Most cases with antituberculosis
drug-induced hepatitis have been attributed to
isoniazid.
Isoniazid is metabolized by hepatic N-
acetyltransferase (
NAT) and
cytochrome P450 2E1 (
CYP2E1) to form hepatotoxins. However, the role of
CYP2E1 in this hepatotoxicity has not yet been reported. The aim of this study was to evaluate whether the polymorphism of the
CYP2E1 gene is associated with antituberculosis
drug-induced hepatitis. A total of 318
tuberculosis patients who received antituberculosis treatment were followed prospectively. Their
CYP2E1 and NAT2 genotypes were determined using a polymerase chain reaction with restriction fragment length polymorphism method. Twenty-one healthy volunteers were recruited for
CYP2E1 phenotype study using a
chlorzoxazone test. Forty-nine (15.4%) patients were diagnosed to have
drug-induced hepatotoxicity. Patients with homozygous wild genotype
CYP2E1 c1/c1 had a higher risk of hepatotoxicity (20.0%; odds ratio [OR], 2.52) than those with mutant allele c2 (
CYP2E1 c1/c2 or c2/c2, 9.0%, P =.009). If
CYP2E1 c1/c2 or c2/c2 genotype combined with rapid acetylator status was regarded as the reference group, the risk of hepatotoxicity increased from 3.94 for
CYP2E1 c1/c1 with rapid acetylator status to 7.43 for
CYP2E1 c1/c1 with slow acetylator status. After adjustment for acetylator status and age, the
CYP2E1 c1/c1 genotype remained an independent risk factor for hepatotoxicity (OR, 2.38; P =.017). Furthermore, under the administration of
isoniazid, the volunteers with
CYP2E1 c1/c1 genotype had higher
CYP2E1 activity than those with other genotypes had and, hence, might produce more hepatotoxins. In conclusion,
CYP 2E1 genetic polymorphism may be associated with susceptibility to antituberculosis
drug-induced hepatitis.