RT Journal Article SR Electronic T1 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) JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 735 OP 742 DO 10.1124/dmd.115.063594 VO 43 IS 5 A1 Shotaro Uehara A1 Yasuhiro Uno A1 Takashi Inoue A1 Norie Murayama A1 Makiko Shimizu A1 Erika Sasaki A1 Hiroshi Yamazaki YR 2015 UL http://dmd.aspetjournals.org/content/43/5/735.abstract AB The potential proneurotoxin 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 and 1-methyl-4-phenylpyridinium ions (MPDP+ and MPP+, respectively) by desaturation reactions. MPTP is deactivated to 4-phenyl-1,2,3,6-tetrahydropyridine (PTP) by N-demethylation and is also deactivated to MPTP N-oxide. The roles of cytochrome P450 (P450) enzymes and flavin-containing monooxygenases (FMOs) in the oxidative metabolism of MPTP-treated marmosets are not yet fully clarified. This study aimed to elucidate P450- and FMO-dependent MPTP metabolism in marmoset liver and brain. Rates of MPTP N-oxygenation in liver microsomes were similar to those in brain microsomes from 11 individual marmosets (substrate concentration, 50 μM) and were correlated with rates of benzydamine N-oxygenation (r = 0.75, P < 0.05); the reactions were inhibited by methimazole (10 μM). MPTP N-oxygenation was efficiently mediated by recombinantly expressed marmoset FMO3. Rates of PTP formation by MPTP N-demethylation in marmoset liver microsomes were correlated with bufuralol 1′-hydroxylation rates (r = 0.77, P < 0.01) and were suppressed by quinidine (1 μM), thereby indicating the importance of marmoset CYP2D6 in PTP formation. MPTP transformations to MPDP+ and MPP+ were efficiently catalyzed by recombinant marmoset CYP2D6 and human CYP1A2. These results indicated the contributions of multiple drug-metabolizing enzymes to MPTP oxidation, especially marmoset FMO3 in deactivation (N-oxygenation) and marmoset CYP2D6 for both MPTP deactivation and MPTP activation to MPDP+ and MPP+. These findings provide a foundation for understanding MPTP metabolism and for the successful production of preclinical marmoset models.