Role of polymorphic N-acetyl transferase2 (NAT2) and cytochrome P4502E1 (CYP2E1) gene in ATT induced hepatitis

Abstract

Background and Aim: Antituberculosis drugs isoniazid and rifampicin in combination are known to develop drug induced hepatotoxicity (DIH). A higher risk of DIH during antituberculosis treatment (ATT) has been reported in Indian subcontinent compared to the western counterparts. The role of genetic factors in higher incidence of ATT hepatotoxicity in Indian population is still unclear. The present study was aimed at investigating the role of N-acetyltransferase2 (NAT2) and Cytochrome P4502E1 (CYP2E1) gene polymorphism in ATT hepatotoxicity. Design: The study population included 218 pulmonary tuberculosis patients who were started on ATT and followed up for the occurrence of ATT induced hepatitis. Genetic polymorphism of NAT2 and CYP2E1 gene was studied by PCR-RFLP. Results: Occurrence of DIH was 18.80% (41/218). There was a higher prevalence of NAT2 slow acetylator genotypes in DIH (70.73%) compared to non-DIH (44.63%), P < 0.05. The frequency of NAT2^∗5/^∗7 and NAT2^∗6/^∗7 genotypes was significantly higher in DIH than non-DIH (19.51% vs. 6.78% and 19.51% vs. 5.08%). No association of CYP2E1 RsaI polymorphism could be demonstrated with DIH. However, DraI C/D genotype of CYP2E1 gene was mostly prevalent in DIH (85.37%) compared to non-DIH (64.41%), P < 0.05. Slow acetylator status and CYP2E1 C/D or C/C genotype together showed higher frequency in DIH (65.85%) compared to non-DIH (28.81%), P < 0.0001. Conclusion: The study demonstrates for the first time a possible association between DraI polymorphism of CYP2E1 gene and the risk of ATT hepatotoxicity. Genotyping of NAT2 and CYP2E1 gene could possibly identifying the high risk group for developing ATT induced hepatitis prior to medication.