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首页 » 帕金森病 » J Biol Chem.:线粒体CYP2D6有望成为治疗帕金森氏病新靶点

J Biol Chem.:线粒体CYP2D6有望成为治疗帕金森氏病新靶点

来源:生物谷 2013-01-20 02:35

2013年1月19日讯 /生物谷BIOON/--科学家通常给予模型动物注射或食用化合物MPTP或者海洛因来模拟帕金森氏病。MPTP导致多巴胺能神经元损伤,产生包括震颤,走路困难等肌肉控制问题。

通常认为MPTP致病机制是MPTP进入神经系统之后被位于神经元线粒体上的MAO-B酶转化为毒性化合物MPP+。之后MPP+通过特异的转运体转到多巴胺能神经元内,抑制线粒体功能最终导致细胞死亡。

发表在Journal of Biological Chemistry的最新研究发现了MPP+的新靶点线粒体蛋白CYP2D6,该蛋白长期以来被科学家忽视。Penn实验室早期研究发现CYP2D6主要集中在内质网上,同时也在线粒体上有表达。

和MAO-B功能相反,内质网相关的CYP2D6被认为能够对抗MPTP毒性,对细胞有保护作用。研究人员发现线粒体上的CYP2D6能够高效的将MPTP转化为MPP+,这就预示CYP2D6很可能与PD有重要联系。

该文章通讯作者Avadhani称,80%的人只有单拷贝的CYP2D6,其他20%的人有不同类型的该基因,甚至有人有多拷贝CYP2D6基因。在CYP2D6多拷贝人群中,线粒体CYP2D6的活性高,这些人的PD发病率增高。

通过细胞培养的方法,研究人员发现线粒体CYP2D6能够氧化MPTP成为MPP+。当引入CYP2D6抑制剂后,转化过程被抑制,神经元损伤同时也大幅减少。

Avadhani称,当同时向多巴胺能神经元培养细胞中加入MPTP和CYP2D6抑制剂时,CYP2D6抑制剂显著的保护了神经元功能。

大量的MAO-B抑制剂用于临床治疗PD,但是都有副作用。而CYP2D6抑制剂更特异,因此可能有少量的副作用。

Avadhani及其研究团队下一步将在动物模型上进一步研究线粒体CYP2D6在PD发展中作用。(生物谷Bioon.com)

Metabolism of 1-Methyl-4-phenyl-1-2-3-6-tetrahydropyridine by Mitochondria-targeted Cytochrome P450 2D6: Implications in Parkinson's Disease.

Bajpai P, Sangar MC, Singh S, Tang W, Bansal S, Chowdhury G, Cheng Q, Fang JK, Martin MV, Guengerich FP, Avadhani NG.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinsons disease. Monoamine oxidase B (MAO-B), present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to toxic 1-methyl-4-phenyl pyridinium ion (MPP+) which then targets the dopaminergic neurons causing neuronal death. Here we demonstrate that mitochondria-targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin (Adx) and adrenodoxin reductase (Adr), can efficiently catalyze the metabolism of MPTP to MPP+, as shown with purified enzymes and also in cells expressing mitochondrial CYP2D6. Neuro-2A cells stably expressing predominantly mitochondria-targeted CYP2D6 were more sensitive to MPTP-mediated mitochondrial respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Mitochondrial CYP2D6 expressing Neuro-2A cells produced higher levels of reactive oxygen species and showed abnormal mitochondrial structures. MPTP treatment also induced mitochondrial translocation of an autophagic marker, Parkin, and a mitochondrial fission marker, Drp1, in differentiated neurons expressing mitochondrial CYP2D6. MPTP mediated toxicity in primary dopaminergic neurons was attenuated by CYP2D6 inhibitor, quinidine, and also partly by MAO-B inhibitors deprenyl and pargyline. These studies show for the first time that dopaminergic neurons expressing mitochondrial CYP2D6 are fully capable of activating the pro-neurotoxin MPTP and inducing neuronal damage, which is effectively prevented by the CYP2D6 inhibitor quinidine.

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