Participation of brain monoamine oxidase B form in the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: relationship between the enzyme inhibition and the neurotoxicity.

A neurotoxin for nigrostriatal dopaminergic neurons, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its oxidized metabolite, 1-methyl-4-phenylpyridine (MPP+), both dose-dependently inhibited rat striatal and forebrain monoamine oxidase (MAO) activity with monoamine oxidase A (MAO-A) selectively reversible (competitive, Ki = 4.5 and 2.0 microM) inhibition. A comparison of the Ki values indicated the affinity of MPP+ for MAO-A to be greater than that of MPTP. MPTP inhibited monoamine oxidase B (MAO-B) with both a reversible (competitive, Ki = 116 microM) and an irreversible time-dependent component, but inhibition by MPP+ was reversible and competitive (Ki = 180 microM). These results, together with previous findings on metabolism of MPTP to MPP+ by brain MAO-B, suggest that MPP+ is a simple inhibitor of MAO-A and MAO-B, but MPTP might be a 'suicide substrate' inhibitor for MAO-B.