STIMULATION OF MOUSE HEART AND LIVER MICROSOMAL LIPID-PEROXIDATION BY ANTHRACYCLINE ANTI-CANCER DRUGS - CHARACTERIZATION AND EFFECTS OF REACTIVE OXYGEN SCAVENGERS

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  • 1 January 1983
    • journal article
    • research article
    • Vol. 226  (3) , 806-816
Abstract
The interaction of adriamycin or several other quinone-containing anthracycline anticancer drugs with mouse heart or liver microsomes resulted in greatly enhanced NADPH oxidation and 5- to 10-fold stimulation of NADPH-dependent, reactive O2-mediated microsomal lipid peroxidation. Adriamycin, daunorubicin, deacetyladriamycin and aclacinomycin A all stimulated lipid peroxidation maximally when included at concentrations of 100-200 .mu.M, whereas carminomilcin and 4-demethoxydaunorubicin produced equivalent enhancement of peroxidation at lower concentrations of 30-50 .mu.M. Mitomycin C markedly increased heart microsomal lipid peroxidation, but, interestingly, had little effect when liver microsomes were used. In contrast, 5-iminodaunorubicin and alkylaminoanthracenedione inhibited both heart and liver microsomal lipid peroxidation. NADPH supported anthracycline-stimulated lipid peroxidation; however, an NADPH-generating system provided greater activity. NADH was only about 50% as effective as NADPH and served as cofactor with liver microsomes but not with heart microsomes. Scavengers of reactive oxygen such as superoxide dismutase, reduced glutathione and 1,3-dimethylurea diminished the anthracycline-stimulated heart and liver microsomal lipid peroxidation, indicating that superoxide radical and hydroxyl radical participated in the peroxidation reactions. EDTA was also inhibitory, which suggests trace amounts of Fe were also required. Adriamycin, 4-demethoxydaunorubicin, carminomicin, aclacinomycin A and mitomycin C strikingly enhanced peroxidation of unsaturated lipids in mouse lung and kidney microsomes, indicating that anthracycline-mediated enhanced reactive oxyradical generation may have toxic consequences in those organs as well as in the heart. These observations support the proposal that anthracycline-accentuated membrane lipid peroxidation may be relevant to the pathogenesis of anthracycline cardiotoxicity.