Associations of HLA class II genes with DILI have also been reported

for the antituberculosis drugs isoniazid (DRB1*03), rifampin (DQA1*0102), see more and ethambutol (DQB1*0201).74 The recognition of the role of immune response regulation and universal downstream mechanisms in DILI defined related genetic variants as new targets for genetic association studies. Polymorphisms affecting the expression of the cytokine system may favor T cell–mediated immune responses, or may also promote hepatotoxicity regardless of the initial mechanism. The first CGAS that investigated IL-10 and IL-4 polymorphisms as risk factors for diclofenac-induced DILI therefore represents a conceptual landmark. This this website study found indeed that variants with low IL-10 (−627 AA/AC), and high IL-4 (−590 TT/CT) gene transcription are more frequently associated with DILI, and concluded that these may promote a T helper 2–mediated immune response to neoantigen formation.29 Another study found no association between IL-10, IL-4, and TNF-alpha variants and mixed DILI cases, but a low IL-10–producing variant was associated with DILI for subgroups of patients without peripheral blood eosinophilia and patients with serious DILI.31 Furthermore, variants of IL-6 were associated with increased aminotransferases under treatment with tacrine.75 Oxidative stress and antioxidant defense are involved

in many hepatotoxic mechanisms, including direct toxicity of reactive metabolites, upstream and downstream immune and inflammatory reactions, and MPT. Studies on DILI pharmacogenetics of oxidative stress relating to CYP450 enzymes and GST have

been discussed above. Considering the central mechanistic role of mitochondria in DILI mitochondrial manganese superoxide dismutase (SOD2) may be of particular interest because its function is essential for the scavenging of mitochondrial superoxide. Indeed, SOD2 knockout mice (SOD2 +/−) showed increased susceptibility to DILI caused by nimesulide76 Smad inhibitor and troglitazone.10 In humans, one study found that patients with a SOD2 mutant c allele have an elevated risk of DILI caused by various drugs.68 Furthermore, it may be of interest that antioxidant defense is under the master control of nuclear factor erythroid-derived 2-like (NFE2L), which has also been shown to be involved in DILI77, 78 and may therefore represent a potential target for future genetic association studies. The bile salt export pump (BSEP, ABCB11 gene) mediates the efflux of bile acids from hepatocytes into the bile canaliculus.79 Impairment of normal BSEP function results in intracellular accumulation of bile acids and consequent liver injury. Genetic variants of ABCB11 have been studied intensely in the context of various cholestatic disorders, including DILI.