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Hepatocellular toxicity of clopidogrel: Mechanisms and risk factors

Zahno, Anja and Bouitbir, Jamal and Maseneni, Swarma and Lindinger, Peter W. and Brecht, Karin and Krähenbühl, Stephan. (2013) Hepatocellular toxicity of clopidogrel: Mechanisms and risk factors. Free radical biology and medicine, 65. pp. 208-216.

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Official URL: http://edoc.unibas.ch/dok/A6338378

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Abstract

Clopidogrel is a prodrug used widely as a platelet aggregation inhibitor. After intestinal absorption, approximately 90% is converted to inactive clopidogrel carboxylate and 10% via a two-step procedure to the active metabolite containing a mercapto group. Hepatotoxicity is a rare but potentially serious adverse reaction associated with clopidogrel. The aim of this study was to find out the mechanisms and susceptibility factors for clopidogrel-associated hepatotoxicity. In primary human hepatocytes, clopidogrel (10 and 100muM) was cytotoxic only after cytochrome P450 (CYP) induction by rifampicin. Clopidogrel (10 and 100muM) was also toxic for HepG2 cells expressing human CYP3A4 (HepG2/CYP3A4) and HepG2 cells co-incubated with CYP3A4 supersomes (HepG2/CYP3A4 supersome), but not for wild-type HepG2 cells (HepG2/wt). Clopidogrel (100muM) decreased the cellular glutathione content in HepG2/CYP3A4 supersome and triggered an oxidative stress reaction (10 and 100microM) in HepG2/CYP3A4, but not in HepG2/wt. Glutathione depletion significantly increased the cytotoxicity of clopidogrel (10 and 100microM) in HepG2/CYP3A4 supersome. Co-incubation with 1muM ketoconazole or 10mM glutathione almost completely prevented the cytotoxic effect of clopidogrel in HepG2/CYP3A4 and HepG2/CYP3A4 supersome. HepG2/CYP3A4 incubated with 100muM clopidogrel showed mitochondrial damage and cytochrome c release, eventually promoting apoptosis and/or necrosis. In contrast to clopidogrel, clopidogrel carboxylate was not toxic for HepG2/wt or HepG2/CYP3A4 up to 100microM. In conclusion, clopidogrel incubated with CYP3A4 is associated with the formation of metabolites that are toxic for hepatocytes and can be trapped by glutathione. High CYP3A4 activity and low cellular glutathione stores may be risk factors for clopidogrel-associated hepatocellular toxicity.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Clinical Pharmacology (Krähenbühl)
05 Faculty of Science
05 Faculty of Science > Departement Pharmazeutische Wissenschaften
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie
05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Klinische Pharmakologie > Klinische Pharmakologie (Krähenbühl)
UniBasel Contributors:Krähenbühl, Stephan and Brecht Brüngger, Karin and Bouitbir, Jamal and Mallaun-Zahno, Anja-Christina and Maseneni, Swarna and Lindinger, Peter
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0891-5849
e-ISSN:1873-4596
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:26 Aug 2020 15:07
Deposited On:10 Apr 2015 09:12

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