title: Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury.
abstract: Antituberculosis drug-induced liver injury (ATDILI) is the most prevalent hepatotoxicity in many countries. All of the three first-line antituberculosis drugs, isoniazid, rifampicin, and pyrazinamide, may induce hepatic damage, especially isoniazid. The major drug-metabolizing enzyme of isoniazid is N-acetyltransferase (NAT). Other possible enzymes are CYP2E1, glutathione S-transferase (GST) and manganese superoxide dismutase (MnSOD, SOD2). There is evidence that variations of the genes that encode these enzymes may influence the activity of the corresponding drug-metabolizing enzymes. Recent studies have demonstrated that these genetic variations may be associated with the risk of ATDILI. Among them, NAT acetylation status has been most studied. The proposed risk-associated genotypes are NAT2 slow acetylator (without wild-type NAT2*4 allele), CYP2E1 *1A/*1A (homozygous wild type), homozygous null GSTM1 genotype and MnSOD mutant C allele. Although the available data in the field are complex and inconsistent, meta-analyses disclosed that NAT2 slow acetylator status possesses the highest association (odds ratio = 3.18). There are associations of CYP2E1 *1A/*1A and homozygous null GSTM1 genotype with ATDILI by meta-analyses, but the odds ratios were lower than that of NAT2. Of note, there was an ethnic difference in this association. The ATDILI in East Asians seems to have a higher correlation with genetic variations of NAT2, CYP2E1 and GSTM1. However, the meta-analyses could not validate these associations in Caucasians, although some showed positive correlations. To mitigate the crucial ATDILI, this review article underlines the importance of this pharmacogenetic endeavor to identify high-risk patients.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital and National Yang-Ming University School of Medicine, Taipei, Taiwan, ROC. Electronic address: yshuang@vghtpe.gov.tw.
authors.forename: Yi-Shin
authors.initials: YS
authors.lastname: Huang
mesh_terms: D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics*; D014644:Genetic Variation; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: D000995:Antitubercular Agents; D013482:Superoxide Dismutase; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D005982:Glutathione Transferase
keywords: arylamine acetyltransferase; cytochrome P450 2E1; drug-induced liver injury; genetic variation; glutathione S-transferase; isoniazid; toxic hepatitis; tuberculosis