Metabolism of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by liver homogenate fractions

Abstract

The piperideine derivative 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a thermal breakdown product of the abused narcotic analgetic agent 1-methyl-4-phenyl-4-(propionyloxy)-1,2,3,6-tetrahydropyridine has been reported to cause a clinical syndrome indistinguishable from idiopathic Parkinson''s disease in man and to destroy selectively the nigrostriatal system in monkeys. The metabolic fate of the nigrostriatal toxin-1-MPTP was 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 contained the 1-methyl-4-phenylpyridinium species as the principal product. NADPH-supplemented microsomal preparations converted MPTP to 2 principal products: 2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide. CO and SKF 525A [proadifen hydrochloride] 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. Hepatic mitochondrial and microsomal enzyme systems evidently catalyze the oxidation of MPTP by different pathways, the former leading to the generation of species that may possess neurotoxic properties.