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1
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Driessen M, van der Plas-Duivesteijn S, Kienhuis AS, van den Brandhof EJ, Roodbergen M, van de Water B, Spaink HP, Palmblad M, van der Ven LTM, Pennings JLA. Identification of proteome markers for drug-induced liver injury in zebrafish embryos. Toxicology 2022; 477:153262. [PMID: 35868597 DOI: 10.1016/j.tox.2022.153262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/26/2022] [Accepted: 07/18/2022] [Indexed: 10/17/2022]
Abstract
The zebrafish embryo (ZFE) is a promising alternative non-rodent model in toxicology, and initial studies suggested its applicability in detecting hepatic responses related to drug-induced liver injury (DILI). Here, we hypothesize that detailed analysis of underlying mechanisms of hepatotoxicity in ZFE contributes to the improved identification of hepatotoxic properties of compounds and to the reduction of rodents used for hepatotoxicity assessment. ZFEs were exposed to nine reference hepatotoxicants, targeted at induction of steatosis, cholestasis, and necrosis, and effects compared with negative controls. Protein profiles of the individual compounds were generated using LC-MS/MS. We identified differentially expressed proteins and pathways, but as these showed considerable overlap, phenotype-specific responses could not be distinguished. This led us to identify a set of common hepatotoxicity marker proteins. At the pathway level, these were mainly associated with cellular adaptive stress-responses, whereas single proteins could be linked to common hepatotoxicity-associated processes. Applying several stringency criteria to our proteomics data as well as information from other data sources resulted in a set of potential robust protein markers, notably Igf2bp1, Cox5ba, Ahnak, Itih3b.2, Psma6b, Srsf3a, Ces2b, Ces2a, Tdo2b, and Anxa1c, for the detection of adverse responses.
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Affiliation(s)
- Marja Driessen
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | | | - Anne S Kienhuis
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands
| | - Evert-Jan van den Brandhof
- Centre for Environmental Quality, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands
| | - Marianne Roodbergen
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | - Bob van de Water
- Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | - Herman P Spaink
- Institute of Biology, Leiden University, Einsteinweg 55, 2333 CC Leiden, the Netherlands
| | - Magnus Palmblad
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands
| | - Leo T M van der Ven
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands
| | - Jeroen L A Pennings
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, the Netherlands.
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Li M, Luo Q, Tao Y, Sun X, Liu C. Pharmacotherapies for Drug-Induced Liver Injury: A Current Literature Review. Front Pharmacol 2022; 12:806249. [PMID: 35069218 PMCID: PMC8766857 DOI: 10.3389/fphar.2021.806249] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 12/16/2021] [Indexed: 12/14/2022] Open
Abstract
Drug-induced liver injury (DILI) has become a serious public health problem. For the management of DILI, discontinuation of suspicious drug or medicine is the first step, but the treatments including drugs and supporting approaches are needed. Reference to clinical patterns and disease severity grades of DILI, the treatment drugs were considered to summarize into hepatoprotective drugs (N-acetylcysteine and Glutathione, Glycyrrhizin acid preparation, Polyene phosphatidylcholine, Bicyclol, Silymarin), anticholestatic drug (Ursodeoxycholic acid, S-adenosylmethionine, Cholestyramine), immunosuppressants (Glucocorticoids) and specific treatment agents (L-carnitine, Anticoagulants). The current article reviewed the accumulated literature with evidence-based medicine researches for DILI in clinical practice. Also the drawbacks of the clinical studies involved in the article, unmet needs and prospective development for DILI therapy were discussed.
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Affiliation(s)
- Meng Li
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qiong Luo
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yanyan Tao
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xin Sun
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Chenghai Liu
- Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Key Laboratory of Liver and Kidney Diseases, Ministry of Education, Shanghai, China
- Shanghai Innovation Center of TCM Health Service, Shanghai, China
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3
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Basiglio CL, Crocenzi FA, Sánchez Pozzi EJ, Roma MG. Oxidative Stress and Localization Status of Hepatocellular Transporters: Impact on Bile Secretion and Role of Signaling Pathways. Antioxid Redox Signal 2021; 35:808-831. [PMID: 34293961 DOI: 10.1089/ars.2021.0021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Significance: Most hepatopathies are primarily or secondarily cholestatic in nature. Oxidative stress (OS) is a frequent trait among them, and impairs the machinery to generate bile by triggering endocytic internalization of hepatocellular transporters, thus causing cholestasis. This is critical, since it leads to accelerated transporter degradation, which could explain the common post-transcriptional downregulation of transporter expression in human cholestatic diseases. Recent Advances: The mechanisms involved in OS-induced hepatocellular transporter internalization are being revealed. Filamentous actin (F-actin) cytoskeleton disorganization and/or detachment of crosslinking actin proteins that afford transporter stability have been characterized as causal factors. Activation of redox-sensitive signaling pathways leading to changes in phosphorylation status of these structures is involved, including Ca2+-mediated activation of "classical" and "novel" protein kinase C (PKC) isoforms or redox-signaling cascades downstream of NADPH oxidase. Critical Issues: Despite the well-known occurrence of hepatocellular transporter internalization in human hepatopathies, the cholestatic implications of this phenomenon have been overlooked. Accordingly, no specific treatment has been established in the clinical practice for its prevention/reversion. Future Directions: We need to improve our knowledge on the pro-oxidant triggering factors and the multiple signaling pathways that mediate this oxidative injury in each cholestatic hepatopathy, so as to envisage tailor-made therapeutic strategies for each case. Meanwhile, administration of antioxidants or heme oxygenase-1 induction to elevate the hepatocellular levels of the endogenous scavenger bilirubin are promising alternatives that need to be re-evaluated and implemented. They may complement current treatments in cholestasis aimed to enhance transcriptional carrier expression, by providing membrane stability to the newly synthesized carriers. Antioxid. Redox Signal. 35, 808-831.
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Affiliation(s)
- Cecilia L Basiglio
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Fernando A Crocenzi
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Enrique J Sánchez Pozzi
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
| | - Marcelo G Roma
- Instituto de Fisiología Experimental (IFISE), Facultad de Ciencias Bioquímicas y Farmacéuticas, CONICET, U.N.R., Rosario, Argentina
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Gui L, Wu Q, Hu Y, Zeng W, Tan X, Zhu P, Li X, Yang L, Jia W, Liu C, Lan K. Compensatory Transition of Bile Acid Metabolism from Fecal Disposition of Secondary Bile Acids to Urinary Excretion of Primary Bile Acids Underlies Rifampicin-Induced Cholestasis in Beagle Dogs. ACS Pharmacol Transl Sci 2021; 4:1001-1013. [PMID: 33860216 DOI: 10.1021/acsptsci.1c00052] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Indexed: 12/12/2022]
Abstract
Drug induced cholestasis (DIC) is complexly associated with dysbiosis of the host-gut microbial cometabolism of bile acids (BAs). Murine animals are not suitable for transitional studies because the murine BA metabolism is quite different from human metabolism. In this work, the rifampicin (RFP) induced cholestasis was established in beagle dogs that have a humanlike BA profile to disclose how RFP affects the host-gut microbial cometabolism of BAs. The daily excretion of BA metabolites in urine and feces was extensively analyzed during cholestasis by quantitative BA profiling along the primary-secondary-tertiary axis. Oral midazolam clearance was also acquired to monitor the RFP-induced enterohepatic CYP3A activities because CYP3A is exclusively responsible for the tertiary oxidation of hydrophobic secondary BAs. RFP treatments caused a compensatory transition of the BA metabolism from the fecal disposition of secondary BAs to the urinary excretion of primary BAs in dogs, resulting in an infantile BA metabolism pattern recently disclosed in newborns. However, the tertiary BAs consistently constituted limitedly in the daily BA excretion, indicating that the detoxification role of the CYP3A catalyzed tertiary BA metabolism was not as strong as expected in this model. Multiple host-gut microbial factors might have contributed to the transition of the BA metabolism, such as inhibition of BA transporters, induction of liver-kidney interplaying detoxification mechanisms, and elimination of gut bacteria responsible for secondary BA production. Transitional studies involving more cholestatic drugs in preclinical animals with a humanlike BA profile and DIC patients may pave the way for understanding the complex mechanism of DIC in the era of metagenomics.
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Affiliation(s)
- LanLan Gui
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17 People's South Road, Chengdu 610041, China
| | - QingLiang Wu
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17 People's South Road, Chengdu 610041, China
| | - YiTing Hu
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17 People's South Road, Chengdu 610041, China
| | - WuShuang Zeng
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17 People's South Road, Chengdu 610041, China
| | - XianWen Tan
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17 People's South Road, Chengdu 610041, China
| | - PingPing Zhu
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17 People's South Road, Chengdu 610041, China
| | - XueJing Li
- Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu 610000, China
| | - Lian Yang
- Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu 610000, China.,WestChina-Frontier PharmaTech Co., Ltd., Chengdu 610041, China
| | - Wei Jia
- School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - ChangXiao Liu
- State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
| | - Ke Lan
- Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17 People's South Road, Chengdu 610041, China.,Chengdu Health-Balance Medical Technology Co., Ltd., Chengdu 610000, China
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Hernández Lozano I, Langer O. Use of imaging to assess the activity of hepatic transporters. Expert Opin Drug Metab Toxicol 2020; 16:149-164. [PMID: 31951754 PMCID: PMC7055509 DOI: 10.1080/17425255.2020.1718107] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/15/2020] [Indexed: 12/13/2022]
Abstract
Introduction: Membrane transporters of the SLC and ABC families are abundantly expressed in the liver, where they control the transfer of drugs/drug metabolites across the sinusoidal and canalicular hepatocyte membranes and play a pivotal role in hepatic drug clearance. Noninvasive imaging methods, such as PET, SPECT or MRI, allow for measuring the activity of hepatic transporters in vivo, provided that suitable transporter imaging probes are available.Areas covered: We give an overview of the working principles of imaging-based assessment of hepatic transporter activity. We discuss different currently available PET/SPECT radiotracers and MRI contrast agents and their applications to measure hepatic transporter activity in health and disease. We cover mathematical modeling approaches to obtain quantitative parameters of transporter activity and provide a critical assessment of methodological limitations and challenges associated with this approach.Expert opinion: PET in combination with pharmacokinetic modeling can be potentially applied in drug development to study the distribution of new drug candidates to the liver and their clearance mechanisms. This approach bears potential to mechanistically assess transporter-mediated drug-drug interactions, to assess the influence of disease on hepatic drug disposition and to validate and refine currently available in vitro-in vivo extrapolation methods to predict hepatic clearance of drugs.
