Hadler H I, Cook G L
J Environ Pathol Toxicol. 1978 Mar-Apr;1(4):419-32.
We have recognized an experimental confluence between oxidative phosphorylation and chemical carcinogenesis and, therefore, became interested in the mitochondrial target of hydrazine, which is not only a potential environmental hazard as a carcinogen but is also a likely metabolite of many drugs. Hydrazine induced a Pi dependent transitory uncoupling of rat liver mitochondria when beta-hydroxybutyrate was the substrate. Uncoupling was inhibited by rutamycin; accordingly, the mitochondrial target for nucleophilic hydrazine is an electrophilic site, presumably involving activated Pi. The protective action of ATP2, ADP, PPi and Mg++ was attributed to a conformational change of the phosphorylating enzyme which participated in oxidative phosphorylation. In a mitochondrial system which included ATP gramicidin potassium ion and sulfate, hydrazine, acting as a large cation but not as a nucleophile, blocked mitochondrial swelling and the increment in ATPase activity associated with potassium ion. These data in conjunction with our previous reports dealing with other carcinogens and certain of their derivatives also contribute to an experimental confluence between oxidative phosphorylation and chemical carcinogenesis and are compatible with toxic effects of hydrazine on mitochondria observed previously by others.
我们已经认识到氧化磷酸化与化学致癌作用之间存在实验性的融合，因此，我们对肼的线粒体靶点产生了兴趣。肼不仅作为一种致癌物是潜在的环境危害，而且还是许多药物的可能代谢产物。当以β-羟基丁酸为底物时，肼会诱导大鼠肝线粒体发生Pi依赖性的短暂解偶联。解偶联被鱼藤霉素抑制；因此，亲核肼的线粒体靶点是一个亲电位点，大概涉及活化的Pi。ATP2、ADP、PPi和Mg++的保护作用归因于参与氧化磷酸化的磷酸化酶的构象变化。在一个包含ATP、短杆菌肽、钾离子和硫酸盐的线粒体系统中，肼作为一种大阳离子而非亲核试剂，阻止了线粒体肿胀以及与钾离子相关的ATP酶活性增加。这些数据与我们之前关于其他致癌物及其某些衍生物的报告相结合，也促成了氧化磷酸化与化学致癌作用之间的实验性融合，并且与其他人之前观察到的肼对线粒体的毒性作用相符。
