Studies on the cytochrome P-450 catalyzed ring .alpha.-carbon oxidation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

Abstract

In vitro metabolic studies have established that rat liver cytochromes P-450IIB1 and P-450IA1 but not rabbit liver cytochrome P-450IIB4 catalyze the oxidation of the Parkinsonian inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the corresponding dihydropyridinium (MPDP+) and pyridinium (MPP+) species. Kinetic experiments with the most effective isozyme, cytochrome P-450IA1, indicate that the reaction proceeds at a moderate velocity [Vmax = 20.1 nmol/(min.nmol of P-450IA1)] and high Km (0.87 mM). Furthermore, kinetic deuterium isotope effect measurements provided DV and D(V/K) values of 2.99 and 1.04, respectively. A comparison with the corresponding values for the monoamine oxidase B (MAO-B) catalyzed reaction (4.37 and 9.35, respectively) suggests that either these enzymes catalyze the ring alpha-carbon oxidation of MPTP by different pathways or that the initial one-electron transfer to generate an aminium radical intermediate previously proposed for both enzyme systems is reversible in the case of MAO-B and irreversible in the case of cytochrome P-450IA1.