POTENTIAL BIOACTIVATION PATHWAYS FOR THE NEUROTOXIN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP)
POTENTIAL BIOACTIVATION PATHWAYS FOR THE NEUROTOXIN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE (MPTP)
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DOI：
10.1016/0024-3205(85)90063-3
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发表时间：
1985-01-01
期刊：
影响因子：
6.1
通讯作者：
TREVOR, AJ
中科院分区：
文献类型：
--
作者：
CASTAGNOLI, N;CHIBA, K;TREVOR, AJ
本文研究了选择性黑质纹状体毒素1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）在大鼠脑线粒体孵育液中的代谢。通过化学电离质谱和核磁共振氢谱对1-甲基-4-苯基吡啶离子的结构进行了表征。还获得了形成中间产物的证据，借助于氘掺入研究，初步鉴定为α-碳氧化产物，1-甲基-4-苯基-2，3 =二氢吡啶鎓物质MPDP+。该代谢产物的二极管阵列UV光谱与MPDP+合成高氯酸盐的光谱比较证实了这一归属。10− 7 M帕吉林可完全抑制MPTP氧化成MPDP+，但不抑制MPDP+氧化成MPP+。另一方面，MPDP+是不稳定的，并且迅速地经历转化为MPTP和MPP+。基于这些结果，我们推测MPTP的神经毒性是由其神经元内氧化成MPDP+介导的，该反应似乎是由MAO催化的。MPDP+和/或MPP+与多巴胺（一种在黑质纹状体中以高浓度存在的易氧化化合物）的相互作用形成神经毒性物质可能是母体药物选择性毒性的原因。
The metabolism of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been studied in rat brain mitochondrial incubation mixtures. The 1-methyl-4-phenylpyridinium species MPP+has been characterized by chemical ionization mass spectral and1H NMR analysis. Evidence also was obtained for the formation of an intermediate product which, with the aid of deuterium incorporation studies, was tentatively identified as the α-carbon oxidation product, the 1-methyl-4-phenyl-2,3=dihydropyridinium species MPDP+. Comparison of the diode array UV spectrum of this metabolite with that of the synthetic perchlorate salt of MPDP+confirmed this assignment. The oxidation of MPTP to MPDP+but not of MPDP+to MPP+is completely inhibited by 10−7M pargyline. MPDP+, on the otherhand, is unstable and rapidly undergoes disproportionation to MPTP and MPP+. Based on these results, we speculate that the neurotoxicity of MPTP is mediated by its intraneuronal oxidation to MPDP+, a reaction which appears to be catalyzed by MAO. The interactions of MPDP+and/or MPP+with dopamine, a readily oxidizable compound present in high concentration in the nigrostriatum, to form neurotoxic species may account for the selective toxic properties of the parent drug.