Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity.
METHODS
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Ohno
M
M
Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
Yamaguchi
I
I
Yamamoto
I
I
Fukuda
T
T
Yokota
S
S
Maekura
R
R
Ito
M
M
Yamamoto
Y
Y
Ogura
T
T
Maeda
K
K
Komuta
K
K
Igarashi
T
T
Azuma
J
J
D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects* / Q000378:metabolism / Q000627:therapeutic use; D007564:Japan; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012293:Rifampin / Q000009:adverse effects* / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000208:ethnology* / Q000235:genetics
D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid; D012293:Rifampin