Ch223191 is a ligand-selective antagonist of the Ah (dioxin) receptor

Bin Zhao, Danica E. DeGroot, Ai Hayashi, Guochun He, Michael S. Denison

Research output: Contribution to journalArticle

107 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)393-403
Number of pages11
JournalToxicological Sciences
Volume117
Issue number2
DOIs
StatePublished - Jul 15 2010

Fingerprint

Aryl Hydrocarbon Receptors
Ligands
Halogenated Hydrocarbons
Aromatic Hydrocarbons
Poisons
Polycyclic Aromatic Hydrocarbons
Reporter Genes
Gene expression
Gene Expression
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide
Signal transduction
Aromatic hydrocarbons
Hydrocarbons
Flavonoids
Rats
Assays
Signal Transduction
Guinea Pigs
Transcription Factors
Cells

Keywords

  • 2,3,7,8-tetrachlorodibenzo-p-dioxin
  • Ah receptor
  • Beta-naphthoflavone
  • CH223191
  • TCDD

ASJC Scopus subject areas

  • Toxicology

Cite this

Zhao, B., DeGroot, D. E., Hayashi, A., He, G., & Denison, M. S. (2010). Ch223191 is a ligand-selective antagonist of the Ah (dioxin) receptor. Toxicological Sciences, 117(2), 393-403. https://doi.org/10.1093/toxsci/kfq217

Ch223191 is a ligand-selective antagonist of the Ah (dioxin) receptor. / Zhao, Bin; DeGroot, Danica E.; Hayashi, Ai; He, Guochun; Denison, Michael S.

In: Toxicological Sciences, Vol. 117, No. 2, 15.07.2010, p. 393-403.

Research output: Contribution to journalArticle

Zhao, B, DeGroot, DE, Hayashi, A, He, G & Denison, MS 2010, 'Ch223191 is a ligand-selective antagonist of the Ah (dioxin) receptor', Toxicological Sciences, vol. 117, no. 2, pp. 393-403. https://doi.org/10.1093/toxsci/kfq217
Zhao, Bin ; DeGroot, Danica E. ; Hayashi, Ai ; He, Guochun ; Denison, Michael S. / Ch223191 is a ligand-selective antagonist of the Ah (dioxin) receptor. In: Toxicological Sciences. 2010 ; Vol. 117, No. 2. pp. 393-403.
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