Metabolism of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by liver homogenate fractions.
The metabolic fate of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been examined in rat and rabbit liver mitochondrial and rabbit liver microsomal preparations. The mitochondrial preparations rapidly oxidized MPTP, in a pargyline-sensitive reaction, to a polar material that was shown to contain the 1-methyl-4-phenylpyridinium species as the principal product. NADPH-supplemented microsomal preparations converted MPTP to two principal products: 4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine N-oxide. Carbon monoxide and SKF 525A selectively inhibited the oxidation of MPTP to the nor compound, indicating that this N-demethylation reaction is cytochrome P-450 catalyzed. Attempts to trap possible unstable iminium metabolites of MPTP in microsomal incubation mixtures with sodium cyanide led to the isolation of a monocyano adduct that proved to be the N-cyanomethyl derivative. Thus, hepatic mitochondrial and microsomal enzyme systems catalyze the oxidation of MPTP by different pathways, the former leading to the generation of species that may possess neurotoxic properties.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001711:Biotransformation; D055598:Chemical Phenomena; D002621:Chemistry; D003342:Corpus Striatum / Q000187:drug effects*; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008930:Mitochondria, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D011725:Pyridines / Q000378:metabolism* / Q000633:toxicity; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D013378:Substantia Nigra / Q000187:drug effects*
D011725:Pyridines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine