A reactive metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is formed in rat brain in vitro by type B monoamine oxidase.
The formation of a reactive intermediate in the oxidative metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) that can covalently bind to monoamine oxidase or other cellular macromolecules has been postulated by several authors. We report here direct in vitro evidence that MPTP is converted by monoamine oxidase, predominantly type B, to a reactive metabolite, which binds irreversibly to proteins in rat brain. Rat brain homogenates were incubated at 37 degrees C with 1-[methyl-3H]MPTP and the perchloric acid precipitates were washed exhaustively with organic solvents and counted for radioactivity. The amount of recovered radioactivity was enzyme-related: it was time- and temperature-dependent and did not occur with preboiled tissue. This metabolic activity required oxygen; it was concentrated in the crude mitochondrial fraction and varied in different brain regions. Pargyline and deprenyl prevented the radioactivity binding, whereas clorgyline was less potent, indicating that monoamine oxidase, predominantly of type B, is the enzyme responsible for the production of the reactive metabolite. Glutathione and, to a lesser extent, cysteine and dithiothreitol, but not ascorbic acid, inhibited the irreversible protein binding, suggesting that sulfhydryl groups may react with the metabolite possibly leading to SH-conjugates. 1-Methyl-4-phenyl-2,3-dihydropyridinium increased the irreversible protein binding, indicating that the reactive metabolite of MPTP may not be identified as the dihydropyridinium compound. This chemically reactive intermediate might play a role in MPTP neurotoxicity.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001711:Biotransformation; D001921:Brain / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000378:metabolism*; D011726:Pyridinium Compounds / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D000975:Antioxidants; D008996:Monoamine Oxidase Inhibitors; D011725:Pyridines; D011726:Pyridinium Compounds; C044755:1-methyl-4-phenyl-2,3-dihydropyridinium; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D008995:Monoamine Oxidase