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Research ArticleArticle

Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

Walter Brand, Marelle G. Boersma, Hanneke Bik, Elisabeth F. Hoek-van den Hil, Jacques Vervoort, Denis Barron, Walter Meinl, Hansruedi Glatt, Gary Williamson, Peter J. van Bladeren and Ivonne M. C. M. Rietjens
Drug Metabolism and Disposition April 2010, 38 (4) 617-625; DOI: https://doi.org/10.1124/dmd.109.031047
Walter Brand
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Marelle G. Boersma
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Hanneke Bik
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Elisabeth F. Hoek-van den Hil
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Jacques Vervoort
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Denis Barron
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Walter Meinl
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Hansruedi Glatt
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Gary Williamson
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Peter J. van Bladeren
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Ivonne M. C. M. Rietjens
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Abstract

Phase II metabolism by UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) is the predominant metabolic pathway during the first-pass metabolism of hesperetin (4′-methoxy-3′,5,7-trihydroxyflavanone). In the present study, we have determined the kinetics for glucuronidation and sulfonation of hesperetin by 12 individual UGT and 12 individual SULT enzymes as well as by human or rat small intestinal, colonic, and hepatic microsomal and cytosolic fractions. Results demonstrate that hesperetin is conjugated at positions 7 and 3′ and that major enzyme-specific differences in kinetics and regioselectivity for the UGT and SULT catalyzed conjugations exist. UGT1A9, UGT1A1, UGT1A7, UGT1A8, and UGT1A3 are the major enzymes catalyzing hesperetin glucuronidation, the latter only producing 7-O-glucuronide, whereas UGT1A7 produced mainly 3′-O-glucuronide. Furthermore, UGT1A6 and UGT2B4 only produce hesperetin 7-O-glucuronide, whereas UGT1A1, UGT1A8, UGT1A9, UGT1A10, UGT2B7, and UGT2B15 conjugate both positions. SULT1A2 and SULT1A1 catalyze preferably and most efficiently the formation of hesperetin 3′-O-sulfate, and SULT1C4 catalyzes preferably and most efficiently the formation of hesperetin 7-O-sulfate. Based on expression levels SULT1A3 and SULT1B1 also will probably play a role in the sulfo-conjugation of hesperetin in vivo. The results help to explain discrepancies in metabolite patterns determined in tissues or systems with different expression of UGTs and SULTs, e.g., hepatic and intestinal fractions or Caco-2 cells. The incubations with rat and human tissue samples support an important role for intestinal cells during first-pass metabolism in the formation of hesperetin 3′-O-glucuronide and 7-O-glucuronide, which appear to be the major hesperetin metabolites found in vivo.

Footnotes

  • This study was supported by the Nestlé Research Center, Nestec Ltd. (Lausanne, Switzerland).

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

    doi:10.1124/dmd.109.031047.

  • ABBREVIATIONS:

    UGT
    UDP-glucuronosyltransferase
    SULT
    sulfotransferase
    HPLC
    high-performance liquid chromatography
    DAD
    diode array detector
    UDPGA
    UDP-glucuronic acid
    PAPS
    3′-phosphoadenosine 5′-phosphosulfate
    DMSO
    dimethyl sulfoxide.

    • Received November 5, 2009.
    • Accepted January 7, 2010.
  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 38 (4)
Drug Metabolism and Disposition
Vol. 38, Issue 4
1 Apr 2010
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Research ArticleArticle

Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

Walter Brand, Marelle G. Boersma, Hanneke Bik, Elisabeth F. Hoek-van den Hil, Jacques Vervoort, Denis Barron, Walter Meinl, Hansruedi Glatt, Gary Williamson, Peter J. van Bladeren and Ivonne M. C. M. Rietjens
Drug Metabolism and Disposition April 1, 2010, 38 (4) 617-625; DOI: https://doi.org/10.1124/dmd.109.031047

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Research ArticleArticle

Phase II Metabolism of Hesperetin by Individual UDP-Glucuronosyltransferases and Sulfotransferases and Rat and Human Tissue Samples

Walter Brand, Marelle G. Boersma, Hanneke Bik, Elisabeth F. Hoek-van den Hil, Jacques Vervoort, Denis Barron, Walter Meinl, Hansruedi Glatt, Gary Williamson, Peter J. van Bladeren and Ivonne M. C. M. Rietjens
Drug Metabolism and Disposition April 1, 2010, 38 (4) 617-625; DOI: https://doi.org/10.1124/dmd.109.031047
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