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

甲基汞神经毒性机制的突破——线粒体产生的氧化应激

基本信息

批准号：
12680548
负责人：
HIRAYAMA Kimiko
金额：
$ 2.37万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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

为阐明甲基汞致中枢神经系统毒性的氧化应激机制，观察了甲基汞对大鼠脑线粒体的影响。本研究获得以下结果：1)在脑线粒体部分及其膜部分(SMP)的实验中，脑线粒体膜上产生的O_2~-可使甲基汞去甲基化。2)体外暴露甲基汞或无机汞可加速脑线粒体膜O_2~-的产生，但无机汞的促进作用远大于甲基汞。3)给予甲基汞后，大鼠大脑和小脑的总汞水平维持在相当长的时间内，而大脑和大脑中的无机汞水平呈时间依赖性增加。小脑线粒体中无机汞含量最高给予甲基汞的大鼠小脑SMP显示O_2~-水平升高的时间比大脑早得多。4)CO…组大鼠小脑线粒体中O_2~-水平升高以苹果酸和谷氨酸为底物时，对照组大鼠小脑的H_2O_2产生率明显高于大脑。当以琥珀酸为底物时，甲基汞处理仅在状态4的小脑增加了H_2O_2的产生。在对照组的线粒体中，小脑的GSHPx活性远低于大脑，尽管甲基汞处理对GSHPx活性没有影响。对照组和甲基汞处理组大鼠大脑和小脑GR活性无明显差异。小脑和对照组小脑线粒体超氧化物歧化酶活性虽无差异，但仅小脑线粒体超氧化物歧化酶活性降低。对照组小脑中GSH含量明显低于大脑，甲基汞处理仅降低小脑中GSH含量。这些结果表明，小脑比大脑对甲基汞更敏感。因此，我们的研究提示，甲基汞或甲基汞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。较少