Evidence for human liver mediated free-radical formation by doxorubicin and mitozantrone

Electron spin resonance (e.s.r.) studies showed the presence of doxorubicin (g = 2.0038) and mitozantrone (g = 2.0036) free radicals in human liver microsomes incubated with drug (50 microD) and supplemented with NADPH. In the same individual liver samples and at the concentration of drug used for e.s.r. studies doxorubicin also stimulated a many-fold increase in the rate of microsomal NADPH oxidation and superoxide anion (O2-) production. In contrast, mitozantrone increased basal rate microsomal NADPH oxidation and O2- production only slightly. These results suggest that a free-radical mechanism other than drug-stimulated O2- production is responsible for the biological activities of mitozantrone. In addition, this study validates the previous use of animal-model systems to investigate the occurrence and consequences of doxorubicin and mitozantrone activation.