Henry T R, Wallace K B
Department of Pharmacology, School of Medicine, University of Minnesota, Duluth 55812, USA.
Toxicol Appl Pharmacol. 1995 Oct;134(2):195-203. doi: 10.1006/taap.1995.1184.
A nonspecific increase in permeability of the inner mitochondrial membrane is implicated in the mechanism of cell killing by a number of structurally diverse agents possessing vastly different chemical reactivities. The objective of this investigation was to distinguish the mechanisms by which quinones of varying redox cycling and arylating reactivities induce this mitochondrial permeability transition in vitro. All of the naphthoquinones examined caused a dose-dependent release of calcium from hepatic mitochondria. Associated with this was the calcium-dependent depolarization of membrane potential and mitochondrial swelling. For substituted naphthoquinones, 2-methyl-, 2,3-dimethyl-, and 2,3-dimethoxy-1, 4-naphthoquinone, induction of the mitochondrial permeability transition correlated with the rate of mitochondrial redox cycling and was strongly inhibited by cyclosporine A. In contrast, unsubstituted 1,4-naphthoquinone induced the permeability transition at concentrations where redox cycling was minimal. Induction of the permeability transition by 1,4-benzoquinone, which does not redox cycle, required that the mitochondria be preloaded with calcium and was not inhibited by cyclosporine A. With benzoquinone, the initiating event was a calcium-independent depolarization of mitochondrial membrane potential. In summary, the evidence indicates that redox cycling naphthoquinones induce the mitochondrial permeability transition by altering the regulation of the cyclosporine A-sensitive pore. In contrast, arylating quinones directly depolarize the mitochondrial membrane which, depending on the availability of matrix calcium, may be expressed as a cyclosporine A-insensitive permeability transition. These results reveal distinct mechanisms for inducing the mitochondrial permeability transition in vitro by quinones of varying chemical reactivities, which may be manifested as different mechanisms of cell killing.
线粒体内膜通透性的非特异性增加与多种具有截然不同化学反应活性的结构多样的药物导致细胞死亡的机制有关。本研究的目的是区分不同氧化还原循环和芳基化反应活性的醌类化合物在体外诱导这种线粒体通透性转变的机制。所有检测的萘醌均导致肝线粒体中钙的剂量依赖性释放。与此相关的是膜电位的钙依赖性去极化和线粒体肿胀。对于取代萘醌，2-甲基-、2,3-二甲基-和2,3-二甲氧基-1,4-萘醌，线粒体通透性转变的诱导与线粒体氧化还原循环速率相关，并被环孢素A强烈抑制。相比之下，未取代的1,4-萘醌在氧化还原循环最小的浓度下诱导通透性转变。不进行氧化还原循环的1,4-苯醌诱导通透性转变需要线粒体预先加载钙，且不受环孢素A抑制。对于苯醌，起始事件是线粒体膜电位的钙非依赖性去极化。总之，证据表明氧化还原循环的萘醌通过改变环孢素A敏感孔的调节来诱导线粒体通透性转变。相比之下，芳基化醌直接使线粒体膜去极化，这取决于基质钙的可用性，可能表现为对环孢素A不敏感的通透性转变。这些结果揭示了不同化学反应活性的醌类化合物在体外诱导线粒体通透性转变的不同机制，这可能表现为不同的细胞杀伤机制。
