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
Shotaro UeharaHiroshi Yamazaki

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 ...Continue Reading

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Apr 30, 2013·Biochemical Pharmacology·Yasuhiro UnoHiroshi Yamazaki
Jul 6, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Yasuhiro UnoHiroshi Yamazaki

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Citations

Oct 28, 2015·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Shotaro UeharaHiroshi Yamazaki
Nov 3, 2016·Experimental Animals·Yoshinori ShimamotoEiki Takahashi
Sep 6, 2017·Neurochemical Research·Mohd Sami Ur RasheedMahendra Pratap Singh
Feb 9, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Toru OshioHiroshi Yamazaki
May 23, 2019·The Journal of Biological Chemistry·Mrittika ChattopadhyayNarayan G Avadhani
Feb 16, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shotaro UeharaHiroshi Yamazaki
Mar 5, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shotaro UeharaHiroshi Yamazaki
Oct 31, 2018·International Journal of Molecular Sciences·Jesus Fernandez-AbascalMassimo Valoti
Feb 28, 2020·Hepatic Medicine : Evidence and Research·Rajagopal N AravalliClifford J Steer
Dec 29, 2020·Drug Metabolism Reviews·Wojciech Kuban, Władysława Anna Daniel

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