Abstract
The cytotoxic properties of quinones, such as menadione, are mediated through one electron reduction to yield semi-quinone radicals which can subsequently enter redox cycles with molecular oxygen leading to the formation of reactive oxygen radicals. In this study the role of reduction and oxidation in the toxicity of mitoxantrone was studied and its toxicity compared with that of adriamycin and menadione. The acute toxicity of mitoxantrone was not mediated through one-electron reduction, since inhibition of the enzymes glutathione reductase and catalase, responsible for protecting the cells against oxidative damage, did not affect its toxicity. Adriamycin was the most potent inhibitor of protein and RNA synthesis of the three quinones. Menadione, at concentrations up to 25 microM, did not inhibit either protein or RNA synthesis unless dicoumarol, an inhibitor of DT-diaphorase, was also present. The two-electron reduction of menadione by DT-diaphorase is therefore a protective mechanism in the cell. This enzyme also protected against the toxicity of high concentrations (100 microM) of mitoxantrone. The inhibitory effect of mitoxantrone, but not of menadione or adriamycin, on cell growth was prevented by inhibiting the activity of cytochrome P450-dependent mixed function oxidase (MFO) system using metyrapone. This suggests that mitoxantrone is oxidised to a toxic intermediate by the MFO system.
Highlights
The results provide evidence that mitoxantrone may be activated to a toxic metabolite by cytochrome P450 dependent oxidation and that one-electron reduction is not involved in the mechanism of toxicity
Inhibition of catalase by 1,2-aminotriazole and of glutathione reductase by BCNU exacerbated the effect of menadione on lactate dehydrogenase leakage but had no effect on the lactate dehydrogenase leakage from cells treated with mitoxantrone
The results of this study indicate that in human liver derived Hep G2 cells mitoxantrone-induced loss in cell viability is not mediated through the one-electron reduction/oxidative stress mechanism which is accepted for the cytotoxicity of quinone drugs such as menadione
Summary
The aim of this study was to investigate the mechanism(s) responsible for activation of mitoxantrone to cytotoxic metabolites and compare its toxicity with that of menadione and adriamycin
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