Effects of rifampin on CYP2E1-dependent hepatotoxicity of isoniazid in rats.
Isoniazid and rifampin are first line drugs used to prevent and treat tuberculosis. The effects of rifampin co-administration on isoniazid-induced oxidative stress were investigated by the determination of the changes in hepatic metabolizing enzymes and DNA damage. Rats were treated with isoniazid alone (100 mg/kg, i.p.) or co-treated with rifampin (100 mg/kg, i.g.) for 10 or 21 days. Activities of CYP2E1, CYP1A1, CYP3A and glutathione S-transferases (GSTs) were analyzed by specific substrates. DNA oxidative damage by drug treatments was analyzed in precision-cut liver slices by HPLC-MS/MS. Isoniazid significantly increased CYP2E1 activities above control levels after 10 or 21 days treatment (2.25-4.59-fold), indicated by both chlorzoxazone hydroxylase and aniline hydroxylase (p<0.01). Isoniazid treatment decreased activities of cytosolic total GST, alpha GST and mu GST after 21 days (p<0.01). No change in activities of CYP1A1, CYP3A, and CYP3A1 mRNA expression was observed after isoniazid treatment. Rifampin co-administration significantly attenuated isoniazid-induced CYP2E1 levels (p<0.01) and inhibition of mu GST (p<0.01). Rifampin did not increase the formation of DNA adducts induced by isoniazid. These results suggest that rifampin co-administration does not increase isoniazid-induced oxidative stress through hepatic CYP2E1 during short-term treatment in experimental rats.
Yue
Jiang
J
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China.
Peng
Renxiu
R
Chen
Jie
J
Liu
Yinghui
Y
Dong
Guicheng
G
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology*; D051544:Cytochrome P-450 CYP3A; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D007538:Isoniazid / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012293:Rifampin / Q000494:pharmacology*
D000080242:8-Hydroxy-2'-Deoxyguanosine; D019392:Cytochrome P-450 CYP2E1; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D005982:Glutathione Transferase; D003849:Deoxyguanosine; D007538:Isoniazid; D012293:Rifampin