Na +-independent release of Ca 2+ from rat heart mitochondria : Induction by adriamycin aglycone

Abstract

The effect of adriamycin aglycones on Ca 2+ 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 μM) triggered Ca 2+ release. Aglycone-induced Ca 2+ release was correlated with Ca 2+ -dependent mitochondrial swelling, Ca 2+-dependent collapse of the mitochondrial membrane potential, Ca 2+-dependent oxidation of mitochondrial pyridine nucleotides, and a transition from the condensed to the orthodox configuration. Aglycone-induced Ca 2+ release was inhibited by dibucaine, dithiothreitol, ATP, and bovine serum albumin. It can be concluded, therefore, that aglycone-induced Ca 2+ release reflects the Ca 2+-dependent increase in the permeability of the inner mitochondrial membrane to solutes of molecular weight < 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 Ca 2+ required to trigger the permeability increase. No effect of the aglycone on Ca 2+ uptake could be discerned. 7-Deoxy-adriamycin aglycone, the more prominent biological metabolite of adriamycin, was similarly effective in inducing Ca 2+ 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 Ca 2+ homeostasis and metabolite compartmentation may mediate anthracycline cardiotoxicity.