N-Acetyltransferase2 Genotype Correlated with Isoniazid Acetylation in Japanese Tuberculous Patients.

Abstract

In the early 1950s, isoniazid (INH) was developed as chemotherapeutic agent for the treatment of tuberculosis. 2)However, serious side effects including peripheral neuritis and hepatic toxicity were recognized in some patients, despite their dosage being similar to that taken by others. Previous studies indicated that INH was catabolized to inactive Nacetylisoniazid (AcINH) by N-acetyltransferase2 (NAT2) (Fig. 1), and that the interindividual variation of plasma concentration and urinary recovery of INH were characterized by a bimodal or trimodal distribution. 3,4) N-acetylation of INH is reported to be genetically determined in a simple Mendelian fashion, and the frequencies of rapid (and/or intermediate) and slow acetylator of INH is different among racial populations. 5) There have been studies on the relationships between the acetylator phenotype and the efficacy or side effects of INH. The rapid acetylators should take larger doses of INH than slow acetylators, 6) and slow acetylators are at risk of adverse reactions such as peripheral neuritis, 4) hepatic toxicity 4,7) and systemic lupus erythematosus-like syndromes.8,9) These findings strongly suggested the necessity of therapeutic drug monitoring (TDM) in blood or serum to define the most appropriate dosage regimen for each individual. 10,11) Recently, Deguchi and his colleagues defined four NAT2 alleles, the wild-type allele (NAT2*4) and three mutant alleles (NAT2*5B, NAT2*6A and NAT2*7B), which could explain 93-97.5% of the trimodal INH acetylator phenotype among Japanese healthy subjects.12,13) An individual INH N-acetyltransferase2 (NAT2). In the present study, the relationship between the NAT2 genotype and the INH acetylator phenotype was examined in Japanese tuberculous patients and compared with healthy subjects. Subjects were classified according to the genotyping into NAT2*5B (allele4), NAT2*6A (allele3) and NAT2*7B (allele2), using the PCR-RFLP method. Twelve healthy subjects and 7 tuberculous patients participated in the INH acetylator phenotyping study, in which each subject was administered an oral dose of INH, followed by urine sampling for 24 h. Urinary concentrations of INH and N-acetylisoniazid (AcINH) were measured by the HPLC method. The urinary recoveries of INH (% of dose) in healthy subjects in relation to NAT2 genotyping were as follows: 6.4؎2.2 in the homozygotes for the wild-type allele, 10.7؎ 2.2 in the compound heterozygotes for the mutant allele, and 38.6؎6.4 in the homozygotes for the mutant allele. In the patients study, the findings in the corresponding three groups were 4.0؎1.7, 8.8 and 18.3؎9.3. Although no significant difference was found because of the lower systemic exposure of INH in patients compared with healthy subjects, there were differences in the disposition kinetics of INH between subjects with and without mutations in the NAT2 gene, and these findings were observed not only in healthy subjects but also in patients who had comedicated drugs and hepatic dysfunctions. The findings indicated that the metabolism ...

The clinical role of genetic polymorphisms in drug-metabolizing enzymes

“…Subsequently, these earlier findings were complemented by genotyping studies showing a linear relationship of isoniazid pharmacokinetic parameters to the number of highly active NAT2 genes. [123][124][125] According to Kinzig-Schippers et al, 125 individual isoniazid clearance could be predicted as clearance (l/h) ¼ 10 þ 9 Â number of NAT2*4 alleles.…”

Genetic variation in carboxylesterase genes and susceptibility to isoniazid-induced hepatotoxicity

“…[15][16][17][18] An amidase enzyme(s) catalyzes two steps in the metabolism of INH. 19,20 There is strong evidence from an animal model that amidase activity levels influence hepatotoxicity; rabbits treated with an amidase inhibitor, bis-p-nitrophenyl phosphate, at the same time they are dosed with INH fail to develop the severe hepatotoxicity developed by animals treated with INH alone. 21 Modulation of hepatic amidase activity therefore affects the development of hepatotoxicity, likely by altering INH metabolism.…”

Effects of N-acetyltransferase 2 (NAT2), CYP2E1 and Glutathione-S-transferase (GST) genotypes on the serum concentrations of isoniazid and metabolites in tuberculosis patients

“…INH is mainly metabolized by N-acetyltransferase 2 (NAT2). The presence of NAT2 gene polymorphisms causes individual variation in the N-acetylation capacity of INH (Kita et al, 2001;Chen et al, 2006;Hiratsuka et al, 2002). People with low NAT2 activity have a higher risk of developing hepatic disorder than those with high NAT2 activity (Ohno et al, 2000;Huang et al, 2002).…”