NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis.

Background: Most cases with anti-tuberculosis drug-induced hepatotoxicity (ATDH) have been attributed to isoniazid.

Objective: To evaluate whether the polymorphisms of the cytochrome P450 2EI (CYP2E1) and N-acetyltransferase 2 (NAT2) gene are associated with ATDH.

Methods: A total of 140 tuberculosis (TB) patients without liver diseases before treatment who received anti-tuberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using the TaqMan polymerase chain reaction assay.

Results: Forty-five (32.1%) patients were diagnosed with ATDH. No significant differences were reported in age and sex between patients with and without ATDH. Slow acetylators defined by NAT2 genotypes had a higher risk of hepatotoxicity than rapid acetylators (51.2% vs. 25.2%, P = 0.0026). Odds ratio (OR) analysis showed that slow acetylator status (OR 3.15, 95%CI 1.47-6.48) was the only independent risk factor for ATDH. Pyrazinamide co-administration induced hepatitis was also associated with NAT2 acetylator status. CYP2E1 c1/c1 homozygotes are prone to developing more severe hepatotoxicity than other c1/c2 and c2/c2 genotypes.

Conclusions: The slow acetylator status of NAT2 is a significant susceptibility risk factor for ATDH. CYP2E1 is associated with the severity of ATDH.