Analyses of the molecular mechanism of adriamycin-induced cardiotoxicity

Free Radic Biol Med. 1997;23(5):775-82. doi: 10.1016/s0891-5849(97)00025-7.


The molecular basis of the adriamycin (AQ)-dependent development of cardiotoxicity is still far from being clear. In contrast to our incomplete understanding of the organ-specific mechanism mitochondria are unequivocally accepted as the locus where the molecular disorder is triggered. A growing number of reports intimate the establishment of unbalanced oxygen activation through heart mitochondria in the presence of anthraquinones. In fact, in contrast to liver mitochondria, isolated heart mitochondria have been unequivocally shown to shuttle single electrons to AQ, giving rise to O2.- formation by autoxidizing AQ. semiquinones. Earlier we have demonstrated the involvement of the exogenous NADH dehydrogenase in this deleterious electron deviation from the respiratory chain. This enzyme that is associated with complex I of the respiratory chain catalyzes the oxidation of cytosolic NADH. AQ activation through isolated heart mitochondria was reported to require the external addition of NADH, suggesting a flux of reducing equivalents from 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 respiration. It appears, therefore, that the exogenous NADH dehydrogenase of heart mitochondria exerts a key function in the myocardial toxicogenesis of anthraquinones via oxygen activation through semireduced AQ. Assessing the toxicological significance of the exogenous NADH dehydrogenase in AQ-related heart injury requires analysis of reaction products and their impact on vital bioenergetic functions, such as energy gain from the oxidation of respiratory substrates. We have applied ESR technique to analyze the identity and possible interactions of radical species emerging from NADH-respiring heart mitochondria in the presence of AQ. The following metabolic steps occur causing depression of energy metabolism in the cardiac tissue. After one-electron transfer to the parent hydrophilic anthraquinone molecule destabilization of the radical formed causes cleavage of the sugar residue. Accumulation of the lipophilic aglycone metabolite in the inner mitochondrial membrane diverts electrons from the regular pathway to electron acceptors out of sequence such as H2O2. HO. radicals are formed and affect the functional integrity of energy-linked respiration. The key and possibly initiating 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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / toxicity*
  • Doxorubicin / analogs & derivatives
  • Doxorubicin / metabolism
  • Doxorubicin / toxicity*
  • Electron Spin Resonance Spectroscopy
  • Hydroxyl Radical / metabolism
  • In Vitro Techniques
  • Kinetics
  • Male
  • Mitochondria, Heart / drug effects*
  • Mitochondria, Heart / metabolism
  • Mitochondria, Liver / drug effects*
  • Mitochondria, Liver / metabolism
  • NADH Dehydrogenase / metabolism*
  • Naphthacenes / metabolism
  • Oxidation-Reduction
  • Oxygen Consumption
  • Rats
  • Rats, Sprague-Dawley
  • Superoxides / metabolism


  • Antibiotics, Antineoplastic
  • Naphthacenes
  • adriamycin semiquinone radicals
  • Superoxides
  • Hydroxyl Radical
  • 7-deoxyadriamycinol aglycone
  • Doxorubicin
  • NADH Dehydrogenase