Contribution of N-oxygenation to the metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) by various liver preparations

Liver microsomes from uninduced mice and rats catalyze NADPH- and oxygen-dependent N-oxygenation of the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). The N-oxide is the principal product and accounts for 95-96% of the total MPTP metabolized by microsomes. Demethylation of MPTP is detectable but the rate of nor-MPTP formation was never more than 4-6% of the rate of N-oxygenation. Studies on the biochemical mechanisms for N-oxygenation of MPTP suggest that this reaction is catalyzed exclusively by the flavin-containing monooxygenase. This conclusion is based on the effects of selective cytochrome P-450 inhibitors, positive effectors, and alternate substrates for the flavin-containing monooxygenase as well as on studies with the purified hog liver enzyme. MPTP is an excellent substrate for this monooxygenase with a Km of 30-33 microM. Limited studies with human liver whole homogenates suggest that N-oxygenation is also a major route for the metabolism of MPTP in man and the rate of N-oxide formation is approximately equal to the rate of mitochondrial monoamine oxidase-dependent MPDP+ (1-methyl-4-phenyl-2,3-dihydropyridinium species) production.