The role of cigarette smoking and liver enzymes polymorphisms in anti-tuberculosis drug-induced hepatotoxicity in Brazilian patients

Tuberculosis (Edinb). 2014 May;94(3):299-305. doi: 10.1016/j.tube.2014.03.006. Epub 2014 Apr 1.

Abstract

Tuberculosis (TB) is still a major health concern and side-effects related to the treatment, especially drug-induced hepatotoxicity (DIH), should be better investigated. In the present study, a possible association between anti-TB DIH and cigarette smoking, N-acetyltransferase 2 (NAT2), Cytochrome P450 2E1 (CYP2E1) and Cytochrome P450 3A4 (CYP3A4) genotypes was studied in 131 TB Brazilian patients. The NAT2 and CYP3A4 genetic polymorphisms were determined using a polymerase chain reaction (PCR) direct sequencing approach and genetic polymorphisms of CYP2E1 gene were determined by restriction fragment length polymorphism (RFLP). The risk of anti-TB DIH was lower in rapid/intermediate acetylators when compared to slow acetylators (OR: 0.34, CI 95: 0.16-0.71; p < 0.01). A decreased risk of developing anti-TB DIH was also observed in active smokers when compared to non-smokers (OR: 0.28, 95 CI: 0.11-0.64; p < 0.01). Significant association between CYP3A4 genotypes and hepatotoxicity was not observed, as well as between CYP2E1 genotype and hepatotoxicity, whose frequency of patients with wild homozygous was more prevalent. The anti-TB drugs interactions with smoking on hepatotoxicity, as well as the NAT2 phenotype, may require to adjust therapeutic regimen dosages or alarm in case of adverse event developments.

Keywords: Anti-tuberculosis drug; Cigarette smoking; Hepatotoxicity; Liver enzymes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antitubercular Agents / adverse effects*
  • Arylamine N-Acetyltransferase / genetics
  • Case-Control Studies
  • Chemical and Drug Induced Liver Injury / enzymology
  • Chemical and Drug Induced Liver Injury / genetics*
  • Cytochrome P-450 CYP2E1 / genetics
  • Cytochrome P-450 CYP3A / genetics
  • Female
  • Genetic Predisposition to Disease / genetics
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Phenotype
  • Polymerase Chain Reaction
  • Polymorphism, Genetic / genetics*
  • Polymorphism, Restriction Fragment Length
  • Retrospective Studies
  • Risk Factors
  • Smoking / genetics*
  • Tuberculosis / drug therapy*
  • Tuberculosis / enzymology
  • Tuberculosis / genetics

Substances

  • Antitubercular Agents
  • Cytochrome P-450 CYP2E1
  • Cytochrome P-450 CYP3A
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human