Horseradish peroxidase-catalyzed oxidation of mitoxantrone: spectrophotometric and electron paramagnetic resonance studies

The clinical anticancer agent mitoxantrone is subject to irreversible oxidation by hydrogen peroxide catalyzed by horseradish peroxidase (HRP). the characteristic absorption changes that result provide evidence for an initial metabolite which is futher oxidized enzymatically. The formation of the metabolite is accompanied by the concomitant generation of a free radical species detected by EPR spectroscopy. The intensity of the latter is dependent on the ratio mitoxantrone to oxidant as well as on the pH of the medium. The metabolite in its oxidized form is a strong electrophile and can be reduced by biologically and physiologically relevant electron donors including ascorbic acid, L-cysteine and reduced glutathione. The results establish a new facile metabolic conversion of this clinically useful anticancer agent that may be relevant to its mode of action.