The toxicity of menadione and mitozantrone in human liver-derived Hep G2 hepatoma cells.
The cytotoxic properties of quinone drugs such as menadione and adriamycin are thought to be mediated through one-electron reduction to semiquinone free radicals. Redox cycling of the semiquinones results in the generation of reactive oxygen species and in oxidative damage. In this study the toxicity of mitozantrone, a novel quinone anticancer drug, was compared with that of menadione in human Hep G2 hepatoma cells. Mitozantrone toxicity in these cells was not mediated by the one-electron reduction pathway. In support of this, inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells from oxidative damage, did not affect the response of the Hep G2 cells to mitozantrone, whereas it exacerbated menadione toxicity. In addition, the toxicity of menadione was preceded by depletion of reduced glutathione which was probably due to oxidation of the glutathione. Mitozantrone did not cause glutathione depletion prior to cell death. DT-diaphorase activity and intracellular glutathione were found to protect the cells from the toxicity of both quinones. Inhibition of epoxide hydrolase potentiated mitozantrone toxicity but did not affect that of menadione. Our experiments indicate that mitozantrone toxicity may involve activation to an epoxide intermediate. Both quinone drugs inhibited cytochrome P-450-dependent mixed-function oxidase activity, although menadione was more potent in this respect.
Duthie
S J
SJ
Clinical Pharmacology Unit, Department of Medicine and Therapeutics, University of Aberdeen, U.K.
Grant
M H
MH
D000328:Adult; D001711:Biotransformation; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000037:antagonists & inhibitors; D006801:Humans; D008658:Inactivation, Metabolic; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D008942:Mitoxantrone / Q000378:metabolism* / Q000494:pharmacology; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000378:metabolism* / Q000494:pharmacology
D014812:Vitamin K; D008942:Mitoxantrone; D010088:Oxidoreductases; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; D005978:Glutathione