Metabolism of the neurotoxin in MPTP by human liver monoamine oxidase B

The neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was oxidized to dihydropyridine MPDP+ and pyridine MPP+ by preparations of monoamine oxidase B (MAO B), including pure human liver MAO B:monoclonal antibody complex, Km,app values for MPTP and benzylamine, a preferred MAO B substrate, were 316 and 64 microM, respectively. 4-Phenyl-1,2,3,6-tetrahydropyridine (PTP), the nor derivative of MPTP, was also a substrate (Km,app = 221 microM). MPDP+, MPTP, and MPP+, but not PTP, were found to be irreversible inhibitors of MAO B. Our studies support the hypothesis that MPTP is oxidized in primate brain by MAO B to MPDP+, which is then converted to MPP+, a major metabolite found in the substantia nigra.