The role of chrysin and the Ah receptor in induction of the human UGT1A1 gene in vitro and in transgenic UGT1 mice

Authors

  • Jessica A. Bonzo,

    1. Laboratory of Environmental Toxicology, Departments of Pharmacology, Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA
    2. Biomedical Sciences Graduate Program at UCSD, CA
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  • Alain Bélanger,

    1. Molecular Endocrinology and Oncology Research Center, CHUL Research Center and the Faculty of Medicine, Laval University, Quebec, Canada
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  • Robert H. Tukey

    Corresponding author
    1. Laboratory of Environmental Toxicology, Departments of Pharmacology, Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA
    • Departments of Pharmacology, Chemistry, and Biochemistry, Leichtag Biomedical Research Building, Room 211, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0722
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    • fax: 858-822-0363


  • Potential conflict of interest: Nothing to report.

Abstract

The flavonoid chrysin is an important dietary substance and induces UGT1A1 protein expression in cell culture. As a representative of the class of dietary flavonoids, clinical investigations have been considered as a means of inducing hepatic UGT1A1 expression. We demonstrate the necessity of a xenobiotic response element (XRE) in support of chrysin induction of UGT1A1 in the human hepatoma cell line HepG2. Receptor binding assays confirm that chrysin is a ligand for the Ah receptor by competition with [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, key differences in Ah receptor recognition and activation of UGT1A1 by chrysin exist when compared with classical mechanisms of UGT1A1 induction by TCDD. Ah receptor degradation, an indicator of Ah receptor activation, does not occur after chrysin treatment, and chrysin cannot transactivate the Ah receptor in a TCDD-dependent fashion. Knock-down of the Ah receptor by siRNA indicates that chrysin uses the Ah receptor in conjunction with other factors through MAP kinase signaling pathways to maximally induce UGT1A1. Most importantly, oral treatment of chrysin to transgenic mice that express the human UGT1 locus is unable to induce UGT1A1 expression in either the small intestine or liver. Conclusion: Although the implications for chrysin as an atypical agonist of the Ah receptor are intriguing at the molecular level, the relevance of chrysin-induced transcription for the purpose of clinical therapies or to regulate phase 2–dependent glucuronidation is questionable given the lack of in vivo regulation of human UGT1A1 by chrysin in a transgenic animal model. (HEPATOLOGY 2007;45:349–360.)

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