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Affiliation(s)
| | - Oliver Langer
- Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
- Division of Nuclear Medicine, Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Vienna, Austria
- Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria
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Guo M, Zhao J, Zhai Y, Zang P, Lv Q, Shang D. A prospective study of hepatic safety of statins used in very elderly patients. BMC Geriatr 2019; 19:352. [PMID: 31842780 PMCID: PMC6915904 DOI: 10.1186/s12877-019-1361-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Accepted: 11/19/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Statins play an important role in the care of patients with cardiovascular disease and have a good safety record in clinical practice. Hepatotoxicity is a barrier that limits the ability of primary care physicians to prescribe statins for patients with elevated liver transaminase values and/or underlying liver disease. However, limited population-based data are available on the use of statin therapy and on the hepatotoxicity of statins in very elderly patients. This prospective study evaluated the liver enzyme elevation during statin therapy in very elderly patients (≥80 years old). METHODS Patients with hypercholesterolemia (LDL-C levels ≥3.4 and < 5.7 mmol/L), atherosclerosis, coronary heart disease (CHD), or a CHD-risk equivalent were enrolled and received once-daily statin treatment. Multivariate logistic regression models were used to study the impact of age, gender, hepatitis B infection, fatty liver disease, biliary calculus, other chronic diseases, drug kinds, alcohol abuse, statin variety, and statin dose variables. RESULTS A total of 515 consecutive patients ranging from 80 to 98 years old were included in the analysis. These patients were treated with simvastatin, fluvastatin, pravastatin, rosuvastatin, or atorvastatin. Twenty-four patients (4.7, 95% CI 2.7-6.6) showed an increase in their hepatic aminotransferase levels. No significant difference of hepatic aminotransferase elevation rates was observed in different statin treatment groups. The incidence of mild, moderate, and severe elevation of aminotransferase levels was 62.5% (15/24), 29.2% (7/24), and 8.3% (2/24), respectively. None of the patients developed hepatic failure. Nine patients with moderate or severe aminotransferase elevations discontinued therapy. The time of onset of hepatic aminotransferase elevation ranged from 2 weeks to 6 months after statin treatment. The onset of hepatic aminotransferase elevation was within 1 month for 70.8% of patients. The patients took 2 weeks to 3 months to recover their liver function after statin therapy cessation. Multivariate analysis identified chronic hepatitis B infection and alcohol consumption as independent factors associated with the hepatic response to statins: OR, 12.83; 95% CI (4.36-37.759) and OR, 2.736; 95% CI (1.373-5.454), respectively. CONCLUSION The prevalence of elevated transaminases was higher than published data in very elderly patients. Overall, statin treatment is safe for patients ≥80 years old.
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Affiliation(s)
- Meizi Guo
- Department of Gereology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Zhou Yuan Road 1500, Pudong New Area, Shanghai, 201318 China
| | - Junli Zhao
- Department of Nephrology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai, 201318 China
| | - Yingjiu Zhai
- Department of Gereology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Zhou Yuan Road 1500, Pudong New Area, Shanghai, 201318 China
| | - Panpan Zang
- Department of Gereology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Zhou Yuan Road 1500, Pudong New Area, Shanghai, 201318 China
| | - Qing Lv
- Department of Gereology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Zhou Yuan Road 1500, Pudong New Area, Shanghai, 201318 China
| | - Dongya Shang
- Department of Gereology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Zhou Yuan Road 1500, Pudong New Area, Shanghai, 201318 China
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7
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Sissung TM, Huang PA, Hauke RJ, McCrea EM, Peer CJ, Barbier RH, Strope JD, Ley AM, Zhang M, Hong JA, Venzon D, Jackson JP, Brouwer KR, Grohar P, Glod J, Widemann BC, Heller T, Schrump DS, Figg WD. Severe Hepatotoxicity of Mithramycin Therapy Caused by Altered Expression of Hepatocellular Bile Transporters. Mol Pharmacol 2019; 96:158-167. [PMID: 31175181 PMCID: PMC6608607 DOI: 10.1124/mol.118.114827] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Accepted: 05/15/2019] [Indexed: 12/14/2022] Open
Abstract
Mithramycin demonstrates preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with germline variants in genes involved in bile disposition: ABCB4 (multidrug resistance 3) rs2302387 and ABCB11 [bile salt export pump (BSEP)] rs4668115 reduce transporter expression (P < 0.05) and were associated with ≥grade 3 transaminitis developing 24 hours after the third infusion of mithramycin (25 mcg/kg, 6 hours/infusion, every day ×7, every 28 days; P < 0.0040). A similar relationship was observed in a pediatric cohort. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, sodium/taurocholate cotransporting polypeptide, organic solute transporter α/β) in several cell lines [Huh7, HepaRG, HepaRG BSEP (-/-)] and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P < 0.0001), and mithramycin inhibited chenodeoxycholic acid- and GW4046-induced FXR-galactose-induced gene 4 luciferase reporter activity (P < 0.001). Mithramycin promoted glycochenodeoxycholic acid-induced cytotoxicity in ABCB11 (-/-) cells and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P < 0.01). Mithramycin is a FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low ABCB11 function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses. SIGNIFICANCE STATEMENT: The present study characterizes a novel mechanism of drug-induced hepatotoxicity in which mithramycin not only alters farnesoid X receptor (FXR) and small heterodimer partner gene expression but also inhibits bile acid binding to FXR, resulting in deregulation of cellular bile homeostasis. Two novel single-nucleotide polymorphisms in bile flow transporters are associated with mithramycin-induced liver function test elevations, and the present results are the rationale for a genotype-directed clinical trial using mithramycin in patients with thoracic malignancies.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B/genetics
- ATP Binding Cassette Transporter, Subfamily B/metabolism
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- Adult
- Aged
- Antibiotics, Antineoplastic/adverse effects
- Cell Line, Tumor
- Chemical and Drug Induced Liver Injury/genetics
- Chemical and Drug Induced Liver Injury/metabolism
- Clinical Trials, Phase II as Topic
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Male
- Membrane Transport Proteins/genetics
- Membrane Transport Proteins/metabolism
- Middle Aged
- Plicamycin/adverse effects
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Thoracic Neoplasms/drug therapy
- Thoracic Neoplasms/genetics
- Thoracic Neoplasms/metabolism
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Affiliation(s)
- Tristan M Sissung
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Phoebe A Huang
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Ralph J Hauke
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Edel M McCrea
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Cody J Peer
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Roberto H Barbier
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Jonathan D Strope
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Ariel M Ley
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Mary Zhang
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Julie A Hong
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - David Venzon
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Jonathan P Jackson
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Kenneth R Brouwer
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Patrick Grohar
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Jon Glod
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Brigitte C Widemann
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - Theo Heller
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - David S Schrump
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
| | - William D Figg
- Clinical Pharmacology Program (T.M.S., C.J.P., W.D.F.), Molecular Pharmacology Section (P.A.H., R.J.H., E.M.M., R.H.B., J.D.S., A.M.L., W.D.F.), Biostatistics and Data Management Section (M.Z., J.A.H., D.V.), Pediatric Oncology Branch (P.G., J.G., B.C.W.), Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute (D.S.S.), and Translational Hepatology Section (T.H.), Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland; and BioIVT, ADME-Tox Division, Durham, North Carolina (J.P.J., K.R.B.)
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8
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Jin S, Li X, Fan Y, Fan X, Dai Y, Lin H, Cai W, Yang J, Xiang X. Association between genetic polymorphisms of SLCO1B1 and susceptibility to methimazole-induced liver injury. Basic Clin Pharmacol Toxicol 2019; 125:508-517. [PMID: 31240859 DOI: 10.1111/bcpt.13284] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 06/19/2019] [Indexed: 01/09/2023]
Abstract
Methimazole (MMI) has been used in the therapy of Grave's disease (GD) since 1954, and drug-induced liver injury (DILI) is one of the most deleterious side effects. Genetic polymorphisms of drug-metabolizing enzymes and drug transporters have been associated with drug-induced hepatotoxicity in many cases. The aim of this study was to investigate genetic susceptibility of the drug-metabolizing enzymes and drug transporters to the MMI-DILI. A total of 44 GD patients with MMI-DILI and 118 GD patients without MMI-DILI development were included in the study. Thirty-three single nucleotide polymorphisms (SNPs) in twenty candidate genes were genotyped. We found that rs12422149 of SLCO2B1, rs2032582_AT of ABCB1, rs2306283 of SLCO1B1 and rs4148323 of UGT1A1 exhibited a significant association with MMI-DILI; however, no significant difference existed after Bonferroni correction. Haplotype analysis showed that the frequency of SLCO1B1*1a (388A521T) was significantly higher in MMI-DILI cases than that in the control group (OR = 2.21, 95% CI = 1.11-4.39, P = 0.023), while the frequency of SLCO1B1*1b (388G521T) was significantly higher in the control group (OR = 0.52, 95% CI = 0.29-0.93, P = 0.028). These results suggested that genetic polymorphisms of SLCO1B1 were associated with susceptibility to MMI-DILI. The genetic polymorphism of SLCO1B1 may be important predisposing factors for MMI-induced hepatotoxicity.
