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Research ArticleArticle

Induction of Human UDP-Glucuronosyltransferase UGT1A1 by Flavonoids—Structural Requirements

U. Kristina Walle and Thomas Walle
Drug Metabolism and Disposition May 2002, 30 (5) 564-569; DOI: https://doi.org/10.1124/dmd.30.5.564
U. Kristina Walle
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Thomas Walle
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Abstract

Recent studies in our laboratory in the human hepatic and intestinal cell lines Hep G2 and Caco-2 have demonstrated induction of UGT1A1 by the flavonoid chrysin (5,7-dihydroxyflavone) using catalytic activity assays and Western and Northern blotting. In the present study, we examined which features of the flavonoid structures were associated with induction of UGT1A1 and whether common drug-metabolizing enzyme inducers also produce this induction. We also determined whether flavonoid treatment affected sulfate conjugation and CYP1A1 activity. We used intact Hep G2 cells for these studies, with chrysin as the model substrate. Both glucuronidation and sulfation were measured. Hep G2 cells were pretreated for 3 days with 25 μM concentrations of 22 flavonoids (n = 4–12). Only four flavonoids demonstrated induction of glucuronidation similar to that of chrysin (i.e., 3–5-fold in the intact cells). These were acacetin, apigenin, luteolin, and diosmetin, all of which, like chrysin, are 5,7-dihydroxyflavones with varying substituents in the B-ring. 5-Hydroxy-7-methoxyflavone and 5-methyl-7-hydroxyflavone produced a modest 1.5 to 2-fold induction, whereas all other flavonoids examined were without effect. None of the flavonoids caused more than a modest change in sulfation activity (60–140% of control). In contrast, all tested 5,7-dihydroxyflavones and -flavonols induced CYP1A1 activity (ethoxyresorufin deethylation). Of seven common drug-metabolizing enzyme inducers only 3-methylcholanthrene and oltipraz showed modest induction of chrysin glucuronidation but not 2,3,7,8-tetrachlorodibenzo-p-dioxin or phenobarbital. Together, these results strongly suggest that the flavonoid induction of UGT1A1 is through a novel nonaryl hydrocarbon receptor-mediated mechanism.

Footnotes

  • This work was supported by National Institutes of Health Grant GM55561 and by U.S. Department of Agriculture Cooperative State Research, Education, and Extension Service (CSREES) Grant 00-35200-9071. This study was presented in part at the 10th North American meeting of the International Society for the Study of Xenobiotics in Indianapolis, IN, October 24–28, 2000.

  • Abbreviations used are::
    UGT
    UDP-glucuronosyltransferase
    AhR
    aryl hydrocarbon receptor
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    3-MC
    3-methylcholanthrene
    DMSO
    dimethyl sulfoxide
    HPLC
    high-performance liquid chromatography
    EROD
    ethoxyresorufin deethylase
    • Received July 6, 2001.
    • Accepted January 31, 2002.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 30 (5)
Drug Metabolism and Disposition
Vol. 30, Issue 5
1 May 2002
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Research ArticleArticle

Induction of Human UDP-Glucuronosyltransferase UGT1A1 by Flavonoids—Structural Requirements

U. Kristina Walle and Thomas Walle
Drug Metabolism and Disposition May 1, 2002, 30 (5) 564-569; DOI: https://doi.org/10.1124/dmd.30.5.564

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Research ArticleArticle

Induction of Human UDP-Glucuronosyltransferase UGT1A1 by Flavonoids—Structural Requirements

U. Kristina Walle and Thomas Walle
Drug Metabolism and Disposition May 1, 2002, 30 (5) 564-569; DOI: https://doi.org/10.1124/dmd.30.5.564
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