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1998 (1)
1Author    H. Nohl, L. Gille, K. StaniekRequires cookie*
 Title    The Exogenous NADH Dehydrogenase of Heart Mitochondria Is the Key Enzyme Responsible for Selective Cardiotoxicity of Anthracyclines  
 Abstract    The molecular mechanism of the anthracycline-dependent developm ent 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 adria­ mycin semiquinones. This one electron reduction of anthracyclines is catalyzed by the exoge­ nous N A D H dehydrogenase associated with complex I o f heart mitochondria, an enzyme which is lacking in liver mitochondria. U pon addition of N A D H heart mitochondria generate significant amounts of adriamycin sem iquinones 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 sem iquinones emerging from an interaction with com plex I were found to trigger homolytic cleavage of H20 2 which results in the formation of hydroxyl radicals. A s demonstrated in this study the activation of adriamycin by the exogenous N A D H dehydrogenase of cardiac mitochondria initiates a cas­ cade of reaction steps leading to the establishment o f oxidative stress. Our experiments sug­ gest the exogenous N A D H dehydrogenase o f 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. 
  Reference    Z. Naturforsch. 53c, 279—5 (1998); received D ecem ber 19 1997/February 3 1998 
  Published    1998 
  Keywords    Anthracyclines, Adriamycin, Rat Heart M itochondria, Rat Liver Mitochondria, Oxygen Radicals 
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 TEI-XML for    default:Reihe_C/53/ZNC-1998-53c-0279.pdf 
 Identifier    ZNC-1998-53c-0279 
 Volume    53