The formation of reactive intermediates in the MAO-catalyzed oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).
Oxidation of MPTP by monoamine oxidase (MAO), leading to the formation of reactive metabolites, is a critical step in the expression of the nigrostriatal toxicity of this molecule. A catalytic mechanism for the 2-electron oxidation of MPTP to MPDP+ and for the further 2-electron oxidation of MPDP+ to MPP+ is proposed, involving the formation of carbon-centered radical intermediates. These radical species appear to be involved in the mechanism-based inactivation of MAO by MPTP, possibly by generating 1,4-dihydropyridine adducts with the enzyme apoprotein or its coenzyme FAD. The pathways of metabolism of MPTP in brain and peripheral tissues and the active accumulation of metabolites of MPTP in dopaminergic neurons are discussed in terms of their possible contribution to the selective cytotoxicity of the compound.
Trevor
A J
AJ
Department of Pharmacology, University of California, San Francisco 94143.
Castagnoli
N
N
Singer
T P
TP
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D001711:Biotransformation; D008995:Monoamine Oxidase / Q000494:pharmacology*; D010084:Oxidation-Reduction; D011725:Pyridines / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000378:metabolism
D011725:Pyridines; D011954:Receptors, Dopamine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase