Adriamycin-dependent release of iron from microsomal membranes.
Microsomes incubated with NADPH and the cardiotoxic anticancer drug adriamycin reductively release their bound nonheme iron, which is accounted for by ferritin and an as yet uncharacterized nonferritin pool. The reaction is mediated by one-electron reduction of adriamycin to semiquinone radical and subsequent reoxidation of this radical at the expense of membrane iron to regenerate adriamycin and promote Fe2+ release. The semiquinone radical of adriamycin can also reoxidize at the expense of molecular oxygen to form superoxide. However, superoxide dismutase does not inhibit Fe2+ release, indicating either that superoxide is not involved in iron reduction or that superoxide reacts at sites which are sterically inaccessible to the enzyme. It is proposed that the reductive mobilization of membrane-bound iron may mediate the therapeutic or toxic effects of adriamycin, irrespective of the superoxide dismutase content of the target cells.
Minotti
G
G
Institute of General Pathology, Catholic University, School of Medicine, Rome, Italy.
D000818:Animals; D004317:Doxorubicin / Q000494:pharmacology*; D005609:Free Radicals; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D005609:Free Radicals; D009249:NADP; D004317:Doxorubicin; D007501:Iron; D010634:Phenobarbital