Enzymatic activation and binding of adriamycin to nuclear DNA.
Enzymatic activation and binding of adriamycin to nuclear DNA.
复制标题
阿霉素与核 DNA 的酶促激活和结合。
作者：
B. Sinha;M. Trush;K. A. Kennedy;E. Mimnaugh
在厌氧条件下，在还原的吡啶核苷酸存在下，蒽环类抗肿瘤药物阿霉素激活大鼠肝微粒体，产生与包括DNA在内的细胞大分子共价结合的活性物种。由于核膜含有能够激活阿霉素的酶，我们研究了分离的细胞核对阿霉素的激活。阿霉素与大鼠肝细胞核厌氧孵育后，产生阿霉素半喹自由基。此外，这种激活导致了阿霉素与核DNA的共价结合。阿霉素与DNA的结合是吡啶核苷酸还原和时间依赖的，在还原型谷胱甘肽或乙基黄原酸酯存在下显着降低。相反，DT-黄递酶的抑制剂Dicumerol对这种结合没有影响。当在氧气存在下进行孵育时，没有检测到半醌自由基；然而，通过自旋捕捉技术很容易检测到超氧自由基和羟基自由基。此外，在有氧条件下，阿霉素与核DNA几乎没有结合。这些观察结果表明，阿霉素的核激活和与DNA的共价结合可能在该药物的生化作用中起重要作用。
Rat liver microsomal activation of the anthracycline antitumor drug, Adriamycin, in the presence of reduced pyridine nucleotide under anaerobic conditions produces reactive species that bind covalently to cellular macromolecules including DNA. Since the nuclear membrane contains enzymes capable of activating Adriamycin, we have examined activation of Adriamycin by isolated nuclei. The anaerobic incubation of Adriamycin with rat hepatic nuclei resulted in the formation of the Adriamycin semiquinone free radical. Moreover, this activation resulted in the covalent binding of Adriamycin to nuclear DNA. The binding of Adriamycin to DNA was reduced pyridine nucleotide and time dependent and was significantly decreased in the presence of reduced glutathione or ethylxanthate . Dicumerol , an inhibitor of DT-diaphorase, in contrast, had no effect on this binding. When the incubation was carried out in the presence of oxygen, no semiquinone radical was detected; however, superoxide and hydroxyl radicals were readily detected by a spin-trapping technique. Furthermore, little binding of Adriamycin to nuclear DNA was observed under aerobic conditions. These observations suggest that the nuclear activation and covalent binding of Adriamycin to DNA may be important in the biochemical actions of this drug.
阿霉素浓度与缺氧和常氧 L1210 细胞中诱导的 DNA 损伤的关系。
影响因子：
11.2
作者：
Potmesil,M;Kirschenbaum,S;Israel,M;Levin,M;Khetarpal,VK;Silber,R
通讯作者：
Silber,R