| | 1 | Author
| EvaP. Aur, RichardJ Y Oungm An, E. Dm, L. En, G. Feld Er, ErichF E Lstner | Requires cookie* | | | Title
| Mechanisms of Adriamycin-Dependent Oxygen Activation Catalyzed by NADPH-Cytochrome c*-(Ferredoxin)-Oxidoreductase  | | | | Abstract
| Under aerobic conditions, 0 2 uptake and production o f 0 2~ and H 20 2 by isolated N A D P H -cytochrome c-(ferredoxin)-oxidoreductase from Euglena gracilis was strongly stim ulated by adriamycin. Further stim ulation was not observed with 0.1 m M F e 3+-EDTA. M ethionine fragmentation (measured as ethylene release), as a reliable indicator for the formation o f O H ' radical-like oxidants under aerobic conditions (1 0 0 |im o l 0 2 in a 10 ml reaction vessel) was strongly stimulated by 0.1 m M F e3+-ED TA or, in the absence o f iron, by partial anaerobiosis (1 (irnol 0 2 per vessel). The highest rate o f m ethionine fragm entation was observed under an aerobic conditions in the presence o f both reduced adriam ycin and added H 20 2. Aerobic methionine fragmentation in the presence o f adriam ycin and F e3+-ED TA was inhibited by superoxide dismutase and catalase by m ore than 90%, w hile m ethionine fragmen tation under semianaerobiosis in the absence o f F e 3+-E D T A was inhibited by superoxide dismutase to only about 50%, while catalase again inhibited by m ore than 90%. These results indicate that the adriamycin-catalyzed production o f a strong oxidant appears to be governed by different mechanisms depending on oxygen availability; nam ely the production o f a Fenton-type oxidant driven by adriamycin-catalyzed superoxide form ation and also, the formation o f the "crypto-OH' radical" by direct electron donation from the adriam ycin sem iquinone radical to H20 2 under oxygen limiting conditions. | | | |
Reference
| Z. Naturforsch. 39c, 261—267 (1984); received D ecem ber 15 1983 | | | |
Published
| 1984 | | | |
Keywords
| Adriamycin, Oxygen Activation, Oxygen Toxicity, Superoxide, H ydroxyl Radical | | | |
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| default:Reihe_C/39/ZNC-1984-39c-0261.pdf | | | | Identifier
| ZNC-1984-39c-0261 | | | | Volume
| 39 | |
| 2 | Author
| H. Nohl, L. Gille, K. Staniek | Requires 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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| default:Reihe_C/53/ZNC-1998-53c-0279.pdf | | | | Identifier
| ZNC-1998-53c-0279 | | | | Volume
| 53 | |
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