Role of CYP2E1 in the mouse model of MPTP toxicity.
Role of CYP2E1 in the mouse model of MPTP toxicity.
复制标题
DOI：
10.1016/j.parkreldis.2008.04.014
复制
发表时间：
2008-01-01
影响因子：
4.1
通讯作者：
Corsini, Giovanni U
中科院分区：
文献类型：
--
作者：
Pardini, Carla;Vaglini, Francesca;Corsini, Giovanni U
研究表明，二乙基二硫代氨基甲酸酯（DDC）可增强小鼠中1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）的毒性，这是由于纹状体中1-甲基-4-苯基吡啶离子（MPP（+））水平增加所致。DDC对C57 B1小鼠脑CYP 2 E1的抑制作用是毒性增加和纹状体MPP（+）蓄积的原因。然而，CYP 2 E1基因敲除小鼠对MPTP的敏感性没有增强，也没有MPP（+）蓄积。这一出乎意料的发现表明，CYP 2 E1缺失小鼠用其他同工酶补偿对乙酰氨基酚诱导的肝损伤。MPP（+）中毒的中脑细胞培养物从CYP 2 E1-null小鼠表明，多巴胺（DA）神经元的敏感性降低敲除动物。令人惊讶的是，在这些条件下MPP（+）细胞分布表明，在敲除培养物中，毒素在细胞内积累更多，进一步表明CYP 2 E1在MPP（+）储存和流出中发挥作用。
It has been shown that diethyldithiocarbamate (DDC) potentiates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice as a result of increased levels of 1-methyl-4-phenylpyridinium ion (MPP(+)) in the striatum. Brain CYP2E1 inhibition by DDC in C57Bl mice was responsible for increased toxicity and striatal MPP(+) accumulation. However, CYP2E1-null mice did not show any enhanced sensitivity to MPTP or any MPP(+) accumulation. This unexpected finding suggested that the CYP2E1-null mice compensate with other isozymes as already described for acetaminophen-induced liver damage. MPP(+) intoxication of mesencephalic cell cultures from CYP2E1-null mice indicated a reduced sensitivity of dopaminergic (DA) neurons from knockout animals. Surprisingly, MPP(+) cell distribution under these conditions indicated that the toxin accumulates more intracellularly in knockout cultures, suggesting further that CYP2E1 has a role in MPP(+) storage and efflux.