Processing of MPTP by monoamine oxidases: implications for molecular toxicology
MPTP (l-methyl-4-phenyl-l, 2,3,6-tetrahydropyridine), a selective nigrostriatal neurotoxin, is bioactivated by MAO-B (and less effectively by MAO-A) to 2,3-MPDP+ and this intermediate undergoes further oxidation to MPP+, partly through the activity of MAO forms. MPTP and its two primary metabolites are competitive inhibitors of both A and B forms of MAO. MPTP and 2,3-MPDP+ are also mechanism-based inactivators of both forms of the enzyme. A catalytic mechanism, involving the formation of radical intermediates, is proposed for the MAO-mediated oxidation of MPTP. Postoxidation biochemical sequelae, possibly involved in the expression of neurotoxicity, include the active accumulation of MPP+ via dopamine reuptake systems, the energy-driven uptake of MPP+ by mitochondria and the inhibition of NADH dehydrogenase by pyridine derivatives. A scheme linking these events as steps in the molecular mechanism of action of MPTP is proposed and discussed in terms of the selective toxicity of the neurotoxin towards nigrostriatal cells.
KeywordsMonoamine Oxidase NADH Dehydrogenase Brain Mitochondrion NADH Oxidation Succinate Oxidation
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- Burns RS, Chiueh CC, Markey SP, Ebert MG, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: Selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-l, 2,3, 6-tetrahydropyridine. Proc Natl Acad Sci USA 80: 4546–4550PubMedCrossRefGoogle Scholar
- DiMonte D, Jewell SA, Ekstrom G, Sandy MS, Smith MT (1986) l-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) and l-methyl-4-phenylpyri-dine (MPP+) cause rapid ATP depletion in isolated hepatocytes. Biochem Biophys Res Commun 137: 310–319Google Scholar
- Heikkila RE, Manzino L, Cabbat FS, Duvoisin RC (1984) Protection against dopaminergic neurotoxicity of l-methyl-4-phenyl-l, 2, 3, 6-tetrahydropyridine by monoamine oxidase inhibitors. Nature 311: 467– 469Google Scholar
- Javitch JA, D’Amato RJ, Strittmatter SM, Snyder SH (1985) Parkinsonism-inducing neurotoxin N-methyl-4-phenyl-l, 2,3, 6-tetrahydropyridine: Uptake of the metabolite N-methyl-4-phenylpyridine by dopamine neurons explains selective toxicity. Proc Natl Acad Sci USA 82: 2173– 2177Google Scholar
- Langston JW, Irwin I, Langston EB, Forno LS (1984) Pargyline prevents MPTP-induced parkinsonism in primates. Science 225: 1480– 1482Google Scholar
- Peterson LA, Caldera PS, Trevor A, Chiba K, Castagnoli N (1985) Studies on the l-methyl-4-phenyl-2,3-dihydropyridinium species, 2,3-MPDP“, the monoamine oxidase catalyzed oxidation product of the nigrostriatal toxin l-methyl-4-phenyl-l, 2,3, 5-tetrahydropyridine (MPTP). J Med Chem 28: 1432–1436PubMedCrossRefGoogle Scholar
- Weissman J, Trevor A, Chiba K, Peterson L, Caldera P, Castagnoli N (1985) Metabolism of the nigrostriatal toxin l-methyl-4-phenyl-l, 2,3, 6-tetrahydropyridine by liver homogenate fractions. J Med Chem 28: 997– 1001Google Scholar