Weissman J, Trevor A, Chiba K, Peterson L A, Caldera P, Castagnoli N, Baillie T
J Med Chem. 1985 Aug;28(8):997-1001. doi: 10.1021/jm00146a005.
The metabolic fate of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been examined in rat and 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 1-methyl-4-phenylpyridinium species as the principal product. NADPH-supplemented microsomal preparations converted MPTP to two principal products: 4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide. Carbon monoxide and SKF 525A selectively inhibited the oxidation of MPTP to the nor compound, indicating that this N-demethylation reaction 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.
已在大鼠和兔肝脏线粒体以及兔肝脏微粒体制剂中研究了黑质纹状体毒素1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）的代谢命运。线粒体准备物在一种对优降宁敏感的反应中迅速将MPTP氧化为一种极性物质，该物质被证明含有1-甲基-4-苯基吡啶鎓作为主要产物。添加了NADPH的微粒体制剂将MPTP转化为两种主要产物：4-苯基-1,2,3,6-四氢吡啶和1-甲基-4-苯基-1,2,3,6-四氢吡啶N-氧化物。一氧化碳和SKF 525A选择性地抑制MPTP氧化为去甲化合物，表明这种N-去甲基化反应是由细胞色素P-450催化的。尝试在微粒体孵育混合物中用氰化钠捕获MPTP可能的不稳定亚胺代谢物，导致分离出一种单氰加合物，事实证明它是N-氰甲基衍生物。因此，肝脏线粒体和微粒体酶系统通过不同途径催化MPTP的氧化，前者导致可能具有神经毒性的物质的产生。
