Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced hepatitis in Brazilian TB patients.
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.
Laboratório de Genética Humana, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil.
Raquel Lima de Figueiredo
RL
Teixeira
Renata Gomes
RG
Morato
Pedro Hernan
PH
Cabello
Ligia Mayumi Kitada
LM
Muniz
Adriana da Silva Rezende
Ada S
Moreira
Afrânio Lineu
AL
Kritski
Fernanda Carvalho Queiroz
FC
Mello
Philip Noel
PN
Suffys
Antonio Basilio de
AB
Miranda
Adalberto Rezende
AR
Santos
D000107:Acetylation; D000328:Adult; D000995:Antitubercular Agents / Q000009:adverse effects*; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D001938:Brazil / Q000208:ethnology; D016022:Case-Control Studies; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy
D000995:Antitubercular Agents; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; C413545:glutathione S-transferase T1; D005982:Glutathione Transferase; D007538:Isoniazid