The mitochondrial enzyme manganese superoxide dismutase (E.C. 18.104.22.168, SOD2)—a critical determinant of cellular defence against toxic insult to the liver—is the major scavenger of mitochondrial superoxide. The SOD2 mutant C allele (T > C polymorphism in codon 16 of the mitochondrial targeting sequence resulting in an alanine for valine substitution) allows the preprotein to be more efficiently imported into the mitochondrial matrix and subsequently enhanced mitochondrial activity of the mature protein.4 Surprisingly, the more efficient C variant allele
has been shown to increase the susceptibility to DILI, particularly related to antituberculosis drugs, but also to other drugs, in Taiwanese patients.5 RAD001 This unexpected finding has been attributed to the accumulation of higher amounts of hydrogen peroxide generated by the enhanced SOD2 activity. In addition to SOD2, glutathione peroxidases can
modulate the intracellular level of hydrogen peroxide. Glutathione peroxidase 1 (E.C. 22.214.171.124, GPX1) is part of the cellular antioxidant defence system by catalyzing the reduction of hydrogen peroxide (and various organic hydroperoxides) to water using reduced glutathione as a co-substrate. GPX1 is the main glutathione peroxidase in the mammalian liver and plays a significant role in preventing mitochondrial PXD101 oxidative stress.6 A polymorphism in codon 200, initially assigned to codon 198 of the human GPX1 gene and designated as rs1050450, encodes for either a proline or a leucine amino acid. The presence of a leucine at this position has been shown to reduce enzyme activity by 40%.7 Scarce information
is available on polymorphisms in the SOD2 and GPX1 genes in Caucasian patients and their relevance in DILI development susceptibility. To perform a more comprehensive selleck screening library approach to the study of mitochondrial antioxidant genetics in DILI, this study was undertaken to investigate potential associations between the SOD2 Val16Ala and GPX1 Pro200Leu polymorphisms and the risk of developing idiosyncratic hepatotoxicity. CI, confidence interval; CNS, central nervous system; DILI, drug-induced liver injury; GPX1, glutathione peroxidase-1; NSAID, nonsteroidal anti-inflammatory drug; OR, odds ratio; ROS, reactive oxygen species; SOD2, manganese superoxide dismutase. Cases of DILI were selected from those submitted to the Spanish DILI Registry, in use in southern Spain since 1994 and coordinated by two of the authors (R.J.A. and M.I.L.).The operational structure of the registry, data recording, and case ascertainment have been reported elsewhere.