Metabolism of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by liver homogenate fractions.
Metabolism of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by liver homogenate fractions.
复制标题
肝匀浆组分对黑质纹状体毒素 1-甲基-4-苯基-1,2,3,6-四氢吡啶的代谢。
DOI：
10.1021/jm00146a005
复制
发表时间：
1985
影响因子：
7.3
通讯作者：
Baillie,T
中科院分区：
文献类型：
--
作者：
Weissman,J;Trevor,A;Chiba,K;Peterson,LA;Caldera,P;CastagnoliJr,N;Baillie,T
本文研究了黑纹体毒素L-甲基-4-苯基-L，2，3，6-四氢吡啶在大鼠、兔肝线粒体和兔肝微粒体中的代谢去向。线粒体制剂在对苯丙氨酸敏感的反应中迅速将MPTP氧化成含有L-甲基-4-苯基吡啶物种的极性物质。添加NADPH的微球制剂将MPTP转化为两个主要产物：4-苯基-L，2，3，6-四氢吡啶和L-甲基-4-苯基-L，2，3，6-四氢吡啶IV-氧化物。一氧化碳和SKF 525A选择性地抑制MPTP氧化为NOR化合物，表明该N-脱甲基化反应是细胞色素P-450催化的。试图在微粒体与氰化钠的混合物中捕获MPTP可能不稳定的亚胺代谢物，从而分离出一种被证明是N-氰甲基衍生物的单氰基加合物。因此，肝脏线粒体和微粒体酶系统通过不同的途径催化MPTP的氧化，前者导致可能具有神经毒性的物种的产生。据报道，哌啶类化合物L-甲基-4-苯基-L，2，3，6-四氢吡啶(MPTP，1)是滥用麻醉性镇痛剂1-甲基-4-苯基-4-(丙酰氧基)-L，2，3，6-四氢吡啶(2)的热分解产物，可引起临床上难以诊断的特发性帕金森病综合征，并选择性地破坏猴的黑质纹状体系统。4、5我们最近提出的证据表明
The metabolic fate of the nigrostriatal toxin l-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine (MPTP) has been examined in ratand rabbit liver mitochondrial and rabbit liver microsomal preparations. The mitochondrial preparations rapidly oxidized MPTP, in a pargyline-sensitive reaction, to a polar material that was shown to contain the l-methyl-4-phenylpyridinium species as the principal product. NADPH-supplemented microsomal preparations converted MPTP to two principal products: 4-phenyl-l, 2, 3, 6-tetrahydropyridine and l-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine IV-oxide. Carbon monoxide and SKF 525A selectively inhibited the oxidation of MPTP to the nor compound, indicating that this N-demethylationreaction is cytochrome P-450 catalyzed. Attempts to trap possible unstable iminium metabolites of MPTP in microsomal incubation mixtures with sodium cyanide led to the isolation of a monocyano adduct that proved to be the N-cyanomethyl derivative. Thus, hepatic mitochondrial and microsomal enzyme systems catalyze the oxidation of MPTP by different pathways, the former leading to the generation of species that may possess neurotoxic properties.The piperideine derivative l-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine (MPTP, 1), a thermal breakdown product of theabused narcotic analgetic agent 1-methyl-4-phenyl-4-(propionyloxy)-l, 2, 3, 6-tetrahydropyridine (2), has been reported to cause a clinical syndrome indistin-guishable from idiopathic Parkinson’s disease in man1" 3 and to destroy selectively the nigrostriatal system in monkeys. 4, 5 We recently presented evidence suggesting