Oxidation of mitochondrial pyridine nucleotides by aglycone derivatives of adriamycin

Adriamycin (AdM) and related anthracyclines are potent antineoplastic agents, the clinical utility of which is limited by severe cardiotoxicity. Aglycone derivatives of AdM have recently been reported to trigger the release of Ca2+ from isolated, preloaded rat heart mitochondria and to modify mitochondrial sulfhydryl (-SH) groups. Both mitochondrial Ca2+ retention and -SH status are sensitive to mitochondrial NAD(P)+/NAD(P)H ratios. This investigation examined the effects of AdM and its aglycone derivatives on the pyridine nucleotide redox status of isolated, intact heart mitochondria with the following results. (i) AdM aglycones induced the slow, Ca2(+)-independent oxidation of mitochondrial NAD(P)H. Oxidation was proportional to aglycone concentration between 5 and 60 microM. (ii) In terms of potency, 7-deoxy AdM aglycone greater than or equal to 7-hydroxy AdM aglycone much greater than AdM. (iii) Inhibitor data suggested that NAD(P)H oxidation reflects the rotenone-insensitive reduction of AdM aglycone and subsequent electron transfer to O2 generating superoxide. (iv) NAD(P)H oxidation mediated by AdM aglycone could be distinguished from the Ca2(+)-dependent NAD(P)H oxidation associated with mitochondrial Ca2+ release. This communication is the first to describe redox interactions of AdM with intact mitochondria.