338 DOI: 10.1038/bjc.2013.604] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2013] [Revised: 08/28/2013] [Accepted: 09/12/2013] [Indexed: 12/17/2022] Open
Abstract
Background: Chemotherapy-associated liver injury (CALI) has been linked to increased morbidity and poorer disease-specific outcomes in patients undergoing resection of colorectal liver metastases (CRLM). The aim of this study was to assess the contribution of tumour-related factors to the development of FOLFOX-induced liver injury. Methods: We assessed the effect of FOLFOX treatment on the murine liver either in the presence or absence of CRLM to evaluate the contribution of both chemotherapy and tumour death to the development of CALI. Results: In the presence of liver metastases, there was increased hepatic expression of plasminogen activator inhibitor-1 (146-fold; P<0.01) and vWF (2.4-fold; P<0.01) transcript as compared with sham-operated controls. In addition, we detected large clusters of megakaryocytes in the spleen of FOLFOX-treated tumour-bearing animals. The livers of FOLFOX-treated animals also showed changes in matrix remodelling genes such as TGFβ (P<0.01), MMP2 (P<0.001), TIMP1 (P<0.001) and Pro-Collagen I (P<0.05) which was exacerbated in the presence of tumour. These genes have previously been demonstrated to have a key role in FOLFOX-induced liver injury. Conclusion: It appears that the toxicity of FOLFOX chemotherapy is enhanced by tumour-related factors.
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