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Affiliation(s)
- Shasha Jin
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China
| | - Xuesong Li
- Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai, China
| | - Yujuan Fan
- Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai, China
| | - Xiaofang Fan
- Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai, China
| | - Yu Dai
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Haishu Lin
- Department of Pharmacy, National University of Singapore, Singapore, Singapore
| | - Weimin Cai
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China
| | - Jialin Yang
- Department of Endocrinology and Metabolism, Minhang Hospital, Fudan University, Shanghai, China
| | - Xiaoqiang Xiang
- Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, China
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9
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De Lombaerde S, Neyt S, Vanhove C, De Vos F. In Vivo Measurement of Hepatic Drug Transporter Inhibition with Radiolabeled Bile Acids. Methods Mol Biol 2019; 1981:87-98. [PMID: 31016649 DOI: 10.1007/978-1-4939-9420-5_6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
Drug-induced liver injury, and more specifically drug-induced cholestasis, is responsible for a large amount of hospitalizations and attrition of new drug candidates in preclinical drug development. Drug-induced cholestasis can be triggered by drugs that are inhibitors of the hepatic bile acid transporters. Therefore, it is of considerable interest in preclinical drug development to detect whether new candidate drugs can cause interference with the hepatic bile acid transporters. Although several cost-effective and fast in vitro assays are available to that end, these do not mimic the in vivo situation completely. In vivo research to monitor a new candidate drug's cholestatic potential is still relevant, yet is time-consuming and requires invasive sampling of a lot of laboratory animals. In this chapter, a protocol is provided to determine in vivo inhibition of the hepatic bile acid transporters in mice, using the nuclear imaging techniques positron emission tomography and single photon emission computed tomography. The protocol includes detailed information on preparation of the animal, scan acquisition, processing, and (statistical) analysis.
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Affiliation(s)
- Stef De Lombaerde
- Faculty of Pharmaceutical Sciences, Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium.
| | - Sara Neyt
- Faculty of Pharmaceutical Sciences, Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium
| | | | - Filip De Vos
- Faculty of Pharmaceutical Sciences, Laboratory of Radiopharmacy, Ghent University, Ghent, Belgium
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10
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Wang X, Han L, Bi Y, Li C, Gao X, Fan G, Zhang Y. Paradoxical Effects of Emodin on ANIT-Induced Intrahepatic Cholestasis and Herb-Induced Hepatotoxicity in Mice. Toxicol Sci 2018; 168:264-278. [DOI: 10.1093/toxsci/kfy295] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Xue Wang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Lifeng Han
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Yajuan Bi
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Caiyu Li
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
| | - Xiumei Gao
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Guanwei Fan
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China
| | - Youcai Zhang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
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11
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Parmentier C, Hendriks DFG, Heyd B, Bachellier P, Ingelman-Sundberg M, Richert L. Inter-individual differences in the susceptibility of primary human hepatocytes towards drug-induced cholestasis are compound and time dependent. Toxicol Lett 2018; 295:187-194. [PMID: 29913214 DOI: 10.1016/j.toxlet.2018.06.1069] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 06/07/2018] [Accepted: 06/14/2018] [Indexed: 01/01/2023]
Abstract
Cholestasis represents a major subtype of drug-induced liver injury and novel preclinical models for its prediction are needed. Here we used primary human hepatocytes (PHH) from different donors in 2D-sandwich (2D-sw) and/or 3D-spheroid cultures to study inter-individual differences in the response towards cholestatic hepatotoxins after short-term (48-72 hours) and long-term repeated exposures (14 days). The cholestatic liabilities of drugs were determined by comparing cell viability upon exposure to the highest non-cytotoxic drug concentration in the presence and absence of a non-cytotoxic concentrated bile acid mixture. In 2D-sw culture, cyclosporine A and amiodarone presented clear cholestatic liabilities in all four PHH donors tested, whereas differences in the susceptibility of the various PHH donors towards the cholestatic toxicity of bosentan, chlorpromazine and troglitazone were observed. In PHH from one donor, the cholestatic liabilities of chlorpromazine and troglitazone could only be detected after long-term repeated exposures when maintained in 3D-spheroid culture, but not after short-term exposures in either 2D-sw or 3D-spheroid culture, suggesting that cholestatic hepatotoxicity may require time to develop. In conclusion, inter-individual susceptibility exists towards drug-induced cholestasis, which depends on the compound as well as the exposure time.
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Affiliation(s)
| | - Delilah F G Hendriks
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden
| | - Bruno Heyd
- Hôpital Jean Minjoz, 3 Boulevard Alexandre Fleming 25000 Besançon, France; Université de Bourgogne Franche-Comté, EA 4267 PEPITE, France
| | | | - Magnus Ingelman-Sundberg
- Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden
| | - Lysiane Richert
- KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim, France; Université de Bourgogne Franche-Comté, EA 4267 PEPITE, France.
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12
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13
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Iliescu M, Craciun RL, Stavar AN. The Role Of Fibroscan In Detecting Hepatic Fibrosis Induced By Methotrexate. ARS MEDICA TOMITANA 2017. [DOI: 10.1515/arsm-2017-0004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Abstract
Introduction: Liver represents the main place of drug metabolisation. Drugs and toxic substances reach the level of liver after absorption at gastro-intestinal level. Drug hepatotoxicity represents an important chapter of iatrogenic pathology, because the hepatic lesions induced by drugs include extremely diverse clinical, biological and histological expressions that can take the aspect of any form of acute or chronic hepatobiliary disease. Hepatic lesions induced by drugs (LHIM) represent a histological and/or biochemical alteration caused and attributed to the consumption of a drug. Hepatic elastography (Fibroscan) represents a noninvasive method of quantification of hepatic fibrosis.
Material and method: We carried out a retrospective study and longitudinally prospective study that included a set of patients under treatment with Methotrexate, amounting to 76, divided into 2 subsets: a subset consisting of patients with hepatitis to Methotrexate, subset 1, of 23 patients, a subset of patients under treatment with Methotrexate but with normal hepatic samples, subset b, of 53 patients.
Results: We carried out fibroscan at all the patients treated with Methotrexate, obtaining a medium score of fibrosis of 6.23 for the subset a with hepatitis at Methotrexate and of 5.33 for the subset b with normal hepatic samples. We made a correlation between the cumulated dose of Methotrexate and the change of hepatic samples.
Conclusions: There is a significant correlation between hepatic fibrosis induced by Methotrexate and the cumulated dose of Methotrexate. The possibility of utilization of fibroscan which is a completely painless method, reproducible, for the monitoring of the treatment with Methotrexate both at patients with changed values of the hepatic tests as weir as those with normal values must be considered.
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Affiliation(s)
| | - R. L. Craciun
- Faculty of Medicine, Constanta, Romania 1st University Alee, Camp B, Romania
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14
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Evaluation of transcriptomic signature as a valuable tool to study drug-induced cholestasis in primary human hepatocytes. Arch Toxicol 2017; 91:2879-2893. [DOI: 10.1007/s00204-017-1930-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/11/2017] [Indexed: 12/22/2022]
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15
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Oorts M, Baze A, Bachellier P, Heyd B, Zacharias T, Annaert P, Richert L. Drug-induced cholestasis risk assessment in sandwich-cultured human hepatocytes. Toxicol In Vitro 2016; 34:179-186. [DOI: 10.1016/j.tiv.2016.03.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Revised: 02/09/2016] [Accepted: 03/11/2016] [Indexed: 12/19/2022]
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16
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Yan JY, Ai G, Zhang XJ, Xu HJ, Huang ZM. Investigations of the total flavonoids extracted from flowers of Abelmoschus manihot (L.) Medic against α-naphthylisothiocyanate-induced cholestatic liver injury in rats. JOURNAL OF ETHNOPHARMACOLOGY 2015; 172:202-213. [PMID: 26133062 DOI: 10.1016/j.jep.2015.06.044] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Revised: 03/23/2015] [Accepted: 06/25/2015] [Indexed: 06/04/2023]
Abstract
ETHNOPHARMACOLOGY RELEVANCE The decoction of the flowers of Abelmoschus manihot (L.) Medic was traditionally used for the treatment of jaundice and various types of chronic and acute hepatitis in Anhui and Jiangsu Provinces of China for hundreds of years. Phytochemical studies have indicated that total flavonoids extracted from flowers of A. manihot (L.) Medic (TFA) were the major constituents of the flowers. Our previous studies have investigated the hepatoprotective effects of the TFA against carbon tetrachloride (CCl4) induced hepatocyte damage in vitro and liver injury in vivo. This study aimed to investigate the protective effects and mechanisms of TFA on α-naphthylisothiocyanate (ANIT)-induced cholestatic liver injury in rats. MATERIAL AND METHODS The hepatoprotective activities of TFA (125, 250 and 500mg/kg) were investigated on ANIT-induced cholestatic liver injury in rats. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were used as indices of hepatic cell damage and measured. Meanwhile, the serum levels of alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), total bilirubin (TBIL), direct bilirubin (DBIL), and total bile acid (TBA) were used as indices of biliary cell damage and cholestasis and evaluated. Hepatic malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), glutathione transferase (GST), tumor necrosis factor-α (TNF-α) and nitric oxide (NO) were measured in the liver homogenates. The bile flow in 4h was estimated and the histopathology of the liver tissue was evaluated. Furthermore, the expression of transporters, bile salt export pump (BSEP), multidrug resistance-associated protein 2 (MRP2), and Na(+)-taurocholate cotransporting polypeptide (NTCP) were studied by western blot and reverse transcription-quantitative real-time polymerase chain reaction (RT-PCR) to elucidate the protective mechanisms of TFA against ANIT-induced cholestasis. RESULTS The oral administration of TFA to ANIT-treated rats could reduce the increases in serum levels of ALT, AST, LDH, ALP, GGT, TBIL, DBIL and TBA. Decreased bile flow by ANIT was restored with TFA treatment. Concurrent administration of TFA reduced the severity of polymorphonuclear neutrophil infiltration and other histological damages, which were consistent with the serological tests. Hepatic MDA and GSH contents in liver tissue were reduced, while SOD and GST activities, which had been suppressed by ANIT, were elevated in the groups pretreated with TFA. With TFA intervention, levels of TNF-α and NO in liver were decreased. Additionally, TFA was found to increase the expression of liver BSEP, MRP2, and NTCP in both protein and mRNA levels in ANIT-induced liver injury with cholestasis. CONCLUSION TFA exerted protective effects against ANIT-induced liver injury. The possible mechanisms could be related to anti-oxidative damage, anti-inflammation and regulating the expression of hepatic transporters. It layed the foundation for the further research on the mechanisms of cholestasis as well as the therapeutic effects of A. manihot (L.) Medic for the treatment of jaundice.
