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Research ArticleArticle

Identification of the Metabolites of the Antioxidant Flavonoid 7-Mono-O-(β-hydroxyethyl)-rutoside in Mice

Hilde Jacobs, Ron Peters, Gertjan J. M. den Hartog, Wim J. F. van der Vijgh, Aalt Bast and Guido R. M. M. Haenen
Drug Metabolism and Disposition May 2011, 39 (5) 750-756; DOI: https://doi.org/10.1124/dmd.110.036525
Hilde Jacobs
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Ron Peters
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Gertjan J. M. den Hartog
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Wim J. F. van der Vijgh
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Aalt Bast
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Guido R. M. M. Haenen
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Abstract

The clinical use of the anticancer drug doxorubicin is limited by severe cardiotoxicity. In mice, the semisynthetic antioxidant flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER) has been successfully used as a protector against doxorubicin-induced cardiotoxicity. However, most monoHER has already been cleared from the body at the time that doxorubicin concentrations are still high. This result suggests that not only the parent compound monoHER itself but also monoHER metabolites could be responsible for the observed cardioprotective effects in mice. Therefore, in the present study, we investigated the metabolism of monoHER in mice. Mice were administered 500 mg/kg monoHER intraperitoneally. At different time points after monoHER administration, bile was collected and analyzed for the presence of monoHER metabolites. The formed metabolites were identified by liquid chromatography-diode array detection-time of flight-mass spectrometry. Thirteen different metabolites were identified. The observed routes of monoHER metabolism are methylation, glucuronidation, oxidation of its hydroxyethyl group, GSH conjugation, and hydrolysis of its disaccharide. In line with other flavonoids, methylated monoHER and the monoHER glucosides are expected to have relatively high cellular uptake and low clearance from the body. Therefore, these metabolites might contribute to the observed protection of monoHER against doxorubicin-induced cardiotoxicity.

Footnotes

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

    doi:10.1124/dmd.110.036525.

  • ABBREVIATIONS:

    monoHER
    7-mono-O-(β-hydroxyethyl)-rutoside
    LC
    liquid chromatography
    DAD
    diode array detection
    TOF
    electrospray time of flight
    MS
    mass spectrometry
    COMT
    catechol-O-methyltransferase
    SAM
    S-adenosyl-l-methionine
    TFA
    trifluoroacetic acid
    HPLC
    high-performance liquid chromatography
    HP-921
    hexakis-(1H,1H,3H-tetrafluoro-pentoxy)phosphazene
    AUC
    area under the curve
    monoCER
    7-mono-O-(β-carboxyethyl)-rutoside
    monoHEG
    7-mono-O-(β-hydroxyethyl)-glucoside
    diHER
    7-di-O-(β-hydroxyethyl)-rutoside
    triHER
    7-tri-O-(β-hydroxyethyl)-rutoside
    tetraHER
    7-tetra-O-(β-hydroxyethyl)-rutoside.

  • Received September 29, 2010.
  • Accepted January 25, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

Identification of the Metabolites of the Antioxidant Flavonoid 7-Mono-O-(β-hydroxyethyl)-rutoside in Mice

Hilde Jacobs, Ron Peters, Gertjan J. M. den Hartog, Wim J. F. van der Vijgh, Aalt Bast and Guido R. M. M. Haenen
Drug Metabolism and Disposition May 1, 2011, 39 (5) 750-756; DOI: https://doi.org/10.1124/dmd.110.036525

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Research ArticleArticle

Identification of the Metabolites of the Antioxidant Flavonoid 7-Mono-O-(β-hydroxyethyl)-rutoside in Mice

Hilde Jacobs, Ron Peters, Gertjan J. M. den Hartog, Wim J. F. van der Vijgh, Aalt Bast and Guido R. M. M. Haenen
Drug Metabolism and Disposition May 1, 2011, 39 (5) 750-756; DOI: https://doi.org/10.1124/dmd.110.036525
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