Crucial role of cytochrome P450 in hepatotoxicity induced by 2,3-dimethoxy-1,4-naphthoquinone in rats.
Quinone toxicity is induced by two principal mechanisms: arylation/alkylation and a redox cycle. We have previously shown that increases in intracellular levels of superoxide anion and cell death induced by 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), a redox cycling quinone, are enhanced by pretreatment of rat primary hepatocytes with cytochrome P450 inhibitors. This indicates a novel interaction of quinones with cytochrome P450, and is thus worthy of further investigation using an in vivo model. The aim of this study was to examine the effects of cytochrome P450 inhibitors on DMNQ-induced hepatotoxicity in rats. When DMNQ was administered intraperitoneally, the activities of serum alanine aminotransferase and aspartate aminotransferase were found to increase in a dose-dependent manner, indicating that hepatotoxicity was induced by treatment with DMNQ. Pretreatment with the cytochrome P450 inhibitors SKF-525A (SKF), cimetidine and ketoconazole potentiated the DMNQ-induced hepatotoxicity. The blood concentration of DMNQ was not affected by administration of SKF. Pretreatment with the antioxidant α-tocopherol almost completely attenuated the hepatotoxicity induced by DMNQ and by the combination of DMNQ with SKF. Levels of reduced glutathione in the liver were decreased and levels of oxidized glutathione were increased by treatment with DMNQ. These effects were potentiated by pretreatment with SKF. DMNQ-induced lipid peroxidation in the liver was also enhanced by pretreatment with SKF. Taken together, these results indicate that DMNQ-induced hepatotoxicity is augmented by inhibition of cytochrome P450 and that this augmentation is due to the enhancement of oxidative stress.
Ishihara
Yasuhiro
Y
Faculty of Pharmaceutical Sciences at Kagawa, Tokushima Bunri University, Sanuki, Kagawa, Japan.
Ishii
Satomi
S
Sakai
Yufu
Y
Yamamura
Nobue
N
Onishi
Yukiko
Y
Shimamoto
Norio
N
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D002927:Cimetidine / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009285:Naphthoquinones / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011335:Proadifen / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015219:Substrate Cycling / Q000187:drug effects; D024502:alpha-Tocopherol / Q000627:therapeutic use
D000975:Antioxidants; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; C063002:2,3-dimethoxy-1,4-naphthoquinone; D002927:Cimetidine; D011335:Proadifen; D005978:Glutathione; D024502:alpha-Tocopherol; D007654:Ketoconazole