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Affiliation(s)
- Jia-Yin Yan
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Guo Ai
- Institute of Aviation Medicine of Air Force, Beijing 100142, China; Institute of Radiation Medicine, Academy of Military Medical Sciences, Beijing 100850, China.
| | - Xiao-Jian Zhang
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Hai-Jiang Xu
- Department of Pharmacy, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Zheng-Ming Huang
- Department of Pharmacy, 302 Hospital of PLA, Beijing 100039, China
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17
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Zollner G, Thueringer A, Lackner C, Fickert P, Trauner M. Alterations of canalicular ATP-binding cassette transporter expression in drug-induced liver injury. Digestion 2015; 90:81-8. [PMID: 25196354 DOI: 10.1159/000365003] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Accepted: 05/27/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND Drug-induced liver injury (DILI) is a major clinical problem and its pathogenesis is poorly understood. The association of DILI with polymorphisms in hepatobiliary transport systems suggests a role for transport proteins in the pathogenesis of DILI. AIM To investigate expression and tissue distribution of hepatobiliary transport systems in DILI. METHODS Expression of the canalicular bile salt export pump BSEP (ABCC11), phospholipid flippase MDR3 (ABCB4) and bilirubin export pump MRP2 (ABCC2) was assessed immunohistochemically in liver biopsies from 23 patients with DILI. RESULTS Of 12 patients with cholestatic DILI (mostly due to antibiotics), 8 displayed a marked reduction of MRP2, MDR3 and BSEP expression. Transporter staining was normal in 4 patients with cholestatic DILI. In 11 patients with necroinflammatory hepatocellular injury (most frequently caused by NSAIDs), transporter staining was normal in areas where hepatocyte morphology was preserved. Due to hepatocyte necrosis and the reduction of the hepatocyte number, overall transporter expression was reduced without a reduction in transporter expression at the single hepatocyte level. CONCLUSIONS Canalicular ABC transporter expression is profoundly disturbed in most cases of cholestatic DILI. Drug-induced hepatitis does not lead to repression of transporter expression but to hepatocyte drop-outs with a numerical loss of bile canaliculi.
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Affiliation(s)
- Gernot Zollner
- Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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18
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A transcriptomics-based hepatotoxicity comparison between the zebrafish embryo and established human and rodent in vitro and in vivo models using cyclosporine A, amiodarone and acetaminophen. Toxicol Lett 2014; 232:403-12. [PMID: 25448281 DOI: 10.1016/j.toxlet.2014.11.020] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 11/18/2014] [Accepted: 11/20/2014] [Indexed: 12/22/2022]
Abstract
The zebrafish embryo (ZFE) is a promising alternative, non-rodent model in toxicology, which has an advantage over the traditionally used models as it contains complete biological complexity and provides a medium to high-throughput setting. Here, we assess how the ZFE compares to the traditionally used models for liver toxicity testing, i.e., in vivo mouse and rat liver, in vitro mouse and rat hepatocytes, and primary human hepatocytes. For this comparison, we analyzed gene expression changes induced by three model compounds for cholestasis, steatosis, and necrosis. The three compounds, cyclosporine A, amiodarone, and acetaminophen, were chosen because of their relevance to human toxicity and these compounds displayed hepatotoxic-specific changes in the mouse in vivo data. Compound induced expression changes in the ZFE model shared similarity with both in vivo and in vitro. Comparison on single gene level revealed the presence of model specific changes and no clear concordance across models. However, concordance was identified on the pathway level. Specifically, the pathway "regulation of metabolism - bile acids regulation of glucose and lipid metabolism via FXR" was affected across all models and compounds. In conclusion, our study with three hepatotoxic model compounds shows that the ZFE model is at least as comparable to traditional models in identifying hepatotoxic activity and has the potential for use as a pre-screen to determine the hepatotoxic potential of compounds.
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19
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Imani F, Motavaf M, Safari S, Alavian SM. The therapeutic use of analgesics in patients with liver cirrhosis: a literature review and evidence-based recommendations. HEPATITIS MONTHLY 2014; 14:e23539. [PMID: 25477978 PMCID: PMC4250965 DOI: 10.5812/hepatmon.23539] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 09/30/2014] [Accepted: 10/04/2014] [Indexed: 12/11/2022]
Abstract
CONTEXT Pain management in cirrhotic patients is a major clinical challenge for medical professionals. Unfortunately there are no concrete guidelines available regarding the administration of analgesics in patients with liver cirrhosis. In this review we aimed to summarize the available literature and suggest appropriate evidence-based recommendations regarding to administration of these drugs. EVIDENCE ACQUISITION An indexed MEDLINE search was conducted in July 2014, using keywords "analgesics", "hepatic impairment", "cirrhosis", "acetaminophen or paracetamol", "NSAIDs or nonsteroidal anti-inflammatory drugs", "opioid" for the period of 2004 to 2014. All randomized clinical trials, case series, case report and meta-analysis studies with the above mentioned contents were included in review process. In addition, unpublished information from the Food and Drug Administration are included as well. RESULTS Paracetamol is safe in patients with chronic liver disease but a reduced dose of 2-3 g/d is recommended for long-term use. Non-steroidal anti-inflammatory drugs (NSAIDs) are best avoided because of risk of renal impairment, hepatorenal syndrome, and gastrointestinal hemorrhage. Most opioids can have deleterious effects in patients with cirrhosis. They have an increased risk of toxicity and hepatic encephalopathy. They should be administrated with lower and less frequent dosing in these patients and be avoided in patients with a history of encephalopathy or addiction to any substance. CONCLUSIONS No evidence-based guidelines exist on the use of analgesics in patients with liver disease and cirrhosis. As a result pain management in these patients generates considerable misconception among health care professionals, leading under-treatment of pain in this population. Providing concrete guidelines toward the administration of these agents will lead to more efficient and safer pain management in this setting.
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Affiliation(s)
- Farnad Imani
- Department of Anesthesiology and Pain Medicine, Iran University of Medical Sciences, Tehran, IR Iran
| | - Mahsa Motavaf
- Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, IR Iran
- Department of Molecular Hepatology, Middle East Liver Disease Center, Tehran, IR Iran
| | - Saeid Safari
- Department of Anesthesiology and Pain Medicine, Iran University of Medical Sciences, Tehran, IR Iran
| | - Seyed Moayed Alavian
- Department of Molecular Hepatology, Middle East Liver Disease Center, Tehran, IR Iran
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Sciences, Tehran, IR Iran
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20
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Driessen M, Kienhuis AS, Vitins AP, Pennings JLA, Pronk TE, van den Brandhof EJ, Roodbergen M, van de Water B, van der Ven LTM. Gene expression markers in the zebrafish embryo reflect a hepatotoxic response in animal models and humans. Toxicol Lett 2014; 230:48-56. [PMID: 25064622 DOI: 10.1016/j.toxlet.2014.06.844] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2014] [Revised: 06/03/2014] [Accepted: 06/27/2014] [Indexed: 02/04/2023]
Abstract
The zebrafish embryo (ZFE) is a promising non-rodent model in toxicology, and initial studies suggested its applicability in detecting hepatotoxic responses. Here, we hypothesize that the detailed analysis of underlying mechanisms of hepatotoxicity in ZFE contributes to the improved identification of hepatotoxic properties of new compounds and to the reduction of rodents used for screening. ZFEs were exposed to nine reference hepatotoxicants, targeted at induction of cholestasis, steatosis and necrosis, and two non-hepatotoxic controls. Histopathology revealed various specific morphological changes in the ZFE hepatocytes indicative of cell injury. Gene expression profiles of the individual compounds were generated using microarrays. Regulation of single genes and of pathways could be linked to hepatotoxic responses in general, but phenotype-specific responses could not be distinguished. Hepatotoxicity-associated pathways included xenobiotic metabolism and oxidoreduction related pathways. Overall analysis of gene expression identified a limited set of potential biomarkers specific for a common hepatotoxicity response. This set included several cytochrome P450 genes (cyp2k19, cyp4v7, cyp2aa3), genes related to liver development (pklr) and genes important in oxidoreduction processes (zgc:163022, zgc:158614, zgc:101858 and sqrdl). In conclusion, the ZFE model allows for identification of hepatotoxicants, without discrimination into specific phenotypes.
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Affiliation(s)
- Marja Driessen
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Division of Toxicology, Leiden/Amsterdam Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
| | - Anne S Kienhuis
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands
| | - Alexa P Vitins
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Department of Toxicogenomics, Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Jeroen L A Pennings
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands
| | - Tessa E Pronk
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Department of Toxicogenomics, Maastricht University, 6200 MD Maastricht, The Netherlands
| | - Evert-Jan van den Brandhof
- Centre for Environmental Quality, National Institute for Public Health and the Environment (RIVM), P.O.Box 1, 3720 BA Bilthoven, The Netherlands
| | - Marianne Roodbergen
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands; Division of Toxicology, Leiden/Amsterdam Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
| | - Bob van de Water
- Division of Toxicology, Leiden/Amsterdam Centre for Drug Research, Leiden University, Einsteinweg 55, 2333CC Leiden, The Netherlands
| | - Leo T M van der Ven
- Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven, The Netherlands.
