Ramsay R R, Singer T P
J Biol Chem. 1986 Jun 15;261(17):7585-7.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), an impurity in certain batches of illicit heroin substitutes, is known to cause parkinsonian symptoms and degeneration of the nigrostriatal cells in drug abusers and primates. Neurotoxicity depends on oxidation of MPTP by monoamine oxidase in brain cells to the dihydropyridinium form, which is further oxidized to N-methyl-4-phenylpyridinium (MPP+), the 4-electron oxidation product. The latter is widely believed to be the compound responsible for neuronal destruction and the NADH dehydrogenase of the inner membrane has been postulated to be its target. This enzyme is inhibited, however, only at very high concentrations of MPP+, while the steady-state concentration of MPP+ in the nigrostriatal cells of MPTP-treated animals is several orders of magnitude lower. This paradox has now been resolved by the discovery of an energized uptake system for MPP+ in mitochondria which rapidly concentrates MPP+ to very high concentrations in the mitochondria at micromolar external concentrations. The process is dependent on the electrical gradient of the membrane, has a Km of about 5 mM, and is completely blocked by respiratory inhibitors and uncouplers.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）是某些批次非法海洛因替代品中的一种杂质，已知会在吸毒者和灵长类动物中引发帕金森氏症状并导致黑质纹状体细胞退化。神经毒性取决于脑细胞中的单胺氧化酶将MPTP氧化为二氢吡啶形式，后者进一步氧化为N-甲基-4-苯基吡啶鎓（MPP+），即4电子氧化产物。人们普遍认为后者是导致神经元破坏的化合物，并且内膜的NADH脱氢酶被假定为其作用靶点。然而，该酶仅在非常高浓度的MPP+下才会受到抑制，而在经MPTP处理的动物的黑质纹状体细胞中，MPP+的稳态浓度要低几个数量级。现在，通过发现在线粒体中存在一个使MPP+活跃摄取的系统，这一矛盾已得到解决，该系统能在微摩尔级的外部浓度下迅速将MPP+在线粒体中浓缩至非常高的浓度。该过程依赖于膜的电势梯度，Km约为5 mM，并且完全被呼吸抑制剂和解偶联剂阻断。
