Reactions of adriamycin with microsomal iron and lipids.
Iron plays a central role in oxidative injury, reportedly because it catalyzes superoxide- and hydrogen peroxide-dependent reactions yielding a powerful oxidant such as the hydroxyl radical. Iron is also thought to mediate the cardiotoxic and antitumour effects of adriamycin and related compounds. NADPH-supplemented microsomes reduce adriamycin to a semiquinone radical, which in turn re-oxidizes in the presence of oxygen to form superoxide and hence hydrogen peroxide. During this redox cycling membrane-bound nonheme iron undergoes superoxide dismutase- and catalase-insensitive reductive release. Membrane iron mobilization triggers lipid peroxidation, which is markedly enhanced by simultaneous addition of superoxide dismutase and catalase. The results indicate that: i) lipid peroxidation is mediated by the release of iron, yet the two reactions are governed by different mechanisms; and ii) oxygen radicals are not involved in or may actually inhibit adriamycin-induced lipid peroxidation. Microsomal iron delocalization and lipid peroxidation might represent oxyradical-independent mechanisms of adriamycin toxicity.
Minotti
G
G
Institute of General Pathology, Catholic University, School of Medicine, Rome, Italy.
D000818:Animals; D004317:Doxorubicin / Q000378:metabolism*; D005609:Free Radicals; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D066298:In Vitro Techniques; D007501:Iron / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D005609:Free Radicals; D006878:Hydroxides; D017665:Hydroxyl Radical; D009249:NADP; D004317:Doxorubicin; D007501:Iron