Identification of the site of adriamycin-activation in the heart cell.
Based on the assumption, the selective cardiotoxicity of anthraquinone antibiotics is due to peculiarities concerning their metabolism in the heart, we have investigated the exogenous NADH oxidoreductase, a heart-specific enzyme recently described (H. Nohl, Eur. J. Biochem. 169, 585 1987) for its possible role in the development of cardiotoxic effects. Cytosolic anthraquinones have direct access since the enzyme was shown to be associated with the cytosolic face of the inner mitochondrial membrane. Redox properties, kinetic data and the poor substrate selectivity suggest the exogenous NADH-oxidoreductase to be involved in the activation of cellular anthraquinones. According to this concept, a direct single electron-shuttle from exogenous NADH to the anthraquinone adriamycin was demonstrated by the detection of adriamycin-semiquinone-related ESR signals. Activation of adriamycin to its semiquinone state at the expense of NADH was also observed with the solubilized NADH-oxidoreductase of heart mitochondria. Microsomal activation of adriamycin was found to result from contaminating exogenous NADH-oxidoreductase of heart mitochondria attached to microsomal membrane fractions. Based on these findings, it was concluded that adriamycin activation in heart cells is due to the existence of the heart specific exogenous NADH-oxidoreductase. Considering the physiological function of this enzyme, activation of cellular adriamycin also appears to be regulated by metabolic changes of cytosolic NADH/NAD ratios.
Nohl
H
H
Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Austria.
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004317:Doxorubicin / Q000378:metabolism* / Q000633:toxicity; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D008929:Mitochondria, Heart / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D010101:Oxygen Consumption; D051381:Rats
D004317:Doxorubicin; D003577:Cytochrome P-450 Enzyme System; D009247:NADH, NADPH Oxidoreductases