Breakthrough of Mechanism for Neurotoxicity of MeHg - Oxidative Stress Produced in Mitochondria

为阐明甲基汞中枢神经系统毒性的氧化应激机制，研究了甲基汞对大鼠脑线粒体的影响。结果表明：（1）脑线粒体及其膜组分（SMP）的实验表明，脑线粒体膜产生的O_2 ~（^-）可使甲基汞脱甲基;（2）甲基汞或无机汞（Hg^++）体外暴露可促进脑SMP产生O_2 ~（^-），3）甲基汞染毒后，大鼠大脑和小脑中总汞含量维持较长时间，而大脑和小脑中无机汞含量则呈时间依赖性升高。结果表明，在大鼠脑内，O_2^-水平的升高在小脑的时间早于大脑。 ...更多信息 对照组大鼠，以苹果酸和谷氨酸为底物时，状态3小脑H_2O_2产生率明显高于大脑。在以琥珀酸为底物时，甲基汞处理仅在状态4时增加了小脑H_2O_2的产生速率。在对照组的线粒体中，尽管甲基汞处理对GSHPx活性没有影响，但小脑的GSHPx活性远低于大脑。对照组和甲基汞处理组大鼠大脑和小脑GR活性无显著差异。对照组大鼠小脑和大脑线粒体SOD活性无明显差异，但甲基汞暴露后仅小脑线粒体SOD活性降低。对照组小脑GSH含量明显低于大脑，甲基汞处理仅降低小脑GSH含量。这些结果表明，小脑对甲基汞的敏感性高于大脑，因此，我们的研究表明，甲基汞或其衍生的无机汞引起的脑线粒体氧化应激可能在甲基汞的神经毒性中起重要作用。少

In order to elucidate oxidative stress mechanism for central nervous system toxictty caused by MeHg, effects of MeHg on rat brain mitochondria were investigated. From this study, following results were obtained.1) In the experiment using brain mitochondria fraction and its membrane fraction (SMP), it is indicated that MeHg was demethylated by O_2^- produced in brain mitochondria membrane.2) O_2^- production in brain SMP was accelerated by in vitro exposure of MeHg or Inorganic Hg (Hg^<++>), though the accerelation was much larger in inorganic Hg than in MeHg.3) Rat brain total Hg levels after administration of MeHg were maintained for considerable time both in cerebrum and cerebellum, whereas inorganic Hg levels were increased timedependently both in cerebrum and cerebellum. Most high levels of inorganic Hg were found in cerebellar mitochondria Brain SMP from rats administered MeHg showed increased O_2^- levels at much earlier time in cerebellum than cerebrum.4) In mitochondria from co … More ntrol rats, the rates of H_2O_2 production were much higher in cerebellum than in cerebrum in state 3 when malate and glutamate were used as substrates. MeHg treatment increased the rates of H_2O_2 production only in cerebellum in state 4 when succinate was used as a substrate. In mitochondria from controls, GSHPx activities were much lower in cerebellum than in cerebrum, though MeHg treatment did not affect on GSHPx activities. GR activities were did not differ between cerebrum and cerebellum in both controls and MeHg treated rats. Although there was no difference in mitochondria SOD activities between cerebellum and cerebrum of controls, its activities decreased only in cerebellum by MeHg exposure. GSH concentration was much lower in cerebellum than in cerebrum in controls, and MeHg treatment decreased GSH concentration only in cerebellum. These results indicated that cerebellum is more susceptible for MeHg than cerebrum.Thus, our study suggetst that oxidative stress in brain mitochondria caused by MeHg or inorganic Hg derived from MeHg may play an important role in neurotoxicity of MeHg. Less