Paraquat neurotoxicity is distinct from that of MPTP and rotenone
Paraquat neurotoxicity is distinct from that of MPTP and rotenone
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DOI：
10.1093/toxsci/kfi304
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发表时间：
2005-11-01
影响因子：
3.8
通讯作者：
Miller, GW
中科院分区：
文献类型：
--
作者：
Richardson, JR;Quan, Y;Miller, GW
百草枯、MPTP和鱼藤酮在实验动物中重现帕金森病（PD）的特征。这些化合物损害多巴胺系统的确切机制尚未确定，但据认为涉及对多巴胺神经元的选择性损害和复合物I的抑制。我们和其他人以前已经证明，MPTP，MPP+的有毒代谢产物，通过多巴胺转运蛋白（DAT）被运送到多巴胺神经元，而鱼藤酮不运输DAT。我们还证明了复合物I抑制和氧化损伤的要求在多巴胺能神经变性鱼藤酮产生。基于与MPP+的结构相似性，有人提出，百草枯通过DAT转运并随后抑制线粒体复合物I而发挥选择性多巴胺能毒性。在这项研究中，我们报告说，百草枯既不是一个底物，也不是抑制剂的DAT。我们还表明，在体内暴露于MPTP和鱼藤酮，但不是百草枯，抑制H-3-二氢鱼藤酮结合到复杂的I在脑线粒体。鱼藤酮和MPP+都是有效的抑制剂，在分离的脑线粒体复合物I活性，而百草枯表现出弱的抑制作用，只有在毫摩尔浓度。这些数据表明，尽管百草枯与MPP+在结构上有明显的相似性，但它对多巴胺神经元的有害影响是鱼藤酮和MPTP所独有的。
Paraquat, MPTP, and rotenone reproduce features of Parkinson's disease (PD) in experimental animals. The exact mechanisms by which these compounds damage the dopamine system are not firmly established, but selective damage to dopamine neurons and inhibition of complex I are thought to be involved. We and others have previously documented that the toxic metabolite of MPTP, MPP+, is transported into dopamine neurons through the dopamine transporter (DAT), while rotenone is not transported by DAT. We have also demonstrated the requirement for complex I inhibition and oxidative damage in the dopaminergic neurodegeneration produced by rotenone. Based on structural similarity to MPP+, it has been proposed that paraquat exerts selective dopaminergic toxicity through transport by the DAT and subsequent inhibition of mitochondrial complex I. In this study we report that paraquat is neither a substrate nor inhibitor of DAT. We also demonstrate that in vivo exposure to MPTP and rotenone, but not paraquat, inhibits binding of H-3-dihydrorotenone to complex I in brain mitochondria. Rotenone and MPP+ were both effective inhibitors of complex I activity in isolated brain mitochondria, while paraquat exhibited weak inhibitory effects only at millimolar concentrations. These data indicate that, despite the apparent structural similarity to MPP+, paraquat exerts its deleterious effects on dopamine neurons in a manner that is unique from rotenone and MPTP.