ANALYSES OF THE MOLECULAR MECHANISM OF ADRIAMYCIN-INDUCED CARDIOTOXICITY

The molecular basis of the adriamycin(AQ)-dependent development of car diotoxicity is still far from being clear. In contrast to our incomple te understanding of the organ-specific mechanism mitochondria are uneq uivocally accepted as the locus where the molecular disorder is trigge red. A growing number of reports intimate the establishment of unbalan ced oxygen activation through heart mitochondria in the presence of an thraquinones. In fact, in contrast to liver mitochondria, isolated hea rt mitochondria have been unequivocally shown to shuttle single electr ons to AQ, giving rise to O-2(.-) formation by autoxidizing AQ(.) semi quinones. Earlier we have demonstrated the involvement of the exogenou s NADH dehydrogenase in this deleterious electron deviation from the r espiratory chain. This enzyme that is associated with complex I of the respiratory chain catalyzes the oxidation of cytosolic NADH. AQ activ ation through isolated heart mitochondria was reported to require the external addition of NADH, suggesting a flux of reducing equivalents f rom NADH to AQ in the cytosol. Unlike heart mitochondria, intact liver mitochondria, which are lacking this NADH-related pathway of reducing equivalents from the cytosol to the respiratory chain, cannot be made to activate AQ to semiquinones by NADH or any other substrate of resp iration. It appears, therefore, that the exogenous NADH dehydrogenase of heart mitochondria exerts a key function in the myocardial toxicoge nesis of anthraquinones via oxygen activation through semireduced AQ. Assessing the toxicological significance of the exogenous NADH dehydro genase in AQ-related heart injury requires analysis of reaction produc ts and their impact on vital bioenergetic functions, such as energy ga in from the oxidation of respiratory substrates. We have applied ESR t echnique to analyze the identity and possible interactions of radical species emerging from NADH-respiring heart mitochondria in the presenc e of AQ. The following metabolic steps occur causing depression of ene rgy metabolism in the cardiac tissue. After one-electron transfer to t he parent hydrophilic anthraquinone molecule destabilization of the ra dical formed causes cleavage of the sugar residue. Accumulation of the lipophilic aglycone metabolite in the inner mitochondrial membrane di verts electrons from the regular pathway to electron accepters out of sequence such as H2O2. HO. radicals are formed and affect the function al integrity of energy-linked respiration. The key and possibly initia ting role of the exogenous NADH dehydrogenase of cardiac mitochondria in this reaction pathway provides a rationale to explain the selective cardiotoxic potency of the cytostatic anthraquinone glycosides. (C) 1 997 Elsevier Science Inc.