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22
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Zhang ZY, Si DY, Yi XL, Liu CX. Inhibitory effect of medicinal plant-derived carboxylic acids on the human transporters hOAT1, hOAT3, hOATP1B1, and hOATP2B1. Chin J Nat Med 2014; 12:131-8. [PMID: 24636064 DOI: 10.1016/s1875-5364(14)60021-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Indexed: 11/18/2022]
Abstract
A significant number of organic carboxylic acids have been shown to influence the absorption and distribution of drugs mediated by organic anion transporters (OATs). In this study, uptake experiments were performed to assess the inhibitory effects of cinnamic acid, ferulic acid, oleanolic acid, deoxycholic acid, and cynarin on hOAT1, hOAT3, hOATP1B1, and hOATP2B1. After a drug-drug interaction (DDI) investigation, cinnamic acid, ferulic acid, deoxycholic acid, and cynarin were found and validated to inhibit hOAT1 in a competitive manner, and deoxycholic acid was found to be an inhibitor of all four transporters. The apparent 50% inhibitory concentrations of cinnamic acid, ferulic acid, deoxycholic acid, and cynarin were estimated to be 133.87, 3.69, 90.03 and 6.03 μmol·L(-1) for hOAT1, respectively. The apparent 50% inhibitory concentrations of deoxycholic acid were estimated to be 9.57 μmol·L(-1) for hOAT3, 70.54 μmol·L(-1) for hOATP1B1, and 168.27 μmol·L(-1) for hOATP2B1. Because cinnamic acid, ferulic acid, and cynarin are ingredients of food or food additives, the present study suggests there are new food-drug interactions to be disclosed. In addition, deoxycholic acid may be used as a probe for studying the correlation of OATs and OATPs.
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Affiliation(s)
- Zhi-Yu Zhang
- School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China; State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
| | - Duan-Yun Si
- State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China
| | - Xiu-Lin Yi
- State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
| | - Chang-Xiao Liu
- State Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China.
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Abstract
Bile acids, synthesized from cholesterol, are known to produce beneficial as well as toxic effects in the liver. The beneficial effects include choleresis, immunomodulation, cell survival, while the toxic effects include cholestasis, apoptosis and cellular toxicity. It is believed that bile acids produce many of these effects by activating intracellular signaling pathways. However, it has been a challenge to relate intracellular signaling to specific and at times opposing effects of bile acids. It is becoming evident that bile acids produce different effects by activating different isoforms of phosphoinositide 3-kinase (PI3K), Protein kinase Cs (PKCs), and mitogen activated protein kinases (MAPK). Thus, the apoptotic effect of bile acids may be mediated via PI3K-110γ, while cytoprotection induce by cAMP-GEF pathway involves activation of PI3K-p110α/β isoforms. Atypical PKCζ may mediate beneficial effects and nPKCε may mediate toxic effects, while cPKCα and nPKCδ may be involved in both beneficial and toxic effects of bile acids. The opposing effects of nPKCδ activation may depend on nPKCδ phosphorylation site(s). Activation of ERK1/2 and JNK1/2 pathway appears to mediate beneficial and toxic effects, respectively, of bile acids. Activation of p38α MAPK and p38β MAPK may mediate choleretic and cholestatic effects, respectively, of bile acids. Future studies clarifying the isoform specific effects on bile formation should allow us to define potential therapeutic targets in the treatment of cholestatic disorders.
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Affiliation(s)
- Mohammed Sawkat Anwer
- Department of Biomedical Sciences, Cummings School of Veterinary Medicine at Tufts University, 200 Westboro Road, North Grafton, MA, USA
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24
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Hepatocyte-based in vitro model for assessment of drug-induced cholestasis. Toxicol Appl Pharmacol 2014; 274:124-36. [DOI: 10.1016/j.taap.2013.10.032] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Revised: 10/25/2013] [Accepted: 10/29/2013] [Indexed: 11/20/2022]
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Reshetnyak VI. Physiological and molecular biochemical mechanisms of bile formation. World J Gastroenterol 2013; 19:7341-7360. [PMID: 24259965 PMCID: PMC3831216 DOI: 10.3748/wjg.v19.i42.7341] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Revised: 09/27/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
This review considers the physiological and molecular biochemical mechanisms of bile formation. The composition of bile and structure of a bile canaliculus, biosynthesis and conjugation of bile acids, bile phospholipids, formation of bile micellar structures, and enterohepatic circulation of bile acids are described. In general, the review focuses on the molecular physiology of the transporting systems of the hepatocyte sinusoidal and apical membranes. Knowledge of physiological and biochemical basis of bile formation has implications for understanding the mechanisms of development of pathological processes, associated with diseases of the liver and biliary tract.
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26
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Gai Z, Chu L, Hiller C, Arsenijevic D, Penno CA, Montani JP, Odermatt A, Kullak-Ublick GA. Effect of chronic renal failure on the hepatic, intestinal, and renal expression of bile acid transporters. Am J Physiol Renal Physiol 2013; 306:F130-7. [PMID: 24197062 DOI: 10.1152/ajprenal.00114.2013] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Although the kidney is believed to play a minor role in bile acid (BA) excretion, chronic renal failure (CRF) has been reported to be associated with increased serum bile acid levels and alterations in BA homeostasis. The mechanisms for elevated BA levels are poorly understood in both clinical and experimental studies. This study was designed to examine the effects of naturally progressing CRF of longer duration on the hepatic and renal mRNA and protein levels of the BA-synthesizing enzyme Cyp7a1 and the BA transporters Ntcp, Bsep, Mrp3, Ost-α, and Ost-β. Sprague-Dawley rats were randomized to the CRF group (⅚ nephrectomy) or to the sham-operated control group and were analyzed 8 wk after surgery. Results obtained in the CRF rats were compared with those obtained in rats that had undergone uninephrectomy (UNX). The CRF group exhibited significantly increased plasma cholesterol and BA concentrations. Hepatic Cyp7a1 mRNA and protein levels were almost identical in the two groups. Hepatic Mrp3, Ost-α, and Ost-β expression was increased, suggesting increased basolateral efflux of bile acids into the blood. However, no such changes in BA transporter expression were observed in the remnant kidney. In UNX rats, similar changes in plasma BA levels and in the expression of BA transporters were found. We hypothesize that the increase in plasma BA is an early event in the progression of CRF and is caused by increased efflux across the basolateral hepatocyte membrane.
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Affiliation(s)
- Zhibo Gai
- Dept. of Clinical Pharmacology and Toxicology, Univ. Hospital Zurich, Rämistrasse 100, CH-8091 Zurich, Switzerland.
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27
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Ulzurrun E, Stephens C, Crespo E, Ruiz-Cabello F, Ruiz-Nuñez J, Saenz-López P, Moreno-Herrera I, Robles-Díaz M, Hallal H, Moreno-Planas JM, Cabello MR, Lucena MI, Andrade RJ. Role of chemical structures and the 1331T>C bile salt export pump polymorphism in idiosyncratic drug-induced liver injury. Liver Int 2013; 33:1378-85. [PMID: 23701583 DOI: 10.1111/liv.12193] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 04/14/2013] [Indexed: 12/23/2022]
Abstract
BACKGROUND & AIMS Several pharmaceutical compounds have been shown to exert inhibitory effects on the bile salt export pump (BSEP) encoded by the ABCB11 gene. We analysed the combined effect on drug-induced liver injury (DILI) development of the ABCB11 1331T>C polymorphism and the presence of specific chemical moieties, with known BSEP inhibiting properties, in the causative drug. METHODS Genotyping using a TaqMan 5' allelic discrimination assay was performed in 188 Spanish DILI patients, 219 healthy controls and 91 sex-, age- and drug-matched controls. A chemical structure analysis was performed for each individual causative drug. RESULTS The CC genotype was significantly associated with hepatocellular damage [odds ratio (OR) = 2.1, P = 0.001], particularly in NSAID DILI cases (OR = 3.4, P = 0.007). In addition, the CC genotype was found to be significantly linked to DILI development from drugs causing <50% BSEP inhibition (OR = 1.8, Pc = 0.011). Of the BSEP inhibitory chemical moieties, 59% of the causative drugs contained a carbocyclic system with at least one aromatic ring, corresponding to 61% of the total cases. The C allele was significantly more frequent in DILI cases containing this chemical moiety, which appear to be conditioned on the ABCB11 1331T>C polymorphism in the absence of other BSEP inhibitory structures. CONCLUSION Patients carrying the C allele in the ABCB11 1331T>C polymorphism are at increased risk of developing hepatocellular type of DILI, when taking drugs containing a carbocyclic system with aromatic rings.
