Vaglini Francesca, Viaggi Cristina, Piro Valentina, Pardini Carla, Gerace Claudio, Scarselli Marco, Corsini Giovanni Umberto
Department of Translational Research and New Technology in Medicine, University of Pisa Pisa, Italy.
Front Behav Neurosci. 2013 Jun 21;7:71. doi: 10.3389/fnbeh.2013.00071. eCollection 2013.
The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD.
本综述更新了乙醛（ACE）与帕金森症之间的关系，特别关注细胞色素P450系统尤其是CYP 2E1同工酶的作用。我们已经表明，ACE能够增强1-甲基-4-苯基-1,2,3,6-四氢吡啶诱导的小鼠帕金森症，该神经毒素能够损害黑质纹状体多巴胺能通路。同样，双硫仑的主要代谢产物二乙基二硫代氨基甲酸盐、烯丙基硫醚（DAS）和异硫氰酸苯酯也能显著增强毒素相关的帕金森症。所有这些化合物都是CYP450 2E1同工酶的底物/抑制剂。在啮齿动物黑质（SN）的多巴胺（DA）神经元中已检测到CYP 2E1的存在，但该酶的确切功能尚未阐明。用神经毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶处理CYP 2E1基因敲除（KO）小鼠后，与野生型动物相比，SN诱导的损伤明显减少。多项体内和体外研究得出结论，CYP 2E1可能通过增加多巴胺能神经元内的自由基产生来增强1-甲基-4-苯基-1,2,3,6-四氢吡啶对小鼠的毒性。与其他底物抑制剂一样，ACE是CYP 2E1酶的良好底物，因此可能会促进多巴胺能神经元对毒性事件的易感性。文献表明，乙醇和/或双硫仑可能是人类中毒性帕金森症的病因，并且表明基底神经节是双硫仑毒性的主要靶点。最近的一项研究报告称，帕金森病（PD）患者大脑中CYP 2E1基因的甲基化减少，CYP 2E1 mRNA的表达增加。这项研究表明，这种细胞色素的表观遗传变异会导致易感性，从而证实了多条证据表明环境毒素与PD之间存在联系。
