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Abstract

Biotransformation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes.

D A Di Monte, E Y Wu, I Irwin, L E Delanney and J W Langston
Journal of Pharmacology and Experimental Therapeutics August 1991, 258 (2) 594-600;
D A Di Monte
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E Y Wu
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I Irwin
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L E Delanney
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J W Langston
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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)

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Journal of Pharmacology and Experimental Therapeutics
Vol. 258, Issue 2
1 Aug 1991
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Abstract

Biotransformation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes.

D A Di Monte, E Y Wu, I Irwin, L E Delanney and J W Langston
Journal of Pharmacology and Experimental Therapeutics August 1, 1991, 258 (2) 594-600;

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Abstract

Biotransformation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in primary cultures of mouse astrocytes.

D A Di Monte, E Y Wu, I Irwin, L E Delanney and J W Langston
Journal of Pharmacology and Experimental Therapeutics August 1, 1991, 258 (2) 594-600;
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