Studies on the molecular mechanism of bioactivation of the selective nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.
Detailed studies have been carried out on the monoamine oxidase B-catalyzed bioactivation of the nigrostriatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by rat brain mitochondrial preparations. Isolates of incubation mixtures run in H2O and D2O displayed chemical ionization mass spectral characteristics expected for the 1-methyl-4-phenyl-2,3-dihydropyridinium species MPDP+, a proposed intermediate in the biotransformation of MPTP to the 1-methyl-4-phenylpyridinium metabolite (MPP+) previously characterized in both in vitro and in vivo experiments. Further characterization of MPDP+ was achieved by comparison of the diode array UV spectral tracings of the metabolite with synthetic MPDP+ perchlorate (CIO4-) and by the isolation of a cyano adduct from mitochondrial coincubation mixtures of MPTP and sodium cyanide. MPDP+ CIO4- was shown to undergo disproportionation to MPP+ and MPTP, a reaction which suggests that this molecule may participate in redox reactions with dopamine that could lead to neurotoxic oxidation products.
Chiba
K
K
Peterson
L A
LA
Castagnoli
K P
KP
Trevor
A J
AJ
Castagnoli
N
N
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D001711:Biotransformation; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism* / Q000633:toxicity; D051381:Rats; D011919:Rats, Inbred Strains; D012966:Sodium Cyanide / Q000378:metabolism
D011725:Pyridines; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D012966:Sodium Cyanide