Na+-independent release of Ca2+ from rat heart mitochondria. Induction by adriamycin aglycone.
The effect of adriamycin aglycones on Ca2+ retention by isolated, preloaded rat heart mitochondria was assessed. After an initial lag, which decreased with increasing drug concentration, the 7-hydroxy-aglycone (5-20 microM) triggered Ca2+ release. Aglycone-induced Ca2+ release was correlated with Ca2+-dependent mitochondrial swelling, Ca2+-dependent collapse of the mitochondrial membrane potential, Ca2+-dependent oxidation of mitochondrial pyridine nucleotides, and a transition from the condensed to the orthodox configuration. Aglycone-induced Ca2+ release was inhibited by dibucaine, dithiothreitol, ATP, and bovine serum albumin. It can be concluded, therefore, that aglycone-induced Ca2+ release reflects the Ca2+-dependent increase in the permeability of the inner mitochondrial membrane to solutes of molecular weight less than 1000 which has been observed with other triggering agents [R. A. Haworth and D. R. Hunter, Archs Biochem. Biophys. 195, 460 (1979); I. Al-Nasser and M. Crompton, Biochem. J. 239, 19 (1986)]. In particular, the 7-hydroxy-aglycone decreased the amount of Ca2+ required to trigger the permeability increase. No effect of the aglycone on Ca2+ uptake could be discerned. 7-Deoxy-adriamycin aglycone, the more prominent biological metabolite of adriamycin, was similarly effective in inducing Ca2+ release, and both aglycones were substantially more effective than the parent drug. Adriamycin and related anthracyclines are potent antineoplastic agents, the clinical use of which is limited by severe cardiotoxicity. These results suggest that aglycone formation and the resultant disruption of both cellular Ca2+ homeostasis and metabolite compartmentation may mediate anthracycline cardiotoxicity.
Sokolove
P M
PM
Department of Pharmacology and Experimental Therapeutics, University of Maryland Medical School, Baltimore 21201.
Shinaberry
R G
RG
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D006706:Homeostasis; D008297:Male; D008854:Microscopy, Electron; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009279:Naphthacenes / Q000494:pharmacology*; D010539:Permeability; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000378:metabolism*
D009279:Naphthacenes; C010012:adriamycin aglycone; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D012964:Sodium; D002118:Calcium; D004121:Dimethyl Sulfoxide