Activation and Deactivation of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine by Cytochrome P450 Enzymes and Flavin-Containing Monooxygenases in Common Marmosets (Callithrix jacchus)

摘要: The potential pro-neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces Parkinson-like syndromes in common marmosets, other primates, and humans. MPTP is metabolically activated to 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+) 1-methyl-4-phenylpyridinium (MPP+) ions by desaturation reactions; deactivated 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) N-demethylation N-oxide. roles of cytochromes P450 (P450s) flavin-containing monooxygenases (FMOs) the oxidative metabolism MPTP-treated marmosets are not yet fully clarified. aim this study was elucidate P450- FMO-dependent marmoset liver brain. Rates N-oxygenation microsomes were similar those brain from 11 individual (substrate concentration, 50 μM) correlated with rates benzydamine (r = 0.75, p < 0.05); reactions inhibited methimazole (10 μM). efficiently mediated recombinantly expressed FMO3. PTP formation bufuralol 1'-hydroxylation 0.77, 0.01) suppressed quinidine (1 μM), thereby indicating importance 2D6 formation. transformations MPDP+ MPP+ catalyzed recombinant human 1A2. These results indicated contributions multiple drug-metabolizing enzymes oxidation, especially FMO3 deactivation (N-oxygenation) for both activation MPP+. present findings provide a foundation understanding successful production preclinical models.