The selleck screening library role of GST

variations for DILI is further supported by several other CGAS that identified positive associations for DILI caused by troglitazone,67 antituberculosis drugs,68, 69 and tacrine.70 The HLA system plays a key role in delayed immune-mediated adverse drug reactions including DILI,12 and after its genetic variability was shown to be strongly associated with abacavir-induced hypersensitivity,71 it has also become one of the most interesting targets for genetic association studies of DILI. Associations of HLA variants with DILI are exemplified by the HLA-B*5701 genotype (rs2395029[G]) in flucloxacillin-induced DILI, which also represents the strongest single risk factor for idiosyncratic DILI ever found. The aforementioned GWAS of flucloxacillin-induced DILI included 51 cases and 282 controls and yielded an exceptionally high odds ratio of 80.6 (22.8-284.9). The authors further estimated a high population-attributable fraction of 64% for DILI associated with HLA-B*5701. Nevertheless, given the rare overall risk AG-014699 mw of DILI associated with flucloxacillin,3 the absolute risk to develop

DILI for individuals with this genotype when treated with flucloxacillin is only 1 in every 500-1000.38 However, predictability of flucloxacillin-induced DILI could be improved by consideration of other risk factors. In HLA-B*5701 positive cases from this study, the ST6GAL1 gene, which encodes an enzyme involved in transfer of sialic Vitamin B12 acid to cell-surface and serum glycoproteins, was also associated

with DILI. The second GWAS mentioned above also identified HLA variants as risk factors for DILI. In 74 cases and 130 controls both treated with ximelagatran, a genetic association between DILI and HLA-DRB1*0701 was found.14 As part of an extended haplotype, there also was an association of this genetic marker with the HLA-DQA1*02 allele, which has been linked to autoimmune hepatitis. Interestingly, metabonomic studies showed that lower pyruvate levels were associated with ximelagatran adverse drug events, suggesting that these patients may have a reduced oxidative stress response. The immunological basis of DILI was further strengthened by the presence of colony-stimulating factor 1 receptor (CSF1R) in serum (shedding of CSF1R is a marker of monocyte activation),72 and ximelagatran also showed competitive binding to HLA-DR7. Pharmacogenetic studies of lumiracoxib, a cyclooxygenase-2 selective inhibitor that was withdrawn for hepatotoxicity after the U.S. Food and Drug Administration issued a “nonapprovable” letter in 2007, identified the DRB1*1501-DQA1*0102-DQB1*0602-DRB5*0101 haplotype to be associated with elevated aminotransferases, the same HLA class II association that has been described for amoxicillin-clavulanate.