Interactions of adriamycin aglycones with mitochondria may mediate adriamycin cardiotoxicity.
Adriamycin and related anthracyclines are potent oncolytic agents, the clinical utility of which is limited by severe cardiotoxicity. Aglycone metabolites of Adriamycin (5-20 microM) induce a Ca(2+)-dependent increase in the permeability of the inner mitochondrial membrane of both heart and liver mitochondria to small (< 1,500 Da) solutes; this phenomenon is accompanied by release of mitochondrial Ca2+, mitochondrial swelling, collapse of the membrane potential, oxidation of mitochondrial pyridine nucleotides [NAD(P)H], uncoupling, and a transition from the condensed to the orthodox conformation and is inhibited by ATP, dithiothreitol, the immunosuppressant cyclosporin A, and the ubiquitous polyamine spermine. Aglycones also modify mitochondrial sulfhydryl groups and induce a Ca2+ independent oxidation of mitochondrial NAD(P)H which appears to reflect electron transport from NADH to oxygen, mediated by the aglycones and resulting in the production of superoxide (O2-). Selenium deficiency and butylated hydroxytoluene inhibit aglycone-induced Ca2+ release from liver, but not heart, mitochondria, suggesting that the interactions of the aglycones with mitochondria differ in these two tissues. It can be proposed that the effects of Adriamycin aglycones on heart mitochondria are responsible for the cardiotoxicity of the parent drug.
Sokolove
P M
PM
Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201.
D000818:Animals; D004317:Doxorubicin / Q000009:adverse effects*; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008929:Mitochondria, Heart / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D009279:Naphthacenes / Q000378:metabolism*
D009279:Naphthacenes; C010012:adriamycin aglycone; D004317:Doxorubicin