Pharmacogenomics in Drug Induced Liver Injury
Abstract:Drug-induced liver injury (DILI) is a severe adverse effect. The majority of DILI cases are idiosyncratic and several mechanisms have been postulated to explain why some subjects develop DILI with drugs that are safe for the majority of individuals. Major mechanisms proposed for DILI are based on the production of reactive metabolites, immune-mediated hepatotoxicity, a “danger signal” hypothesis and/or alterations in mitochondrial function. These mechanisms are compatible with the hypothesis for genetic variability in drug metabolism or bioactivation and are a major determinant for DILI. In this review we summarize present knowledge on underlying mechanisms, and clinical expression as well as genetic and non-genetic factors that modulate the risk of developing DILI. With regard to DILI pharmacogenomics, we summarize current evidence on the role of polymorphisms in genes coding for the drug-metabolizing enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, NAT2, GSTM1, GSTT1, UGT1A1, UGT1A3, UGT1A9 and UGT2B7. Conclusive evidence for association with DILI risk has been obtained for non-mutated CYP2E1, slow NAT2 and slow GSTM1 genotypes. For the rest of the genes additional pharmacogenomics and toxicogenomics studies are required. We identify potential sources of heterogeneity in studies carried out so far as well as new genetic targets which require further investigation.
Document Type: Research Article
Publication date: November 1, 2009
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- Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.