title: CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor.
abstract: The aryl hydrocarbon (dioxin) receptor (AhR) is a ligand-dependent transcription factor that produces a wide range of biological and toxic effects in many species and tissues. Whereas the best-characterized high-affinity ligands include structurally related halogenated aromatic hydrocarbons (HAHs) and polycyclic aromatic hydrocarbons (PAHs), the AhR is promiscuous and can also be activated by structurally diverse exogenous and endogenous chemicals. However, little is known about how these diverse ligands actually bind to and activate the AhR. Utilizing AhR ligand binding, DNA binding, and reporter gene expression assays, we have identified a novel ligand-selective antagonist (CH223191) that preferentially inhibits the ability of some classes of AhR agonists (2,3,7,8-tetrachlorodibenzo-p-dioxin and related HAHs), but not others (PAHs, flavonoids, or indirubin), to bind to and/or activate the AhR and AhR signal transduction. HAH-specific antagonism of AhR-dependent reporter gene expression by CH223191 was observed with mouse, rat, human, and guinea pig cell lines. Ligand- and species-selective antagonism was also observed with the AhR antagonists 3'-methoxy-4'-nitroflavone and 6,2',4',-trimethoxyflavone. Our results suggest that the differences in the binding by various ligands to the AhR contribute to the observed structural diversity of AhR ligands and could contribute in ligand-specific variation in AhR functionality and the toxic and biological effects of various classes of AhR agonists.
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, California 95616-8588, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhao
authors.forename: Danica E
authors.initials: DE
authors.lastname: Degroot
authors.forename: Ai
authors.initials: A
authors.lastname: Hayashi
authors.forename: Guochun
authors.initials: G
authors.lastname: He
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
mesh_terms: D000818:Animals; D001391:Azo Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000145:classification / Q000378:metabolism / Q000633:toxicity; D015870:Gene Expression; D006168:Guinea Pigs; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D011485:Protein Binding; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D019324:beta-Naphthoflavone / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity
chemical_list: C511621:2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide; D001391:Azo Compounds; D004785:Environmental Pollutants; D004791:Enzyme Inhibitors; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D011720:Pyrazoles; D018336:Receptors, Aryl Hydrocarbon; D019324:beta-Naphthoflavone