Protective effects of thiopronin against isoniazid-induced hepatotoxicity in rats.
Isoniazid is a widely used drug for the treatment of tuberculosis, but hepatotoxicity is a major concern during treatment. Thiopronin contains an SH-group and is generally considered an antioxidant. The aim of the present study was to investigate the effects of thiopronin during liver injury and DNA damage induced by isoniazid. Rats were injected daily with isoniazid (100 mg/kg, i.p.) for 21 days with or without thiopronin co-administration (60 mg/kg, i.p.) from day 11 to day 21. The influence of thiopronin on isoniazid-induced DNA oxidative damage was analyzed in precision-cut rat liver slices by HPLC-MS/MS. Thiopronin prevented isoniazid-induced hepatotoxicity, indicated by both diagnostic indicators of liver damage (alanine aminotransferase and aspartate aminotransferase) and histopathological analysis. In vivo, thiopronin significantly inhibited isoniazid-induced CYP2E1 activity as assessed by both chlorzoxazone hydroxylase and aniline hydroxylase (p<0.001). Thiopronin concentration-dependently inhibited CYP2E1-dependent aniline hydroxylation, and the Dixon plots suggest that thiopronin is a competitive inhibitor of CYP2E1. Thiopronin markedly attenuated isoniazid-induced inhibition of the detoxification system through cytosolic glutathione S-transferases (GSTs), including mu GST and alpha GST. In precision-cut liver slices, the free radical scavenging activity of thiopronin reduced the generation of DNA adducts induced by isoniazid (p<0.05). Altogether, these results suggest that thiopronin exerts its hepatoprotective activity against isoniazid-induced hepatotoxicity by inhibiting the production of free radicals in addition to its role as a scavenger. Thiopronin may reduce free radical generation via inhibition of hepatic CYP2E1 and increase the removal of free radicals directly or through the induction of cytosolic GSTs.
Yue
Jiang
J
Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China.
Dong
Guicheng
G
He
Chunyan
C
Chen
Jie
J
Liu
Yinghui
Y
Peng
Renxiu
R
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000410:Alanine Transaminase / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D002753:Chlorzoxazone / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D019610:Cytoprotection; D018736:DNA Adducts; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005982:Glutathione Transferase / Q000378:metabolism; D006900:Hydroxylation; D007538:Isoniazid; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D008625:Tiopronin / Q000494:pharmacology*
D000814:Aniline Compounds; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D018736:DNA Adducts; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D000080242:8-Hydroxy-2'-Deoxyguanosine; D008625:Tiopronin; D019392:Cytochrome P-450 CYP2E1; D005982:Glutathione Transferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003849:Deoxyguanosine; D002753:Chlorzoxazone; C023650:aniline; D007538:Isoniazid