Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatotoxicity in Tunisian patients with tuberculosis

Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring

“…The main metabolic pathway is by Nacetylation catalyzed by N-acetyltransferase 2 (NAT2), which exhibits genetic polymorphism [35]. Slow acetylators show a higher incidence of hepatotoxicity [36][37][38]. Rapid acetylators, on the other hand, may have a higher risk of therapeutic failure [6,39].…”

“…Several recent studies have shown that fast acetylators are at higher risk of treatment failure, whereas slow acetylators may have a higher risk for hepatotoxicity [6,[36][37][38][39]90]. Azuma et al carried out a randomized controlled trial for pharmacogenetic-controlled tuberculosis therapy [39].…”

PharmGKB summary

“…Consequently, the NAT2 slow acetylator phenotype and genotype have been associated with an increased risk of INH-induced hepatotoxicity in the majority of published pharmacogenetic studies (Table 1); the patient cohorts genotyped are of various geographic origins, mainly from South America [62–66], East Asia [35, 67–75], South Asia [40, 76–78], Iran [79], Turkey [80] and Tunisia [81]. The labels of all INH-containing drug formulations currently approved by the FDA inform that slow acetylators may have increased blood levels of the compound, which results in an increased risk of hepatotoxicity and peripheral neuropathy [10].…”

PharmGKB summary

“…An economic 4-SNP genotyping panel was reported to accurately predict NAT2 acetylator phenotype in different populations; rs1801280, rs1799930, rs1799931 and rs1801279 (Table 1) [40–42]. Early genotyping methods based on PCR-RFLP typically used Kpn I (cuts wildtype allele C at position 481 rs1799929), Taq 1 (cuts wildtype allele G at position 590 rs1799930) and BamH I (cuts wildtype allele G at position 857 rs1799931) enzymes to distinguish NAT2 * 4 from the slow alleles described as *5 , *6 and *7 , respectively (for example [43, 44]) or defined as *5B , *6A , and *7B , respectively (for example [45, 46]). However, such approaches may lead to misclassification as the three SNPs they detect are present in numerous NAT2* alleles (see Table 1).…”