Document Detail


The role of CYP3A4 in amiodarone-associated toxicity on HepG2 cells.
MedLine Citation:
PMID:  21070748     Owner:  NLM     Status:  In-Process    
Abstract/OtherAbstract:
Amiodarone is a class III antiarrhythmic drug with potentially life-threatening hepatotoxicity. Recent in vitro investigations suggested that the mono-N-desethyl (MDEA) and di-N-desethyl (DDEA) metabolites may cause amiodarone's hepatotoxicity. Since cytochrome P450 (CYP) 3A4 is responsible for amiodarone N-deethylation, CYP3A4 induction may represent a risk factor. Our aim was therefore to investigate the role of CYP3A4 in amiodarone-associated hepatotoxicity. First, we showed that 50μM amiodarone is more toxic to primary human hepatocytes after CYP induction with rifampicin. Second, we overexpressed human CYP3A4 in HepG2 cells (HepG2 cells/CYP3A4) for studying the interaction between CYP3A4 and amiodarone in more detail. We also used HepG2 wild type cells (HepG2 cells/wt) co-incubated with human CYP3A4 supersomes for amiodarone activation (HepG2 cells/CYP3A4 supersomes). Amiodarone (10-50μM) was cytotoxic for HepG2 cells/CYP3A4 or HepG2 cells/CYP3A4 supersomes, but not for HepG2 cells/wt or less toxic for HepG2 cells/wt incubated with control supersomes without CYP3A4. Co-incubation with ketoconazole, attenuated cytotoxicity of amiodarone incubated with HepG2 cells/CYP3A4 or HepG2 cells/CYP3A4 supersomes. MDEA and DDEA were formed only in incubations containing HepG2 cells/CYP3A4 or HepG2 cells/CYP3A4 supersomes but not by HepG2 cells/wt or HepG2 cells/wt with control supersomes. Metabolized amiodarone triggered the production of reactive oxygen species, induced mitochondrial damage and cytochrome c release, and promoted apoptosis/necrosis in HepG2 cells/CYP3A4, but not HepG2 cells/wt. This study supports the hypothesis that a high CYP3A4 activity is a risk factor for amiodarone's hepatotoxicity. Since CYP3A4 inducers are used frequently and amiodarone-associated hepatotoxicity can be fatal, our observations may be clinically relevant.
Authors:
Anja Zahno; Karin Brecht; Réjane Morand; Swarna Maseneni; Michael Török; Peter W Lindinger; Stephan Krähenbühl
Related Documents :
17365688 - Cytotoxic activity of antioxidant constituents from hypericum triquetrifolium turra.
11091138 - Effect of the polyamine oxidase inactivator mdl 72527 on n(1)-(n-octanesulfonyl)spermin...
21374158 - Cryopreservation of hybridomas.
16080538 - Biological evaluation of omega-(dialkylamino)alkyl derivatives of 6h-indolo[2,3-b]quino...
2461988 - Biosynthesis and function of lfa-3 in human mutant cells deficient in phosphatidylinosi...
3072898 - Mitochondrial function in normal and genetically altered cells and tissues.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-11-09
Journal Detail:
Title:  Biochemical pharmacology     Volume:  81     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2010-12-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  432-41     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Division of Clinical Pharmacology & Toxicology, University Hospital, Basel, Switzerland.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  CYP1D1, pseudogenized in human, is expressed and encodes a functional drug-metabolizing enzyme in cy...
Next Document:  Prostaglandin E? regulates cellular migration via induction of vascular endothelial growth factor re...