NAT2 variants are associated with drug-induced liver injury caused by anti-tuberculosis drugs in Indonesian patients with tuberculosis

Abstract

Drug-induced liver injury (DILI) is the most common adverse drug reaction in the treatment of tuberculosis (TB). Several studies showed that patients with TB and the slow-acetylator phenotype caused by NAT2 variants are highly susceptible to DILI caused by anti-TB drugs, hereafter designated AT-DILI. However, the role of NAT2 variants in AT-DILI has never been assessed for an Indonesian population. We recruited 50 patients with TB and AT-DILI and 191 patients with TB but without AT-DILI; we then used direct DNA sequencing to assess single-nucleotide polymorphisms in the coding region of NAT2. NAT2*6A was significantly associated with susceptibility to AT-DILI (P=7.7 × 10(-4), odds ratio (OR)=4.75 (1.8-12.55)). Moreover, patients with TB and the NAT2-associated slow-acetylator phenotype showed higher risk of AT-DILI than patients with the rapid- or intermediate-acetylator phenotypes (P=1.7 × 10(-4), OR=3.45 (1.79-6.67)). In conclusion, this study confirms the significance of the association between slow-acetylator NAT2 variants and susceptibility to AT-DILI in an Indonesian population.

Sequence analysis of theN-acetyltransferase 2 gene (NAT2) among Jordanian volunteers

“…The NAT2 191G>A, 341T>C, and 590G>A clinically decrease the metabolism of isoniazid, sulphasalazine, and hydralazine associated with drug toxicity, such as hepatic, neuro-toxicity, and systemic lupus erythmatosus [2,7,8,10]. As Jordanian populations have a high frequency of slow-encoding NAT2 haplotype, the risk of toxicity induced by drugs metabolized by the NAT2 enzyme may be high among Jordanians.…”

“…Human N -acetyltransferase 2 ( NAT2 ) is a phase II drug-metabolizing enzyme, which is responsible for the acetylation of some drugs such as antituberculosis isoniazid and antimicrobial sulfonamides [1,2]. …”

High frequency of NAT2 slow acetylator alleles in the Malay population of Indonesia: an awareness to the anti-tuberculosis drug induced liver injury and cancer

“…5 A meta-analysis of 26 case-control studies also reported that the NAT2 SA genotype was a risk factor of antituberculosis drug induced liver injury (AT-DILI), but the associations are diverse in different ethnic populations. Significant results were found in East Asians, South Asians, Brazilians and Middle Eastern, but not in Caucasians.…”

“…3 The NAT2 slow acetylator phenotypes have been investigated to have association with cancer risk 4 and isoniazid-induced hepatotoxicity in tuberculosis treatment. 5 According to Sabbagh et al 6 the slow acetylator status is more frequent in all populations in Europe in which more than 50% of individuals (59% on average) carry the slow acetylator genotype. High prevalence of slow acetylator phenotype is also observed in many parts of Asia (Middle East, India, North Asia, and Southeast Asia).…”

Differentiation of N-acetyltransferase 2 (NAT2) rapid and intermediate acetylator based on genotype and urinary assay

“…Individuals can be classified as slow or rapid acetylators, on the basis of their NAT2 genotype, 6,7 although some authors consider a third intermediate category. 1,8,9 Slow (SA), intermediate (IA) and rapid acetylators (RA) consisted of homozygous of two slow alleles, heterozygous between rapid and slow allele and homozygous of two rapid alleles, respectively.…”