title: Biotransformation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes.
abstract: Astrocytes are likely to be a main locus for the metabolic bioactivation of the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, a detailed analysis of MPTP metabolism was conducted in primary cultures of mouse astrocytes. A constant rate of conversion of 1.22 nmol/mg of protein per hr was observed when astrocyte cultures were incubated in the presence of 250 microM MPTP for 4 days. Three metabolites were detected as products of this conversion: 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP+), 1-methyl-4-phenylpyridinium ion (MPP+) and MPTP N-oxide. Production of MPP+ and MPTP N-oxide occurred at constant rates of 0.68 and 0.43 nmol/mg of protein per hr, respectively, whereas the level of MPDP+ remained quite stable and relatively low throughout the time of incubation. Both clorgyline, an inhibitor of monoamine oxidase (MAO) type A, and deprenyl, a MAO B inhibitor, blocked MPTP conversion to MPDP+ and MPP+; quantitative analysis of the effects of these two inhibitors revealed that MAO A and MAO B contribute to a similar extent to MPP+ production in astrocyte cultures. MAO inhibition did not result in an increased production of MPTP N-oxide and, in fact, the level of this metabolite was reduced markedly in the presence of 100 microM clorgyline. Formation of MPTP N-oxide was probably dependent upon the activity of the flavin-containing monooxygenase because: 1) it was blocked completely by thiobenzamide, a competitive substrate for this microsomal enzyme and 2) it was increased in the presence of n-octylamine, a known positive effector for flavin-containing monooxygenase.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: California Institute for Medical Research, San Jose.
authors.forename: D A
authors.initials: DA
authors.lastname: Di Monte
authors.forename: E Y
authors.initials: EY
authors.lastname: Wu
authors.forename: I
authors.initials: I
authors.lastname: Irwin
authors.forename: L E
authors.initials: LE
authors.lastname: Delanney
authors.forename: J W
authors.initials: JW
authors.lastname: Langston
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000378:metabolism*; D015655:1-Methyl-4-phenylpyridinium / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001711:Biotransformation; D002478:Cells, Cultured; D003010:Clorgyline / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D051379:Mice; D008995:Monoamine Oxidase / Q000032:analysis; D010105:Oxygenases / Q000502:physiology; D012642:Selegiline / Q000494:pharmacology
chemical_list: D012642:Selegiline; D003577:Cytochrome P-450 Enzyme System; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D008995:Monoamine Oxidase; D003010:Clorgyline; D015655:1-Methyl-4-phenylpyridinium