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Vol. 55, Issue 4, 716-725, April 1999
Departments of
Environmental Medicine (E.C.H., G.R., J.J.W.,
S.D.D., T.A.G.),
Chemistry (A.S.K., M.J.T.), and
Pharmacology & Physiology (J.P.J.), University of Rochester, Rochester, New York; and
Department of Biochemistry & Molecular Biology (R.S.P.), Medical
University of South Carolina, Charleston, South Carolina
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.
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