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Affiliation(s)
- Eugenia Ulzurrun
- S Farmacología Clínica and Unidad de Hepatogía, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain
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28
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Kienhuis AS, Vitins AP, Pennings JL, Pronk TE, Speksnijder EN, Roodbergen M, van Delft JH, Luijten M, van der Ven LT. Cyclosporine A treated in vitro models induce cholestasis response through comparison of phenotype-directed gene expression analysis of in vivo Cyclosporine A-induced cholestasis. Toxicol Lett 2013; 221:225-36. [DOI: 10.1016/j.toxlet.2013.06.236] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Revised: 06/24/2013] [Accepted: 06/25/2013] [Indexed: 01/05/2023]
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29
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Hoekstra R, Nibourg GAA, van der Hoeven TV, Plomer G, Seppen J, Ackermans MT, Camus S, Kulik W, van Gulik TM, Elferink RPO, Chamuleau RAFM. Phase 1 and phase 2 drug metabolism and bile acid production of HepaRG cells in a bioartificial liver in absence of dimethyl sulfoxide. Drug Metab Dispos 2013; 41:562-7. [PMID: 23238784 DOI: 10.1124/dmd.112.049098] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
The human liver cell line HepaRG has been recognized as a promising source for in vitro testing of metabolism and toxicity of compounds. However, currently the hepatic differentiation of these cells relies on exposure to dimethylsulfoxide (DMSO), which, as a side effect, has a cytotoxic effect and represses an all-round hepatic functionality. The AMC-bioartificial liver (AMC-BAL) is a three-dimensional bioreactor that has previously been shown to upregulate various liver functions of cultured cells. We therefore cultured HepaRG cells in the AMC-BAL without DMSO and characterized the drug metabolism. Within 14 days of culture, the HepaRG-AMC-BALs contained highly polarized viable liver-like tissue with heterogeneous expression of CYP3A4. We found a substantial metabolism of the tested substrates, ranging from 26% (UDP-glucuronosyltransferase 1A1), 47% (CYP3A4), to 240% (CYP2C9) of primary human hepatocytes. The CYP3A4 activity could be induced 2-fold by rifampicin, whereas CYP2C9 activity remained equally high. The HepaRG-AMC-BAL secreted bile acids at 43% the rate of primary human hepatocytes and demonstrated hydroxylation, conjugation, and transport of bile salts. Concluding, culturing HepaRG cells in the AMC-BAL yields substantial phase 1 and phase 2 drug metabolism, while maintaining high viability, rendering DMSO addition superfluous for the promotion of drug metabolism. Therefore, AMC-BAL culturing makes the HepaRG cells more suitable for testing metabolism and toxicity of drugs.
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Affiliation(s)
- Ruurdtje Hoekstra
- Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands.
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Chen Y, Tang Y, Guo C, Wang J, Boral D, Nie D. Nuclear receptors in the multidrug resistance through the regulation of drug-metabolizing enzymes and drug transporters. Biochem Pharmacol 2012; 83:1112-26. [PMID: 22326308 PMCID: PMC3339266 DOI: 10.1016/j.bcp.2012.01.030] [Citation(s) in RCA: 170] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2011] [Revised: 01/23/2012] [Accepted: 01/25/2012] [Indexed: 01/18/2023]
Abstract
Chemotherapy is one of the three most common treatment modalities for cancer. However, its efficacy is limited by multidrug resistant cancer cells. Drug metabolizing enzymes (DMEs) and efflux transporters promote the metabolism, elimination, and detoxification of chemotherapeutic agents. Consequently, elevated levels of DMEs and efflux transporters reduce the therapeutic effectiveness of chemotherapeutics and, often, lead to treatment failure. Nuclear receptors, especially pregnane X receptor (PXR, NR1I2) and constitutive androstane activated receptor (CAR, NR1I3), are increasingly recognized for their role in xenobiotic metabolism and clearance as well as their role in the development of multidrug resistance (MDR) during chemotherapy. Promiscuous xenobiotic receptors, including PXR and CAR, govern the inducible expressions of a broad spectrum of target genes that encode phase I DMEs, phase II DMEs, and efflux transporters. Recent studies conducted by a number of groups, including ours, have revealed that PXR and CAR play pivotal roles in the development of MDR in various human carcinomas, including prostate, colon, ovarian, and esophageal squamous cell carcinomas. Accordingly, PXR/CAR expression levels and/or activation statuses may predict prognosis and identify the risk of drug resistance in patients subjected to chemotherapy. Further, PXR/CAR antagonists, when used in combination with existing chemotherapeutics that activate PXR/CAR, are feasible and promising options that could be utilized to overcome or, at least, attenuate MDR in cancer cells.
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Affiliation(s)
- Yakun Chen
- Department of Medical Microbiology, Immunology, and Cell Biology, Southern Illinois University School of Medicine, Springfield, IL 62794, United States
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Abstract
Recent progress in understanding the molecular mechanisms of bile formation and cholestasis have led to new insights into the pathogenesis of drug-induced cholestasis. This review summarizes their variable clinical presentations, examines the role of transport proteins in hepatic drug clearance and toxicity, and addresses the increasing importance of genetic determinants, as well as practical aspects of diagnosis and management.
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Affiliation(s)
- Manmeet S. Padda
- Division of Gastroenterology, Centennial Hills Hospital Medical Center, Las Vegas, NV
| | - Mayra Sanchez
- Department of Internal Medicine, Digestive Disease Section and Liver Center, Yale University School of Medicine 333 Cedar Street, P.O. Box 208019, New Haven, CT 06520-8019
| | - Abbasi J. Akhtar
- Division of Gastroenterology, Charles Drew University of Medicine and Science, Los Angeles, CA
| | - James L. Boyer
- Department of Internal Medicine, Digestive Disease Section and Liver Center, Yale University School of Medicine 333 Cedar Street, P.O. Box 208019, New Haven, CT 06520-8019
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Abstract
Pain management in patients with cirrhosis is a difficult clinical challenge for health care professionals, and few prospective studies have offered an evidence-based approach. In patients with end-stage liver disease, adverse events from analgesics are frequent, potentially fatal, and often avoidable. Severe complications from analgesia in these patients include hepatic encephalopathy, hepatorenal syndrome, and gastrointestinal bleeding, which can result in substantial morbidity and even death. In general, acetaminophen at reduced dosing is a safe option. In patients with cirrhosis, nonsteroidal anti-inflammatory drugs should be avoided to avert renal failure, and opiates should be avoided or used sparingly, with low and infrequent dosing, to prevent encephalopathy. For this review, we searched the available literature using PubMed and MEDLINE with no limits.
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Affiliation(s)
- Natasha Chandok
- Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
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Russmann S, Kullak-Ublick GA, Grattagliano I. Current concepts of mechanisms in drug-induced hepatotoxicity. Curr Med Chem 2009; 16:3041-53. [PMID: 19689281 PMCID: PMC2765083 DOI: 10.2174/092986709788803097] [Citation(s) in RCA: 260] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Drug-induced liver injury (DILI) has become a leading cause of severe liver disease in Western countries and therefore poses a major clinical and regulatory challenge. Whereas previously drug-specific pathways leading to initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as initial upstream events and appreciate that subsequent common downstream pathways and their attenuation by drugs and other environmental and genetic factors also have a profound impact on the risk of an individual patient to develop overt liver disease. This review summarizes current mechanistic concepts of DILI in a 3-step model that limits its principle mechanisms to three main ways of initial injury, i.e. direct cell stress, direct mitochondrial impairment, and specific immune reactions. Subsequently, initial injury initiates further downstream events, i.e. direct and death receptor-mediated pathways leading to mitochondrial permeability transition, which then results in apoptotic or necrotic cell death. For all mechanisms, mitochondria play a central role in events leading to apoptotic vs. necrotic cell death. New treatment targets consequently focus on interference with downstream pathways that mediate injury and therefore determine the ultimate outcome of DILI. Genome wide and targeted pharmacogenetic as well as metabonomic approaches are now used in order to reach the key goals of a better understanding of mechanisms in hepatotoxicity, and to develop new strategies for its prediction and treatment. However, the complexity of interactions between genetic and environmental risk factors is considerable, and DILI therefore currently remains unpredictable for most hepatotoxins.
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Affiliation(s)
- Stefan Russmann
- Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Zurich, Switzerland.
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Grattagliano I, Bonfrate L, Diogo CV, Wang HH, Wang DQH, Portincasa P. Biochemical mechanisms in drug-induced liver injury: Certainties and doubts. World J Gastroenterol 2009; 15:4865-76. [PMID: 19842215 PMCID: PMC2764962 DOI: 10.3748/wjg.15.4865] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca2+-dependent ATPase, reduced capability to sequester Ca2+ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.
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[Cholestatic syndrome in patients with systemic erythematous lupus--differential diagnostic aspects]. ACTA ACUST UNITED AC 2008; 61:291-4. [PMID: 19102078 DOI: 10.2298/mpns0806291t] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Systemic lupus erythematosus is a multisystemic inflammatory disease with diverse clinical manifestations. Hepatic lesion is a rarely seen complication of systemic lupus erythematosus. We report a case of complication of lupus presented as cholestatic syndrome in a 41-year old woman with lupus in her medical history for the past seven years. A general examination showed jaundice and hepatomegaly, with elevated bilirubin and aminotransferase levels in the liver function tests. The liver biopsy was performed and the microscopic examination revealed cholestasis with bile plugs without any signs of inflammation and liver tissue necrosis. After the three months steroid therapy the clinical symptoms resolved and the laboratory values normalized. The various factors are considered to be involved in the ethiopathogenesis of liver damage. Previous treatment with potentially hepatotoxic drugs (imuran in this case) or viral hepatitis have usually been implicated as the main cause of liver disease in lupus patients. On the other hand, even after careful exclusion of these ethiologies, the problem remains whether to classify the patient as having a primary liver disease with associated autoimmune and laboratory features resembling lupus, or as having a liver disease as a manifaestaion of lupus.
