Enhanced induction of the mitochondrial permeability transition following acute menadione administration.
Enhanced induction of the mitochondrial permeability transition following acute menadione administration.
复制标题
急性甲萘醌给药后线粒体通透性转变的诱导增强。
DOI：
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发表时间：
1995
影响因子：
3.9
通讯作者：
K. Wallace
中科院分区：
文献类型：
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作者：
K. Saxena;T. Henry;L. Solem;K. Wallace
体外诱导线粒体通透性转变已被充分表征，并广泛涉及氧化诱导的细胞死亡机制。尽管有大量的体外实验证据，但线粒体功能障碍在体内化学毒性机制中的意义有待于在中毒动物组织中诱导线粒体通透性转变的证明。本研究采用单次给药的方法，对成年雄性大鼠肝线粒体进行分离，24 h后分离肝线粒体。甲萘醌处理大鼠的线粒体对钙诱导的状态3呼吸抑制和呼吸控制丧失的敏感性增加，以及对环孢素a抑制的钙诱导的钙释放的敏感性增加。与此相关的是甲萘醌处理动物的膜电位去极化和线粒体肿胀，而对照组动物则没有。添加环孢素A或钌红均可抑制甲萘醌处理大鼠线粒体钙依赖性去极化和肿胀。结果与线粒体通透性转变的诱导一致，并为体内化学暴露导致对这种反应的敏感性增加提供了第一个证据。
Induction of the mitochondrial permeability transition in vitro is well-characterized and widely implicated in the mechanism of oxidant-induced cell death. Despite an abundance of in vitro evidence, implication of mitochondrial dysfunction in the mechanism of chemical toxicity in vivo awaits demonstration of the induction of the mitochondrial permeability transition in tissues from intoxicated animals. Menadione (2-methyl-1,4-naphthoquinone), an agent known to induce the permeability transition in isolated liver mitochondrial in vitro, was administered as a single bolus to adult male rats, and hepatic mitochondria were isolated 24 h later. Mitochondria from menadione-treated rats exhibited an increased sensitivity to calcium-induced inhibition of state 3 respiration and loss of respiratory control, as well as a greater sensitivity to calcium-induced calcium release that was inhibited by cyclosporine A. Associated with this was the depolarization of membrane potential and swelling of mitochondria from menadione-treated animals, but not control animals. Both the calcium-dependent depolarization and swelling of mitochondria from menadione-treated rats were inhibited by adding either cyclosporine A or ruthenium red. The results are consistent with the induction of the mitochondrial permeability transition and provide the first evidence for the manifestation of an increased sensitivity to this response as a result of chemical exposure in vivo.