Sex, ethnicity, and slow acetylator profile are the major causes of hepatotoxicity induced by antituberculosis drugs

Abstract

Abstract Background and Aim Treatment with antituberculosis ( TB ) drugs produces liver damage in a large proportion of patients. Isoniazid, an antibacterial drug, is primarily responsible for this hepatotoxicity. Several polymorphisms of the N ‐acetyltransferase 2 ( NAT ‐2) and cytochrome P 450 2 E 1 enzymes, which are involved in the metabolism of isoniazid, may be directly associated with the development of hepatotoxicity. This study was designed to analyze the association between the NAT ‐2 and CYP 2 E 1 polymorphisms with the development of anti‐ TB drug‐induced hepatotoxicity ( ATDH ). Methods One hundred and seventy‐five TB patients who had been treated with anti‐ TB drugs were studied. The allelic and genotypic frequency distributions of the NAT ‐2 and CYP 2 E 1 enzymes were studied using polymerase chain reaction–restriction fragment length polymorphisms methodology. A binary logistic regression analysis was used to compare the results between TB patients with and without the development of hepatotoxicity. Results Having a slow acetylator status (odds ratio [ OR ] = 2.615; confidence interval [ CI ] = 1.264–5.411; P = 0.01), being female ( OR = 2.734; CI = 1.325–5.639, P = 0.006), and having B olivian ethnicity ( OR = 2.711; CI = 1.307–6.625, P = 0.007) were found to be independent predictor variables for ATDH . Conclusions This study showed that a patient's NAT ‐2 acetylator status, gender, and ethnic origin may be regarded as important risk factors for developing hepatotoxicity. Contrary to expectations, the CYP 2 E 1 c1/c2 polymorphism did not show a significant association with hepatotoxicity in this study. Given the increases in TB cases and ATDH incidence levels, as well as the associated hospitalization costs, it may also be helpful to know patients’ acetylator status prior to or at the beginning of the TB treatment regimen.