Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients

Mem Inst Oswaldo Cruz. 2011 Sep;106(6):716-24. doi: 10.1590/s0074-02762011000600011.

Abstract

Isoniazid (INH), one of the most important drugs used in antituberculosis (anti-TB) treatment, is also the major drug involved in hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, such as NAT2, CYP2E1, GSTM1 and GSTT1, that code for drug-metabolising enzymes. Our goal was to examine the polymorphisms in these enzymes as susceptibility factors to anti-TB drug-induced hepatitis in Brazilian individuals. In a case-control design, 167 unrelated active tuberculosis patients from the University Hospital of the Federal University of Rio de Janeiro, Brazil, were enrolled in this study. Patients with a history of anti-TB drug-induced acute hepatitis (cases with an increase to 3 times the upper limit of normal serum transaminases and symptoms of hepatitis) and patients with no evidence of anti-TB hepatic side effects (controls) were genotyped for NAT2, CYP2E1, GSTM1 and GSTT1 polymorphisms. Slow acetylators had a higher incidence of hepatitis than intermediate/rapid acetylators [22% (18/82) vs. 9.8% (6/61), odds ratio (OR), 2.86, 95% confidence interval (CI), 1.06-7.68, p = 0.04). Logistic regression showed that slow acetylation status was the only independent risk factor (OR 3.59, 95% CI, 2.53-4.64, p = 0.02) for the occurrence of anti-TB drug-induced hepatitis during anti-TB treatment with INH-containing schemes in Brazilian individuals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Adult
  • Antitubercular Agents / adverse effects*
  • Arylamine N-Acetyltransferase / genetics*
  • Brazil / ethnology
  • Case-Control Studies
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Cytochrome P-450 CYP2E1 / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Glutathione Transferase / genetics*
  • Humans
  • Isoniazid / adverse effects*
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Genetic*
  • Risk Factors
  • Tuberculosis, Pulmonary / drug therapy

Substances

  • Antitubercular Agents
  • Cytochrome P-450 CYP2E1
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • glutathione S-transferase T1
  • Glutathione Transferase
  • Isoniazid