Mitochondrial Superoxide Dismutase and Glutathione Peroxidase in Idiosyncratic Drug-Induced Liver Injury

Abstract

Drug-induced liver injury (DILI) susceptibility has a potential genetic basis. We have evaluated possible associations between the risk of developing DILI and common genetic variants of the manganese superoxide dismutase (SOD2Val16Ala) and glutathione peroxidase (GPX1Pro200Leu) genes, which are involved in mitochondrial oxidative stress management. Genomic DNA from 185 DILI patients assessed by the Council for International Organizations of Medical Science scale and 270 sex- and age-matched controls were analyzed. TheSOD2andGPX1genotyping was performed using polymerase chain reaction restriction fragment length polymorphism and TaqMan probed quantitative polymerase chain reaction, respectively. The statistical power to detect the effect of variant alleles with the observed odds ratio (OR) was 98.2% and 99.7% for bilateral association ofSOD2andGPX1, respectively. TheSOD2Ala/Ala genotype was associated with cholestatic/mixed damage (OR = 2.3; 95% confidence interval [CI] = 1.4-3.8; correctedP[Pc] = 0.0058), whereas theGPX1Leu/Leu genotype was associated with cholestatic injury (OR = 5.1; 95%CI = 1.6-16.0;Pc= 0.0112). The presence of two or more combined risk alleles (SOD2Ala andGPX1Leu) was more frequent in DILI patients (OR = 2.1; 95%CI = 1.4-3.0;Pc= 0.0006). Patients with cholestatic/mixed injury induced by mitochondria hazardous drugs were more prone to have theSOD2Ala/Ala genotype (OR = 3.6; 95%CI = 1.4-9.3;Pc= 0.02). This genotype was also more frequent in cholestatic/mixed DILI induced by pharmaceuticals producing quinone-like or epoxide metabolites (OR = 3.0; 95%CI = 1.7-5.5;Pc= 0.0008) and S-oxides, diazines, nitroanion radicals, or iminium ions (OR = 16.0; 95%CI = 1.8-146.1;Pc= 0.009).