Formation of reactive intermediates by cytochrome P-450 mediated oxidation of the anti-cancer drug mitoxantrone

Abstract

Oxidative activation of mitoxantrone (1) is involved in the biotransformation of the anti-cancer drug. Two distinct reactive intermediates (5 and 6) interconnected by a tautomeric equilibrium are formed by enzymatic oxidation. Intermediate 5 showing Michael acceptor properties at ring C reacts intramolecularly to afford metabolite 7. In contrast, intermediate 6 presents electrophilic character at ring A and reacts intermolecularly with nucleophiles. Nucleophilic attack of glutathione gives rise to the formation of thioether derivatives (8–11). In the presence of the cytochrome P-450 inhibitor metyrapone, the oxidation of mitoxantrone is blocked as shown by the absence of formation of the metabolites 7 and 8. Under these conditions, the damaging effect of mitoxantrone on rat hepatocytes and human derived hepatoma (HepG2) cells is lost. Thus, it can be concluded, that the oxidative activation of mitoxantrone is involved in the cytotoxic effect of the drug. © 1994 IUPAC