Singer T P, Ramsay R R, McKeown K, Trevor A, Castagnoli N E
Department of Pharmacy, University of California, San Francisco 94143.
Toxicology. 1988 Apr;49(1):17-23. doi: 10.1016/0300-483x(88)90169-2.
It is widely believed that the nigrostriatal toxicity of MPTP is due to its oxidation by brain monoamine oxidase first to MPDP+, and eventually to MPP+. Following uptake by the synaptic dopamine reuptake system, it is concentrated in the matrix of striatal mitochondria by an energy-dependent carrier, energized by the electrical gradient of the membrane. At the very high intramitochondrial concentrations thus reached, MPP+ combines with NADH dehydrogenase at a point distal to its iron-sulfur clusters but prior to the Q10 combining site. This leads to cessation of oxidative phosphorylation, ATP depletion, and cell death. Other pyridine derivatives act similarly on NADH dehydrogenase but they are not acutely toxic unless concentrated by the MPP+ carrier.
人们普遍认为，MPTP的黑质纹状体毒性是由于其首先被脑单胺氧化酶氧化为MPDP+，最终氧化为MPP+。通过突触多巴胺再摄取系统摄取后，它由一种能量依赖载体浓缩在纹状体线粒体基质中，该载体由膜的电化学梯度提供能量。在如此达到的非常高的线粒体内浓度下，MPP+在其铁硫簇远端但在Q10结合位点之前的一点与NADH脱氢酶结合。这导致氧化磷酸化停止、ATP耗竭和细胞死亡。其他吡啶衍生物对NADH脱氢酶的作用类似，但除非被MPP+载体浓缩，否则它们不会产生急性毒性。
