Summary
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.
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Trevor, A.J., Singer, T.P., Ramsay, R.R., Castagnoli, N. (1987). Processing of MPTP by monoamine oxidases: implications for molecular toxicology. In: Oreland, L., Callingham, B.A. (eds) Monoamine Oxidase Enzymes. Journal of Neural Transmission, vol 23. Springer, Vienna. https://doi.org/10.1007/978-3-7091-8901-6_5
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DOI: https://doi.org/10.1007/978-3-7091-8901-6_5
Publisher Name: Springer, Vienna
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