Processing of MPTP by monoamine oxidases: implications for molecular toxicology

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.