The exogenous NADH dehydrogenase of heart mitochondria is the key enzyme responsible for selective cardiotoxicity of anthracyclines.
The molecular mechanism of the anthracycline-dependent development of cardiotoxicity is still far from being clear. However, it is generally accepted, that mitochondria play a significant role in triggering this organ specific injury. The results presented in this study demonstrate that, in contrast to liver mitochondria, isolated heart mitochondria shuttle single electrons to adriamycin, giving rise to oxygen radical formation via autoxidation of adriamycin semiquinones. This one electron reduction of anthracyclines is catalyzed by the exogenous NADH dehydrogenase associated with complex I of heart mitochondria, an enzyme which is lacking in liver mitochondria. Upon addition of NADH heart mitochondria generate significant amounts of adriamycin semiquinones while liver mitochondria were ineffective. Adriamycin semiquinones undergo both autoxidation leading to superoxide radical release and complex reactions under formation of adriamycin aglycone. Due to the high lipophilicity adriamycin aglycones accumulate in the inner mitochondrial membrane where they interfere with electron carriers of the respiratory chain. Adriamycin aglycone semiquinones emerging from an interaction with complex I were found to trigger homolytic cleavage of H2O2 which results in the formation of hydroxyl radicals. As demonstrated in this study the activation of adriamycin by the exogenous NADH dehydrogenase of cardiac mitochondria initiates a cascade of reaction steps leading to the establishment of oxidative stress. Our experiments suggest the exogenous NADH dehydrogenase of heart mitochondria to play a key role in the cardiotoxicity of adriamycin. This organ-specific enzyme initiates a sequence of one electron transfer reactions ending up in the establishment of oxidative stress.
Nohl
H
H
Institute of Pharmacology and Toxicology, Veterinary University Vienna, Austria. hans.nohl@vu-wien.ac.at
Gille
L
L
Staniek
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000633:toxicity*; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D007700:Kinetics; D008929:Mitochondria, Heart / Q000201:enzymology*; D008956:Models, Chemical; D009245:NADH Dehydrogenase / Q000378:metabolism*; D051381:Rats
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin; D009245:NADH Dehydrogenase