title: Are Polymorphisms in Genes Relevant to Drug Disposition Predictors of Susceptibility to Drug-Induced Liver Injury?
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.
authors.affiliation: Institute of Cellular Medicine, Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK. a.k.daly@ncl.ac.uk.
authors.forename: Ann K
authors.initials: AK
authors.lastname: Daly
mesh_terms: D000123:Acetyltransferases / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D000123:Acetyltransferases; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human
keywords: ABC transporter; UDP-glucurononosyltransferase; cytochrome P450; drug-induced liver injury