NAT2*6A, a haplotype of the N-acetyltransferase 2 gene, is an important biomarker for risk of anti-tuberculosis drug-induced hepatotoxicity in Japanese patients with tuberculosis

Abstract

The present study shows that NAT2 is one of the determinants of anti-TB drug-induced hepatotoxicity. Moreover, the haplotypes, NAT2 4 and NAT2 6A, are useful new biomarkers for predicting anti-TB drug-induced hepatotoxicity.

The distribution of allelic and genotypic frequencies of N-Acetyltransferase-2 variants in an Argentine population

“…Expected genotype frequencies were calculated from respective single allele frequencies and were consistent with Hardy Weinberg equilibrium. Table 1 describes the allelic distribution of the four variants of NAT-2 that had the strongest impact on the acetylation profile in the Buenos Aires population and in different populations from various regions of Europe [1], Africa [1,12], Asia [1,6,9] and America [1,7 ,9, 13]. Our study group consisted of an admixture of ethnic groups with European (mainly from Spain, Italy and, to a lesser extent, from Germany and other countries of Eastern Europe), and Native American ancestries.…”

“…The major alleles groups associated with decreased enzyme activity due to amino acid changes and, therefore, a slow acetylator phenotype, are NAT-2*5, NAT-2*6, NAT-2*7 and NAT-2*14 [4]; in several surveys homozygous wild type alleles at all four loci that have no variations are called RA and are represented as NAT-2*4 [4][5][6][7].…”

“…INH, a substrate of NAT-2, is a first-line drug used in tuberculosis (TB) treatment, and it is considered to be responsible for adverse drug reactions that lead to hepatotoxicity [6,8,9]. Although an association between NAT-2 acetylation polymorphism and INH-induced hepatotoxicity has been reported by several studies, considerable controversies remain as a consequence of the wide variability in the results of these studies [5][6][8][9].…”

“…In patients, it can result in liver failure and death. In public health, TB is associated with a prolonged hospital treatment and the risk of developing bacterial resistance, implying an increase in health costs [5,6].…”

Pharmacogenetics and Metabolism: Past, Present and Future

“…On the other hand, fast acetylation of AcHZ and Hz in NAT2 rapid acetylators should theoretically form DiAcHZ efficiently and therefore reducing the oxidative metabolites accumulation from AcHZ. In fact, several studies found an increased risk in slow versus fast acetylators through genetically determined phenotype (Higuchi et al 2007). However, there are conflicting data on whether CYP2E1 genotypes do or do not increase the risk of isoniazid-induced (Cho et al 2007).…”