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36
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Flucloxacillin-induced liver injury. Toxicology 2008; 254:158-63. [DOI: 10.1016/j.tox.2008.08.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 08/15/2008] [Accepted: 08/15/2008] [Indexed: 01/28/2023]
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Crocenzi FA, Sánchez Pozzi EJ, Ruiz ML, Zucchetti AE, Roma MG, Mottino AD, Vore M. Ca(2+)-dependent protein kinase C isoforms are critical to estradiol 17beta-D-glucuronide-induced cholestasis in the rat. Hepatology 2008; 48:1885-95. [PMID: 18972403 PMCID: PMC3004396 DOI: 10.1002/hep.22532] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
UNLABELLED The endogenous estradiol metabolite estradiol 17beta-D-glucuronide (E(2)17G) induces an acute cholestasis in rat liver coincident with retrieval of the canalicular transporters bile salt export pump (Bsep, Abcc11) and multidrug resistance-associated protein 2 (Mrp2, Abcc2) and their associated loss of function. We assessed the participation of Ca(2+)-dependent protein kinase C isoforms (cPKC) in the cholestatic manifestations of E(2)17G in perfused rat liver (PRL) and in isolated rat hepatocyte couplets (IRHCs). In PRL, E(2)17G (2 mumol/liver; intraportal, single injection) maximally decreased bile flow, total glutathione, and [(3)H] taurocholate excretion by 61%, 62%, and 79%, respectively; incorporation of the specific cPKC inhibitor Gö6976 (500 nM) in the perfusate almost totally prevented these decreases. In dose-response studies using IRHC, E(2)17G (3.75-800 muM) decreased the canalicular vacuolar accumulation of the Bsep substrate cholyl-lysylfluorescein with an IC50 of 54.9 +/- 7.9 muM. Gö6976 (1 muM) increased the IC50 to 178.4 +/- 23.1 muM, and similarly prevented the decrease in the canalicular vacuolar accumulation of the Mrp2 substrate, glutathione methylfluorescein. Prevention of these changes by Gö6976 coincided with complete protection against E(2)17G-induced retrieval of Bsep and Mrp2 from the canalicular membrane, as detected both in the PRL and IRHC. E(2)17G also increased paracellular permeability in IRHC, which was only partially prevented by Gö6976. The cPKC isoform PKCalpha, but not the Ca(2+)-independent PKC isoform, PKCepsilon, translocated to the plasma membrane after E(2)17G administration in primary cultured rat hepatocytes; Gö6976 completely prevented this translocation, thus indicating specific activation of cPKC. This is consistent with increased autophosphorylation of cPKC by E(2)17G, as detected via western blotting. CONCLUSION Our findings support a central role for cPKC isoforms in E(2)17G-induced cholestasis, by inducing both transporter retrieval from the canalicular membrane and opening of the paracellular route.
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Affiliation(s)
- Fernando A. Crocenzi
- Institute of Experimental Physiology, National University of Rosario, S2002LRL-Rosario, Argentina, Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305
| | - Enrique J. Sánchez Pozzi
- Institute of Experimental Physiology, National University of Rosario, S2002LRL-Rosario, Argentina
| | - María Laura Ruiz
- Institute of Experimental Physiology, National University of Rosario, S2002LRL-Rosario, Argentina
| | - Andrés E. Zucchetti
- Institute of Experimental Physiology, National University of Rosario, S2002LRL-Rosario, Argentina
| | - Marcelo G. Roma
- Institute of Experimental Physiology, National University of Rosario, S2002LRL-Rosario, Argentina
| | - Aldo D. Mottino
- Institute of Experimental Physiology, National University of Rosario, S2002LRL-Rosario, Argentina, Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305
| | - Mary Vore
- Graduate Center for Toxicology, University of Kentucky, Lexington, KY 40536-0305
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Roma MG, Crocenzi FA, Mottino AD. Dynamic localization of hepatocellular transporters in health and disease. World J Gastroenterol 2008; 14:6786-801. [PMID: 19058304 PMCID: PMC2773873 DOI: 10.3748/wjg.14.6786] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Vesicle-based trafficking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal, submembrane compartment, followed by exocytic targeting to the plasma membrane. Once delivered to the plasma membrane, the transporters usually undergo recycling between the plasma membrane and the endosomal compartment, which usually serves as a reservoir of pre-existing transporters available on demand. The balance between exocytic targeting and endocytic internalization from/to this recycling compartment is therefore a chief determinant of the overall capability of the liver epithelium to secrete bile and to detoxify endo and xenobiotics. Hence, it is a highly regulated process. Impaired regulation of this balance may lead to abnormal localization of these transporters, which results in bile secretory failure due to endocytic internalization of key transporters involved in bile formation. This occurs in several experimental models of hepatocellular cholestasis, and in most human cholestatic liver diseases. This review describes the molecular bases involved in the biology of the dynamic localization of hepatocellular transporters and its regulation, with a focus on the involvement of signaling pathways in this process. Their alterations in different experimental models of cholestasis and in human cholestatic liver disease are reviewed. In addition, the causes explaining the pathological condition (e.g. disorganization of actin or actin-transporter linkers) and the mediators involved (e.g. activation of cholestatic signaling transduction pathways) are also discussed. Finally, several experimental therapeutic approaches based upon the administration of compounds known to stimulate exocytic insertion of canalicular transporters (e.g. cAMP, tauroursodeoxycholate) are described.
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Julie NL, Julie IM, Kende AI, Wilson GL. Mitochondrial dysfunction and delayed hepatotoxicity: another lesson from troglitazone. Diabetologia 2008; 51:2108-16. [PMID: 18726085 DOI: 10.1007/s00125-008-1133-6] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2008] [Accepted: 06/26/2008] [Indexed: 12/16/2022]
Abstract
AIMS/HYPOTHESIS Troglitazone was approved for treatment of type 2 diabetes mellitus, but by 2000 it had been removed from all world markets due to severe drug-induced liver injury. Even today, we still do not know how many patients sustained a long-term liver injury. No system is in place to acquire that knowledge. Regarding toxicity mechanisms, controversy persists as to which ones are class effects of thiazolidinediones (TZDs) and which are unique to troglitazone. This study aims to provide long-term outcome data and new insights on mechanisms of troglitazone-induced liver injury. METHODS This case series reports the liver injuries sustained by eleven type 2 diabetic patients treated with troglitazone between 1997 and 2000. Exhaustive review of medical records was performed for all patients. Long-term outcomes were available for all the non-fatal cases. A comprehensive literature review was also performed. RESULTS Long-term liver injury progressing to cirrhosis was identified in seven patients. All eleven cases had liver injury patterns consistent with troglitazone toxicity. Analysis of these cases and of the experimental troglitazone toxicity data points to mitochondrial toxicity as a central factor. The general clinical patterns of mitochondrial hepatotoxic events are reviewed, as are the implications for other members of the TZD family. CONCLUSIONS/INTERPRETATION This analysis enables the liver injury induced by troglitazone to be better understood. In future cases of delayed drug-induced liver injury that progresses after discontinuation, the possibility of mitochondrial toxicity should be considered. When appropriate, this can then be evaluated experimentally. Such proactive investigation may anticipate clinical risk before a large-scale therapeutic misadventure occurs. Drug-induced liver injury due to mitochondrial hepatotoxins may be less unpredictable than has previously been surmised.
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Affiliation(s)
- N L Julie
- Department of Pathology, Shady Grove Adventist Hospital, Rockville, MD, USA.
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40
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Stahl S, Davies MR, Cook DI, Graham MJ. Nuclear hormone receptor-dependent regulation of hepatic transporters and their role in the adaptive response in cholestasis. Xenobiotica 2008; 38:725-77. [DOI: 10.1080/00498250802105593] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Hepatocellular transport in acquired cholestasis: new insights into functional, regulatory and therapeutic aspects. Clin Sci (Lond) 2008; 114:567-88. [PMID: 18377365 DOI: 10.1042/cs20070227] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The recent overwhelming advances in molecular and cell biology have added enormously to our understanding of the physiological processes involved in bile formation and, by extension, to our comprehension of the consequences of their alteration in cholestatic hepatopathies. The present review addresses in detail this new information by summarizing a number of recent experimental findings on the structural, functional and regulatory aspects of hepatocellular transporter function in acquired cholestasis. This comprises (i) a short overview of the physiological mechanisms of bile secretion, including the nature of the transporters involved and their role in bile formation; (ii) the changes induced by nuclear receptors and hepatocyte-enriched transcription factors in the constitutive expression of hepatocellular transporters in cholestasis, either explaining the primary biliary failure or resulting from a secondary adaptive response; (iii) the post-transcriptional changes in transporter function and localization in cholestasis, including a description of the subcellular structures putatively engaged in the endocytic internalization of canalicular transporters and the involvement of signalling cascades in this effect; and (iv) a discussion on how this new information has contributed to the understanding of the mechanism by which anticholestatic agents exert their beneficial effects, or the manner in which it has helped the design of new successful therapeutic approaches to cholestatic liver diseases.
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Marschall HU, Wagner M, Zollner G, Trauner M. Clinical Hepatotoxicity. Regulation and Treatment with Inducers of Transport and Cofactors. Mol Pharm 2007; 4:895-910. [DOI: 10.1021/mp060133c] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Affiliation(s)
- Hanns-Ulrich Marschall
- Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden, and Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Martin Wagner
- Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden, and Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Gernot Zollner
- Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden, and Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
| | - Michael Trauner
- Karolinska Institutet, Department of Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden, and Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Austria
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Choi JH, Ahn BM, Yi J, Lee JH, Lee JH, Nam SW, Chon CY, Han KH, Ahn SH, Jang IJ, Cho JY, Suh Y, Cho MO, Lee JE, Kim KH, Lee MG. MRP2 haplotypes confer differential susceptibility to toxic liver injury. Pharmacogenet Genomics 2007; 17:403-15. [PMID: 17502832 DOI: 10.1097/01.fpc.0000236337.41799.b3] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVES Multidrug resistance protein 2 (MRP2, ABCC2) plays an important role in the biliary clearance of a wide variety of endogenous and exogenous toxic compounds. Therefore, polymorphisms and mutations in the MRP2 gene may affect individual susceptibility to hepatotoxic reactions. METHODS Associations between genetic variations of MRP2 and toxic hepatitis were investigated using integrated population genetic analysis and functional molecular studies. RESULTS Using a gene scanning method, 12 polymorphisms and mutations were found in the MRP2 gene in a Korean population. Individual variation at these sites was analyzed by conventional DNA screening in 110 control subjects and 94 patients with toxic hepatitis induced mostly by herbal remedies. When haplotypes were identified, over 85% of haploid genes belonged to the five most common haplotypes. Among these, a haplotype containing the g.-1774delG polymorphism showed a strong association with cholestatic or mixed-type hepatitis, and a haplotype containing the g.-1549G>A, g.-24C>T, c.334-49C>T, and c.3972C>T variations was associated with hepatocellular-type hepatitis. A comprehensive functional study of these sites revealed that genetic variations in the promoter of this gene are primarily responsible for the susceptibility to toxic liver injuries. The g.-1774delG variation and the combined variation of g.-1549G>A and g.-24C>T decreased MRP2 promoter activity by 36 and 39%, respectively. In addition, the promoter carrying the g.-1774delG allele showed a defect in the bile acid-induced induction of promoter activity. CONCLUSIONS These results suggest that genetic variations of MRP2 are an important predisposing factor for herbal-induced or drug-induced toxic liver injuries.
