Floridi A, Lehninger A L
Arch Biochem Biophys. 1983 Oct 1;226(1):73-83. doi: 10.1016/0003-9861(83)90272-2.
The effect of lonidamine, an antispermatogenic and antitumor drug, on the oxygen consumption, ATPase activity, and redox state of the electron carriers of Ehrlich ascites tumor mitochondria has been studied. Lonidamine inhibits ADP- and uncoupler-stimulated respiration on various NAD- and FAD-linked substrates, but does not affect state 4 respiration. Experiments to determine its site of action showed that lonidamine does not significantly inhibit electron flow through cytochrome oxidase. Electron flow through site 2, the ubiquinone-cytochrome b-cytochrome c1 complex, also was unaffected by lonidamine, which failed to inhibit the oxidation of duroquinol. Moreover, inhibition of electron flow through site 2 was also excluded because of the inability of the N,N,N',N'-tetramethyl-p-phenylenediamine bypass to relieve the lonidamine inhibition of the oxidation of pyruvate + malate. The F0F1ATPase activity and vectorial H+ ejection are also unaffected by lonidamine. The inhibition of succinate oxidation by lonidamine was found to take place at a point between succinate and iron-sulfur center S3. Spectroscopic experiments demonstrated that lonidamine inhibits the reduction of mitochondrial NAD+ by pyruvate + malate and other NAD-linked substrates in the transition from state 1 to state 4. However, lonidamine does not inhibit reduction of added NAD+ by submitochondrial vesicles or by soluble purified NAD-linked dehydrogenases. These observations, together with other evidence, suggest that electron transport in tumor mitochondria is inhibited by lonidamine at the dehydrogenase-coenzyme level, particularly when the electron carriers are in a relatively oxidized state and/or when the inner membrane-matrix compartment is in the condensed state. The action of lonidamine in several respects resembles the selective inhibition of electron transport in tumor cells produced by cytotoxic macrophages (D. L. Granger and A. L. Lehninger (1982) J. Cell Biol. 95, 527).
已对抗生精和抗肿瘤药物氯尼达明对艾氏腹水瘤线粒体的氧消耗、ATP酶活性及电子载体氧化还原状态的影响进行了研究。氯尼达明抑制ADP和解偶联剂刺激的、以各种NAD和FAD连接底物为基础的呼吸作用，但不影响状态4呼吸。确定其作用位点的实验表明，氯尼达明不会显著抑制电子通过细胞色素氧化酶的流动。电子通过位点2，即泛醌 - 细胞色素b - 细胞色素c1复合体的流动，也不受氯尼达明影响，氯尼达明未能抑制杜罗醌醇的氧化。此外，由于N，N，N'，N'-四甲基对苯二胺旁路无法解除氯尼达明对丙酮酸 + 苹果酸氧化的抑制作用，因此也排除了对位点2电子流动的抑制。F0F1ATP酶活性和矢量性H+排出也不受氯尼达明影响。发现氯尼达明对琥珀酸氧化的抑制发生在琥珀酸与铁硫中心S3之间的某个点。光谱实验表明，氯尼达明在从状态1转变为状态4时，抑制丙酮酸 + 苹果酸及其他NAD连接底物对线粒体NAD+的还原。然而，氯尼达明并不抑制亚线粒体小泡或可溶性纯化的NAD连接脱氢酶对添加的NAD+的还原。这些观察结果与其他证据一起表明，氯尼达明在脱氢酶 - 辅酶水平抑制肿瘤线粒体中的电子传递，特别是当电子载体处于相对氧化状态和/或内膜 - 基质区室处于浓缩状态时。氯尼达明在几个方面的作用类似于细胞毒性巨噬细胞对肿瘤细胞电子传递的选择性抑制（D.L.格兰杰和A.L.莱宁格（1982年）《细胞生物学杂志》95卷，527页）。
