STUDIES ON THE MOLECULAR MECHANISM OF BIOACTIVATION OF THE SELECTIVE NIGROSTRIATAL TOXIN 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE

Abstract

Detailed studies were carried out on the monoamine oxidase B-catalyzed bioactivation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [a 6-membered cyclic tertiary allylamine and thermal degradation product of a meperidine-type narcotic analgestic, reported to cause parkinsonism in humans] by rat brain mitochondrial preparations. Isolates of incubation mixtures run in H2O and D2O displayed chemical ionization mass spectral characteristics expected for the 1-methyl-4-phenyl-2,3-dihydropyridinium species MPDP+, a proposed intermediate in the biotransformation of MPTP to the 1-methyl-4-phenylpyridinium metabolite (MPP+) previously characterized in both in vitro and in vivo experiments. Further characterization of MPDP+ was achieved by comparison of the diode array UV spectral tracings of the metabolite with synthetic MPDP+ perchlorate (CIO4-) and by the isolation of a cyano adduct from mitochondrial coincubation mixtures of MPTP and sodium cyanide. MPDP+ CIO4- underwent disproportionation to MPP+ and MPTP, a reaction which suggests that this molecule may participate in redox reactions with dopamine that could lead to neurotoxic oxidation products.