Processing of MPTP by monoamine oxidases: implications for molecular toxicology.

A. J. Trevor*, T. P. Singer, R. R. Ramsay, N. Castagnoli

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

41 Citations (Scopus)

Abstract

MPTP (1-methyl-4-phenyl-1,2,3,6-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. Post-oxidation 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.

Original languageEnglish
Pages (from-to)73-89
Number of pages17
JournalJournal of Neural Transmission, Supplement
Volume23
Publication statusPublished - 1 Jan 1987

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