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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).
Drug Metab Dispos. 2015 May; 43(5):735-42.DM

Abstract

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.

Authors+Show Affiliations

Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., N.M., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., N.M., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., N.M., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., N.M., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., N.M., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., N.M., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.).Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan (S.U., N.M., M.S., H.Y.); Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Wakayama, Japan (Y.U.); Department of Applied Developmental Biology, Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan (T.I., E.S.); and Keio Advanced Research Center, Keio University, Minato-ku, Tokyo, Japan (E.S.) hyamazak@ac.shoyaku.ac.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25735838

Citation

Uehara, Shotaro, et al. "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)." Drug Metabolism and Disposition: the Biological Fate of Chemicals, vol. 43, no. 5, 2015, pp. 735-42.
Uehara S, Uno Y, Inoue T, et al. 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). Drug Metab Dispos. 2015;43(5):735-42.
Uehara, S., Uno, Y., Inoue, T., Murayama, N., Shimizu, M., Sasaki, E., & Yamazaki, H. (2015). 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). Drug Metabolism and Disposition: the Biological Fate of Chemicals, 43(5), 735-42. https://doi.org/10.1124/dmd.115.063594
Uehara S, et al. 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). Drug Metab Dispos. 2015;43(5):735-42. PubMed PMID: 25735838.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR 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). AU - Uehara,Shotaro, AU - Uno,Yasuhiro, AU - Inoue,Takashi, AU - Murayama,Norie, AU - Shimizu,Makiko, AU - Sasaki,Erika, AU - Yamazaki,Hiroshi, Y1 - 2015/03/03/ PY - 2015/3/5/entrez PY - 2015/3/5/pubmed PY - 2015/12/15/medline SP - 735 EP - 42 JF - Drug metabolism and disposition: the biological fate of chemicals JO - Drug Metab Dispos VL - 43 IS - 5 N2 - 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. SN - 1521-009X UR - https://www.unboundmedicine.com/medline/citation/25735838/Activation_and_deactivation_of_1_methyl_4_phenyl_1236_tetrahydropyridine_by_cytochrome_P450_enzymes_and_flavin_containing_monooxygenases_in_common_marmosets__Callithrix_jacchus__ DB - PRIME DP - Unbound Medicine ER -