Genotyping of the N-acetyltransferase2 Polymorphism in the Prediction of Adverse Drug Reactions to Isoniazid in Japanese Patients

Abstract

To investigate the association between NAT2 genotypes and the incidence of isoniazid (INH)-induced adverse reactions, in the hope of identifying a pharmacogenetic approach that could be useful in the prediction and prevention of adverse reactions in Japanese patients, we retrospectively studied the genotypes of NAT2 in 102 Japanese patients treated with INH (without rifampicin co-administration). The subjects were classified into three groups according to their genotypes: rapid-type, intermediate-type, and slow-type. The clinical conditions of the patients were followed-up in order to evaluate the development of any adverse drug reactions (ADRs) and correlate them with patient genotypes. Six out of the 102 patients (5.9%) developed various ADRs following INH treatment. These reactions included nausea/vomiting, fever, visual impairment, and peripheral neuritis. We found a statistically significant difference between the incidence of ADRs and NAT2 genotype. The incidence of ADRs was significantly higher in the slow type than in the other two types, as 5 out of the 6 ADR patients were of the slow-type, and the other one was of the intermediate-type, while no patients of the rapid-type developed any ADRs. The results indicated that the genes coding for slow acetylation were associated with the incidence of serious ADRs following INH treatment. Our findings suggest that determination of NAT2 genotype might be clinically useful in the evaluation of patients at high risk of developing ADRs induced by INH.

Acetylator Status on Tuberculosis Patients Receiving Isoniazid-Contained Antituberculosis Regiment

“…The proportion of rapid acetylator was also dominant in China (71-80%) and Japan (91-94%). 4,5,9,10,11 Contrary to our result, the slow acetylator was dominant in several populations. The proportion of slow acetylator was slightly higher than rapid acetylator on studied conducted in India (55%) and Brazil (55%).…”

“…This included several studies conducted in China, Japan, India, and Brazil. 3,5,6,9,10,11,12 This study showed the major acetylator status in tuberculosis patients were rapid acetylator. This indicated that the risk of hepatotoxic effect after tuberculosis treatment in most of our subjects was relatively not high.…”

“…Several studies had been studied about the relationship between acetylator status and risk of hepatotoxic; all of which showed a significant correlation. 3,5,6,9,10,11,12 Otherwise, the proportions of slow acetylator were varies in several studies. Thus indicated the different risk for hepatotoxic effect in different population.…”

“…Slow acetylator was considered to be a significant risk factor related to hepatotoxic effect of antituberculosis. 3,5,6,9,10,11,12 The acetylator status of tuberculosis patients based on subject characteristics were shown on Table 2. Isoniazid was considered to be antituberculosis that most responsible for the incidence of hepatotoxic effect after tuberculosis treatment.…”

Genotype and phenotype of NAT2 and the occurrence of adverse drug reactions in Mexican individuals to an isoniazid-based prophylactic chemotherapy for tuberculosis

“…Despite the dosage of the drug used for chemotherapy of TB, different drug-related adverse reactions have been observed, including peripheral neuritis, fever, visual damage, gastric intolerance, nettle rash and hepatic toxicity (1,2).…”