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Research ArticleArticle

A Baeyer-Villiger Oxidation Specifically Catalyzed by Human Flavin-Containing Monooxygenase 5

W. George Lai, Nadia Farah, George A. Moniz and Y. Nancy Wong
Drug Metabolism and Disposition January 2011, 39 (1) 61-70; DOI: https://doi.org/10.1124/dmd.110.035360
W. George Lai
Drug Metabolism and Pharmacokinetics-Andover, Biopharmaceutical Assessments (W.G.L., N.F., Y.N.W.) and Process Research-Andover (G.A.M.), Eisai Inc., Andover, Massachusetts
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Nadia Farah
Drug Metabolism and Pharmacokinetics-Andover, Biopharmaceutical Assessments (W.G.L., N.F., Y.N.W.) and Process Research-Andover (G.A.M.), Eisai Inc., Andover, Massachusetts
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George A. Moniz
Drug Metabolism and Pharmacokinetics-Andover, Biopharmaceutical Assessments (W.G.L., N.F., Y.N.W.) and Process Research-Andover (G.A.M.), Eisai Inc., Andover, Massachusetts
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Y. Nancy Wong
Drug Metabolism and Pharmacokinetics-Andover, Biopharmaceutical Assessments (W.G.L., N.F., Y.N.W.) and Process Research-Andover (G.A.M.), Eisai Inc., Andover, Massachusetts
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Abstract

10-((4-Hydroxypiperidin-1-yl)methyl)chromeno[4,3,2-de]phthalazin-3(2H)-one (E7016), an inhibitor of poly(ADP-ribose) polymerase, is being developed for anticancer therapy. One of the major metabolites identified in preclinical animal studies was the product of an apparent oxidation and ring opening of the 4-hydroxypiperidine. In vitro, this oxidized metabolite could not be generated by incubating E7016 with animal or human liver microsomes. Further studies revealed the formation of this unique metabolite in hepatocytes. In a NAD(P)+-dependent manner, this metabolite was also generated by liver S9 fractions and recombinant human flavin-containing monooxygenase (FMO) 5 that was fortified with liver cytosol fractions. In animal and human liver S9, this metabolic pathway could be inhibited by 4-methylpyrazole, bis-p-nitrophenylphosphate (BNPP), or a brief heat treatment at 50°C. Based on these results, the overall metabolic pathway was believed to involve a two-step oxidation process: dehydrogenation of the secondary alcohol in liver cytosol followed by an FMO5-mediated Baeyer-Villiger oxidation in liver microsomes. The two oxidation steps were coupled via regeneration of NAD(P)+ and NAD(P)H. To further confirm this mechanism, the proposed ketone intermediate was independently synthesized. In an NAD(P)H-dependent manner, the synthetic ketone intermediate was metabolized to the same ring-opened metabolite in animal and human liver microsomes. This metabolic reaction was also inhibited by BNPP or a brief heat treatment at 50°C. Methimazole, the substrate/inhibitor of FMO1 and FMO3, did not inhibit this reaction. The specificity of FMO5 toward catalyzing this Baeyer-Villiger oxidation was further demonstrated by incubating the synthetic ketone intermediate in recombinant enzymes.

Footnotes

    • Received July 8, 2010.
    • Accepted October 13, 2010.
  • Parts of this work were previously presented at the following conference: Lai WG, Farah N, Moniz GA, and Wong YN (2010) Baeyer-Villiger oxidation specifically catalyzed by human flavin-containing monooxygenase 5. 9th International Meeting of the International Society for the Study of Xenobiotics; 2010 Sept 4–8; Istanbul, Turkey. International Society for the Study of Xenobiotics, Washington, DC.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035360.

  • ABBREVIATIONS:

    FMO
    flavin-containing monooxygenase
    Org 30659
    (17α)-17-hydroxy-11-methylene-19-norpregna-4,15-dien-20-yn-3-one
    E7016
    10-((4-hydroxypiperidin-1-yl)methyl)chromeno[4,3,2-de]phthalazin-3(2H)-one
    ER-879123
    3-((2-hydroxyethyl)((3-oxo-2,3-dihydrochromeno[4,3,2-de]phthalazin-10-yl)methyl)amino)propanoic acid
    ER-879819
    10-((4-oxopiperidin-1-yl)methyl)chromeno[4,3,2-de]phthalazin-3(2H)-one
    HPLC
    high-performance liquid chromatography
    SRM
    selected reaction monitoring
    DMSO
    dimethyl sulfoxide
    ER-886830
    tert-butyl 3-((2-hydroxyethyl)((3-oxo-2,3-dihydrochromeno[4,3,2-de]phthalazin-10-yl)methyl)amino)propanoate
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry
    HPLC
    high-performance liquid chromatography
    BNPP
    bis(p-nitrophenyl)phosphate
    BVMO
    Baeyer-Villiger monooxygenase.

  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Research ArticleArticle

A Baeyer-Villiger Oxidation Specifically Catalyzed by Human Flavin-Containing Monooxygenase 5

W. George Lai, Nadia Farah, George A. Moniz and Y. Nancy Wong
Drug Metabolism and Disposition January 1, 2011, 39 (1) 61-70; DOI: https://doi.org/10.1124/dmd.110.035360

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Research ArticleArticle

A Baeyer-Villiger Oxidation Specifically Catalyzed by Human Flavin-Containing Monooxygenase 5

W. George Lai, Nadia Farah, George A. Moniz and Y. Nancy Wong
Drug Metabolism and Disposition January 1, 2011, 39 (1) 61-70; DOI: https://doi.org/10.1124/dmd.110.035360
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