CYP2E1 mediated isoniazid-induced hepatotoxicity in rats.
OBJECTIVE
To investigate the role of CYP2E1 in isoniazid (INH)-induced hepatotoxicity and the influence of rifampicin (RFP) on INH-induced liver injury.


METHODS
Rats were treated with INH alone (100 mg/kg, ip) or co-administered with RFP (100 mg/kg, ig) for 10 d and 21 d. Hepatotoxicity was assayed by plasma enzymes (sALT, sAST) and histopathological examinations. Hepatic CYP2E1 activity was measured by aniline hydroxylase (ANH), and CYP2E1 mRNA expression was determined by RT-PCR. Plasma hydrazine concentration was determined by RP-HPLC.


RESULTS
For a 10 d INH-treatment, hepatic CYP2E1 level was increased to 3.7-fold over the control; liver impairment appeared after 21 d treatment, while CYP2E1 and plasma hydrazine were, respectively, increased to 4.6-fold and 1.7-fold. However, in INH-RFP group for 10 d, CYP2E1 and plasma hydrazine were, respectively, decreased by 13 % and 18 % over INH group; similarly, hepatic injury is equal to INH group appeared after 21 d, and CYP2E1 was further decreased by 26 %. Correlation analysis showed that sALT had a positive correlation with plasma hydrazine and with CYP2E1 activity; CYP2E1 activity was also markedly correlated with plasma hydrazine. And compared with control, there is no difference in changes of CYP2E1 mRNA expression in INH and INH-RFP treatment for 21 d.


CONCLUSIONS
The metabolite of INH, hydrazine, plays an important role in INH-induced hepatotoxicity in rats. The induction of CYP2E1 by hydrazine is involved in the hepatotoxicity of INH. RFP does not exacerbate INH-induced hepatotoxicity in short term, which relates to down-regulation of CYP2E1.
Yue
Jiang
J
Department of Pharmacology, Medical College of Wuhan University, Wuhan 430071, China.
Peng
Ren-xiu
RX
Yang
Jing
J
Kong
Rui
R
Liu
Juan
J
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000995:Antitubercular Agents / Q000009:adverse effects*; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D006834:Hydrazines / Q000097:blood; D007538:Isoniazid / Q000009:adverse effects*; D008099:Liver / Q000473:pathology; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D012293:Rifampin / Q000494:pharmacology
D000995:Antitubercular Agents; D006834:Hydrazines; D012333:RNA, Messenger; C029424:hydrazine; D019392:Cytochrome P-450 CYP2E1; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D007538:Isoniazid; D012293:Rifampin