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. Aglyco ne metabolites of Adriamycin (5-20 mu M) induce a Ca2+-dependent incre ase in the permeability of the inner mitochondrial membrane of both he art and liver mitochondria to small (<1500 Da) solutes, this phenomeno n is accompanied by release of mitochondrial Ca2+, mitochondrial swell ing, collapse of the membrane potential, oxidation of mitochondrial py ridine nucleotides [NAD(P)H], uncoupling, and a transition from the co ndensed to the orthodox conformation and is inhibited by ATP, dithioth reitol, the immunosuppressant cyclosporin A, and the ubiquitous polyam ine spermine. Aglycones also modify mitochondrial sulfhydryl groups an d induce a Ca2+ independent oxidation of mitochondrial NAD(P)H which a ppears to reflect electron transport from NADH to oxygen, mediated by the aglycones and resulting in the production of superoxide (O-2(-)). Selenium deficiency and butylated hydroxytoluene inhibit aglycone-indu ced Ca2+ release from liver, but not heart, mitochondria, suggesting t hat the interactions of the aglycones with mitochondria differ in thes e two tissues. It can be proposed that the effects of Adriamycin aglyc ones on heart mitochondria are responsible for the cardiotoxicity of t he parent drug.