Nohl H
Institute of Pharmacology and Toxicology, Veterinary University of Vienna, Austria.
Biochem Pharmacol. 1988 Jul 1;37(13):2633-7. doi: 10.1016/0006-2952(88)90257-2.
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.
基于蒽醌类抗生素的选择性心脏毒性归因于其在心脏中代谢特性的假设，我们研究了外源性NADH氧化还原酶，这是一种最近被描述的心脏特异性酶（H.诺尔，《欧洲生物化学杂志》169, 585 1987），以探究其在心脏毒性作用发展中可能发挥的作用。由于该酶与线粒体内膜的胞质面相关联，胞质中的蒽醌能够直接接触到它。氧化还原特性、动力学数据以及较差的底物选择性表明外源性NADH氧化还原酶参与了细胞内蒽醌的激活过程。根据这一概念，通过检测与阿霉素半醌相关的电子自旋共振信号，证明了从外源性NADH到蒽醌阿霉素存在直接的单电子穿梭。在心线粒体溶解的NADH氧化还原酶作用下，也观察到了以NADH为代价将阿霉素激活至其半醌状态的现象。发现微粒体对阿霉素的激活是由于附着在微粒体膜组分上的心脏线粒体中污染的外源性NADH氧化还原酶所致。基于这些发现，得出结论：心脏细胞中阿霉素的激活是由于心脏特异性外源性NADH氧化还原酶的存在。考虑到该酶的生理功能，细胞内阿霉素的激活似乎也受胞质NADH/NAD比值代谢变化的调节。