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Affiliation(s)
- Ji Ha Choi
- Department of Pharmacology, Institute of Gastroenterology, Yonsei University College of Medicine, 134 Sinchon-Dong Seoul 120-752, Korea
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Meletiadis J, Chanock S, Walsh TJ. Human pharmacogenomic variations and their implications for antifungal efficacy. Clin Microbiol Rev 2006; 19:763-87. [PMID: 17041143 PMCID: PMC1592689 DOI: 10.1128/cmr.00059-05] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Pharmacogenomics is defined as the study of the impacts of heritable traits on pharmacology and toxicology. Candidate genes with potential pharmacogenomic importance include drug transporters involved in absorption and excretion, phase I enzymes (e.g., cytochrome P450-dependent mixed-function oxidases) and phase II enzymes (e.g., glucuronosyltransferases) contributing to metabolism, and those molecules (e.g., albumin, A1-acid glycoprotein, and lipoproteins) involved in the distribution of antifungal compounds. By using the tools of population genetics to define interindividual differences in drug absorption, distribution, metabolism, and excretion, pharmacogenomic models for genetic variations in antifungal pharmacokinetics can be derived. Pharmacogenomic factors may become especially important in the treatment of immunocompromised patients or those with persistent or refractory mycoses that cannot be explained by elevated MICs and where rational dosage optimization of the antifungal agent may be particularly critical. Pharmacogenomics has the potential to shift the paradigm of therapy and to improve the selection of antifungal compounds and adjustment of dosage based upon individual variations in drug absorption, metabolism, and excretion.
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Affiliation(s)
- Joseph Meletiadis
- Pediatric Oncology Branch, National Cancer Institute, CRC, 1-5750 10 Center Drive, Bethesda, MD 20892, USA
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Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y. Inhibition of bile acid transport across Na+/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)-coexpressing LLC-PK1 cells by cholestasis-inducing drugs. Drug Metab Dispos 2006; 34:1575-81. [PMID: 16760228 DOI: 10.1124/dmd.105.008748] [Citation(s) in RCA: 120] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Vectorial transport of bile acids across hepatocytes is a major driving force for bile flow, and bile acid retention in the liver causes hepatotoxicity. The basolateral and apical transporters for bile acids are thought to be targets of drugs that induce cholestasis. Previously, we constructed polarized LLC-PK1 cells that express both a major bile acid uptake transporter human Na+/taurocholate cotransporting polypeptide (SLC10A1) (NTCP) and the bile acid efflux transporter human bile salt export pump (ABCB 11) (BSEP) and showed that monolayers of such cells can be used to characterize vectorial transcellular transport of bile acids. In the present study, we investigated whether cholestasis-inducing drugs could inhibit bile acid transport in such cells. Because fluorescent substrates allow the development of a high-throughput screening method, we examined the transport by NTCP and BSEP of fluorescent bile acids as well as taurocholate. The aminofluorescein-tagged bile acids, chenodeoxycholylglycylamidofluorescein and cholylglycylamidofluorescein, were substrates of both NTCP and BSEP, and their basal-to-apical transport rates across coexpressing cell monolayers were 4.3 to 4.5 times those of the vector control, although smaller than for taurocholate. The well known cholestatic drugs, rifampicin, rifamycin SV, glibenclamide, and cyclosporin A, reduced the basal-to-apical transport and the apical efflux clearance of taurocholate across NTCP- and BSEP-coexpressing cell monolayers. Further analysis indicated that the drugs inhibited both NTCP and BSEP. Our study suggests that such coexpressing cells can provide a useful system for the identification of inhibitors of these two transport systems, including potential drug candidates.
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Affiliation(s)
- Sachiko Mita
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan
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Dupas B, Gournay J, Frampas E, Leaute F, Le Borgne J. [Anicteric cholestasis: imaging and diagnostic strategy]. ACTA ACUST UNITED AC 2006; 87:441-59. [PMID: 16691175 DOI: 10.1016/s0221-0363(06)74026-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Cholestasis is due to abnormal biliary secretion, from hepatic or extra hepatic causes. The diagnostic strategy of anicteric cholestasis will be discussed, defining hepatic biologic abnormalities, and the role and sequence of imaging techniques based on clinical and biological findings. Main causes will be emphasized and illustrated with different radiological techniques (US, CT and MRI).
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Affiliation(s)
- B Dupas
- Service Centre de Radiologie et d'Imagerie Médicale, Hôtel-Dieu, 1, place Alexis-Ricordeau, 44093 Nantes Cedex 1.
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Zamek-Gliszczynski MJ, Hoffmaster KA, Nezasa KI, Tallman MN, Brouwer KLR. Integration of hepatic drug transporters and phase II metabolizing enzymes: Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur J Pharm Sci 2006; 27:447-86. [PMID: 16472997 DOI: 10.1016/j.ejps.2005.12.007] [Citation(s) in RCA: 187] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2005] [Accepted: 12/06/2005] [Indexed: 12/12/2022]
Abstract
The liver is the primary site of drug metabolism in the body. Typically, metabolic conversion of a drug results in inactivation, detoxification, and enhanced likelihood for excretion in urine or feces. Sulfation, glucuronidation, and glutathione conjugation represent the three most prevalent classes of phase II metabolism, which may occur directly on the parent compounds that contain appropriate structural motifs, or, as is usually the case, on functional groups added or exposed by phase I oxidation. These three conjugation reactions increase the molecular weight and water solubility of the compound, in addition to adding a negative charge to the molecule. As a result of these changes in the physicochemical properties, phase II conjugates tend to have very poor membrane permeability, and necessitate carrier-mediated transport for biliary or hepatic basolateral excretion into sinusoidal blood for eventual excretion into urine. This review summarizes sulfation, glucuronidation, and glutathione conjugation reactions, as well as recent progress in elucidating the hepatic transport mechanisms responsible for the excretion of these conjugates from the liver. The discussion focuses on alterations of metabolism and transport by chemical modulators, and disease states, as well as pharmacodynamic and toxicological implications of hepatic metabolism and/or transport modulation for certain active phase II conjugates. A brief discussion of issues that must be considered in the design and interpretation of phase II metabolite transport studies follows.
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Abstract
Idiosyncratic drug induced liver injury (DILI) remains poorly understood. It is assumed that the affected individuals possess a rare combination of genetic and non genetic factors that, if identified, would greatly improve understanding of the underlying mechanisms. This single topic conference brought together basic scientists, translational investigators, and clinicians with an interest in DILI. The goal was to define high priority areas of investigation that will soon be made possible by The Drug-Induced Liver Injury Network (DILIN). Since 2004 DILIN has been collecting clinical data, genomic DNA and some tissues from patients who have experienced bone fide DILI. The presentations spanned many different areas of DILI, and included novel data concerning mechanisms of hepatotoxicity, new "omics" approaches, and the challenges of improving causation assessment.
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Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y. Vectorial transport of unconjugated and conjugated bile salts by monolayers of LLC-PK1 cells doubly transfected with human NTCP and BSEP or with rat Ntcp and Bsep. Am J Physiol Gastrointest Liver Physiol 2006; 290:G550-6. [PMID: 16474011 DOI: 10.1152/ajpgi.00364.2005] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Na(+)-taurocholate-cotransporting peptide (NTCP)/SLC10A1 and bile salt export pump (BSEP)/ABCB11 synergistically play an important role in the transport of bile salts by the hepatocyte. In this study, we transfected human NTCP and BSEP or rat Ntcp and Bsep into LLC-PK1 cells, a cell line devoid of bile salts transporters. Transport by these cells was characterized with a focus on substrate specificity between rats and humans. The basal to apical flux of taurocholate across NTCP- and BSEP-expressing LLC-PK1 monolayers was 10 times higher than that in the opposite direction, whereas the flux across the monolayer of control and NTCP or BSEP single-expressing cells did not show any vectorial transport. The basal to apical flux of taurocholate was saturated with a K(m) value of 20 microM. Vectorial transcellular transport was also observed for cholate, chenodeoxycholate, ursodeoxycholate, their taurine and glycine conjugates, and taurodeoxycholate and glycodeoxycholate, whereas no transport of lithocholate was detected. To evaluate the respective functions of NTCP and BSEP and to compare them with those of rat Ntcp and Bsep, we calculated the clearance by each transporter in this system. A good correlation in the clearance of the examined bile salts (cholate, chenodeoxycholate, ursodeoxycholate, and their taurine or glycine conjugates) was observed between transport by human and that of rat transporters in terms of their rank order: for NTCP, taurine conjugates > glycine conjugates > unconjugated bile salts, and for BSEP, unconjugated bile salts and glycine conjugates > taurine conjugates. In conclusion, the substrate specificity of human and rat NTCP and BSEP appear to be very similar at least for monovalent bile salts under physiological conditions.
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Affiliation(s)
- Sachiko Mita
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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