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Research ArticleTOXICOLOGY

Antagonism of Aryl Hydrocarbon Receptor Signaling by 6,2′,4′-Trimethoxyflavone

Iain A. Murray, Colin A. Flaveny, Brett C. DiNatale, Chris R. Chairo, Jennifer C. Schroeder, Ann Kusnadi and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 135-144; DOI: https://doi.org/10.1124/jpet.109.158261
Iain A. Murray
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, The Pennsylvania State University, University Park, Pennsylvania
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Colin A. Flaveny
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, The Pennsylvania State University, University Park, Pennsylvania
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Brett C. DiNatale
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, The Pennsylvania State University, University Park, Pennsylvania
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Chris R. Chairo
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, The Pennsylvania State University, University Park, Pennsylvania
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Jennifer C. Schroeder
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, The Pennsylvania State University, University Park, Pennsylvania
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Ann Kusnadi
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, The Pennsylvania State University, University Park, Pennsylvania
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Gary H. Perdew
Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary Sciences, The Pennsylvania State University, University Park, Pennsylvania
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This article has a correction. Please see:

  • Correction to “Antagonism of Aryl Hydrocarbon Receptor Signaling by 6, 2′,4′-Trimethoxyflavone” - November 01, 2018

Abstract

The aryl hydrocarbon receptor (AHR) is regarded as an important homeostatic transcriptional regulator within physiological and pathophysiological processes, including xenobiotic metabolism, endocrine function, immunity, and cancer. Agonist activation of the AHR is considered deleterious based on toxicological evidence obtained with environmental pollutants, which mediate toxic effects through AHR. However, a multitude of plant-derived constituents, e.g., polyphenols that exhibit beneficial properties, have also been described as ligands for the AHR. It is conceivable that some of the positive aspects of such compounds can be attributed to suppression of AHR activity through antagonism. Therefore, we conducted a dioxin response element reporter-based screen to assess the AHR activity associated with a range of flavonoid compounds. Our screen identified two flavonoids (5-methoxyflavone and 7,4′-dimethoxyisoflavone) with previously unidentified AHR agonist potential. In addition, we have identified and characterized 6,2′,4′-trimethoxyflavone (TMF) as an AHR ligand that possesses the characteristics of an antagonist having the capacity to compete with agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and benzo[a]pyrene, thus effectively inhibiting AHR-mediated transactivation of a heterologous reporter and endogenous targets, e.g., CYP1A1, independent of cell lineage or species. Furthermore, TMF displays superior action by virtue of having no partial agonist activity, in contrast to other documented antagonists, e.g., α-napthoflavone, which are partial weak agonists. TMF also exhibits no species or promoter dependence with regard to AHR antagonism. TMF therefore represents an improved tool allowing for more precise dissection of AHR function in the absence of any conflicting agonist activity.

Footnotes

    • Received June 26, 2009.
    • Accepted October 14, 2009.
  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES04869].

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

    doi:10.1124/jpet.109.158261

  • ↵Embedded Image The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    AHR
    aryl hydrocarbon receptor
    ARNT
    aryl hydrocarbon receptor nuclear translocator
    TMF
    6,2′,4′-trimethoxyflavone
    α-NF
    α-napthoflavone
    β-NF
    β-napthoflavone
    MNF
    3′-methoxy-4′-nitroflavone
    6-MCDF
    6-methoxy-1,3,8-trichlorodibenzofuran
    ER
    estrogen receptor
    B[a]P
    benzo[a]pyrene
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    DRE
    dioxin response element
    PAL
    2-azido-3-[125I]iodo-7,8-dibromodibenzo-p-dioxin
    CH-223191
    2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)-amide
    PD98059
    5′-methoxy-6′-aminoflavone
    DMSO
    dimethyl sulfoxide
    PVDF
    polyvinylidene difluoride
    PAGE
    polyacrylamide gel electrophoresis
    PBS
    phosphate-buffered saline
    PCR
    polymerase chain reaction
    MOPS
    4-morpholinepropanesulfonic acid
    HSP90
    heat-shock protein 90.

  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleTOXICOLOGY

Antagonism of Aryl Hydrocarbon Receptor Signaling by 6,2′,4′-Trimethoxyflavone

Iain A. Murray, Colin A. Flaveny, Brett C. DiNatale, Chris R. Chairo, Jennifer C. Schroeder, Ann Kusnadi and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 135-144; DOI: https://doi.org/10.1124/jpet.109.158261

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Research ArticleTOXICOLOGY

Antagonism of Aryl Hydrocarbon Receptor Signaling by 6,2′,4′-Trimethoxyflavone

Iain A. Murray, Colin A. Flaveny, Brett C. DiNatale, Chris R. Chairo, Jennifer C. Schroeder, Ann Kusnadi and Gary H. Perdew
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 135-144; DOI: https://doi.org/10.1124/jpet.109.158261
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