NAT2 and CYP2E1 polymorphisms and susceptibility to first-line anti-tuberculosis drug-induced hepatitis.
BACKGROUND
Most cases with anti-tuberculosis drug-induced hepatotoxicity (ATDH) have been attributed to isoniazid.


OBJECTIVE
To evaluate whether the polymorphisms of the cytochrome P450 2EI (CYP2E1) and N-acetyltransferase 2 (NAT2) gene are associated with ATDH.


METHODS
A total of 140 tuberculosis (TB) patients without liver diseases before treatment who received anti-tuberculosis treatment were followed prospectively. Their CYP2E1 and NAT2 genotypes were determined using the TaqMan polymerase chain reaction assay.


RESULTS
Forty-five (32.1%) patients were diagnosed with ATDH. No significant differences were reported in age and sex between patients with and without ATDH. Slow acetylators defined by NAT2 genotypes had a higher risk of hepatotoxicity than rapid acetylators (51.2% vs. 25.2%, P = 0.0026). Odds ratio (OR) analysis showed that slow acetylator status (OR 3.15, 95%CI 1.47-6.48) was the only independent risk factor for ATDH. Pyrazinamide co-administration induced hepatitis was also associated with NAT2 acetylator status. CYP2E1 c1/c1 homozygotes are prone to developing more severe hepatotoxicity than other c1/c2 and c2/c2 genotypes.


CONCLUSIONS
The slow acetylator status of NAT2 is a significant susceptibility risk factor for ATDH. CYP2E1 is associated with the severity of ATDH.
Lee
S-W
SW
Chest Medicine, Department of Internal Medicine, Taoyuan General Hospital, Taoyuan, Taiwan.
Chung
L S-C
LS
Huang
H-H
HH
Chuang
T-Y
TY
Liou
Y-H
YH
Wu
L S-H
LS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D011718:Pyrazinamide / Q000009:adverse effects / Q000627:therapeutic use; D012307:Risk Factors; D012720:Severity of Illness Index; D055815:Young Adult
D000995:Antitubercular Agents; D011718:Pyrazinamide; D019392:Cytochrome P-450 CYP2E1; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid