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Molecular Pharmacology

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Research ArticleArticle

Flavone Antagonists Bind Competitively with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) to the Aryl Hydrocarbon Receptor But Inhibit Nuclear Uptake and Transformation

Ellen C. Henry, Andrew S. Kende, George Rucci, Michael J. Totleben, J. Jeffrey Willey, Stephen D. Dertinger, Richard S. Pollenz, Jeffrey P. Jones and Thomas A. Gasiewicz
Molecular Pharmacology April 1999, 55 (4) 716-725;
Ellen C. Henry
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Andrew S. Kende
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George Rucci
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Michael J. Totleben
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J. Jeffrey Willey
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Stephen D. Dertinger
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Richard S. Pollenz
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Jeffrey P. Jones
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Thomas A. Gasiewicz
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Abstract

Previous analyses suggested that potent aryl hydrocarbon receptor (AhR) antagonists were planar, with a lateral electron-rich center. To further define structural requirements and mechanism for antagonism, ten additional flavone derivatives were synthesized. Based on their ability to 1) compete with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) for binding to the AhR; 2) inhibit TCDD-elicited binding of AhR to dioxin-responsive elements (DRE) in vitro; and 3) inhibit TCDD-induced transcription of DRE-dependent luciferase in stably transfected hepatoma cells, the most potent flavones contained a 3′-methoxy group and a 4′-substituent having one or more terminal atoms of high electron density (−N3, −NO2, or −NCS). Furthermore, these had low agonist activity as assessed by their inability to elicit AhR · DRE binding or to induce luciferase. Compounds containing bulkier 3′ or 4′-substituents, or a 3′-OH group were less potent antagonists, and some were partial agonists. In rat liver cytosol, 3′-methoxy-4′-azido- and 3′-methoxy-4′-nitroflavones bound competitively (with TCDD) to the AhR, indicating that they bind to the TCDD-binding site. When hepatoma cells were exposed to these flavones, AhR complexes were primarily immunoprecipitable from the cytosol and contained 90 kDa heat shock protein. In contrast, AhR in TCDD-treated cells was primarily immunoprecipitated from nuclear extracts and was associated with Arnt but not 90 kDa heat shock protein. Immunocytofluorescence analysis in intact cells further indicated that the potent antagonist inhibited nuclear uptake of AhR and blocked TCDD-dependent down-regulation of AhR. Together, these data indicate that the most potent antagonists bind the AhR with high affinity but cannot initiate receptor transformation and nuclear localization.

Footnotes

  • Send reprint requests to: Dr. E.C. Henry, Box EHSC, Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York 14642. E-mail:henrye{at}envmed.rochester.edu

  • This research was funded by National Institutes of Health Grant ES02515, Center Grant ES01247, and Training Grant ES07026. These data were presented in part at the Society of Toxicology Annual Meeting, March 1998, Seattle, Washington (Toxicol Sci42:383).

  • Abbreviations:
    AhR
    aryl hydrocarbon receptor
    Arnt
    Ah receptor nuclear translocator
    DRE
    dioxin responsive element
    EMSA
    electrophoretic mobility shift assay
    hsp90
    90 kDa heat shock protein
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    SDS-PAGE
    sodium dodecyl sulfate polyacrylamide gel electrophoresis
    Hepa
    hepatoma cells (Hepa lclc7)
    • Received September 2, 1998.
    • Accepted January 25, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (4)
Molecular Pharmacology
Vol. 55, Issue 4
1 Apr 1999
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Research ArticleArticle

Flavone Antagonists Bind Competitively with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) to the Aryl Hydrocarbon Receptor But Inhibit Nuclear Uptake and Transformation

Ellen C. Henry, Andrew S. Kende, George Rucci, Michael J. Totleben, J. Jeffrey Willey, Stephen D. Dertinger, Richard S. Pollenz, Jeffrey P. Jones and Thomas A. Gasiewicz
Molecular Pharmacology April 1, 1999, 55 (4) 716-725;

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Research ArticleArticle

Flavone Antagonists Bind Competitively with 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) to the Aryl Hydrocarbon Receptor But Inhibit Nuclear Uptake and Transformation

Ellen C. Henry, Andrew S. Kende, George Rucci, Michael J. Totleben, J. Jeffrey Willey, Stephen D. Dertinger, Richard S. Pollenz, Jeffrey P. Jones and Thomas A. Gasiewicz
Molecular Pharmacology April 1, 1999, 55 (4) 716-725;
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