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

JR Cashman and DM Ziegler

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.

Volume 29, Issue 2, pp. 163-167, 02/01/1986
Copyright © 1986 by American Society for Pharmacology and Experimental Therapeutics

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