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Free Content Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity

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SETTING: Japanese in-patients with pulmonary tuberculosis and normal liver function receiving treatment with isoniazid and rifampicin (INH + RMP).

OBJECTIVE: To elucidate the relationship between N-acetyltransferase 2 (NAT2) genotype and the incidence of isoniazid + rifampicin-induced hepatotoxicity.

DESIGN: Prospective study. After NAT2* genotyping, 77 patients were classified into three groups according to their NAT2* genotypes: rapid-type (a homozygote of NAT2*4), intermediate-type (a heterozygote of NAT2*4 and mutant alleles) and slow-type (a combination of mutant alleles). Their biochemical profiles of liver function test were investigated for 3 months to assess the development of serum aminotransferase elevation.

RESULT: Of the 77 patients, 18.2% developed adverse hepatic reaction within the first month of INH + RMP treatment. A significant association was observed between hepatotoxicity and NAT2* genotype: compared with rapid-type, the relative risk was 4.0 (95%CI 1.94–6.06) for intermediate-type and 28.0 (95%CI 26.0–30.0) for slow-type. Especially in slow-type, the incidence of hepatotoxicity and serum aminotransferase elevation was significantly higher than in the other two types.

CONCLUSION: Slow NAT2* genotype significantly affected the development of INH + RMP-induced hepatotoxicity. This suggests the possibility that NAT2* genotyping prior to medication may be useful in evaluating patients with high risk for INH + RMP-induced hepatotoxicity.
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Keywords: N-acetyltransferase 2 (NAT2); genotype; hepatotoxicity; isoniazid; rifampicin

Document Type: Regular Paper

Affiliations: 1: Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan 2: Department of Internal Medicine, Toneyama National Hospital, Osaka, Japan 3: Clinical Laboratory, Toneyama National Hospital, Osaka, Japan 4: Second Department of Internal Medicine, NIT West Osaka Hospital, Osaka, Japan

Publication date: 01 March 2000

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  • The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on tuberculosis and lung health world-wide.

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