Abstract
Despite considerable progress in identifying specific HLA alleles as genetic risk factors for some forms of drug-induced liver injury, progress in understanding whether genetic polymorphisms relevant to drug disposition also contribute to risk for developing this serious toxicity has been more limited. Evidence from both candidate-gene case control studies and genome-wide association studies is now discussed. In the case of genes relevant to drug metabolism, polymorphisms in cytochromes P450, UDP-glucuronosyltransferases, N-acetyltransferases and glutathione S-transferases as risk factors for DILI are assessed. The relevance of ABC transporters to drug-induced liver injury is also considered, together with data showing associations of particular ABCB11, ABCB1 and ABCC2 polymorphisms with some forms of drug-induced liver injury. Very few of the associations with genes relevant to drug disposition that have been reported have been well replicated. Even apparently well-studied associations such as that between isoniazid liver injury and N-acetyltransferase 2 slow acetylators remain problematic, though it seems likely that polymorphisms in drug metabolism genes do contribute to risk for some specific drugs. A better understanding of genetic risk factors for drug-induced liver injury will require further genome-wide association studies with larger numbers of cases, especially for forms of drug-induced liver injury where HLA genotype does not appear to be a risk factor.
Highlights
Drug-induced liver injury (DILI) is one of the most common reasons for drug withdrawal, either at a late stage of the drug development process or soon after licensing [1]
It is generally considered that metabolism of the causative drug to a reactive intermediate is an important step in the DILI process [3]
The formation of reactive intermediates may contribute to an inappropriate immune response so a role for genes contributing to drug disposition alongside HLA genes in DILI remains plausible
Summary
Are Polymorphisms in Genes Relevant to Drug Disposition Predictors of Susceptibility to Drug-Induced Liver Injury?. This article is published with open access at SpringerLink.com
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