CH223191 Is a Ligand-Selective Antagonist of the Ah (Dioxin) Receptor
Open accessAbstract
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.
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The ligand binding promiscuity of a given AHR may result from differential binding of structurally diverse ligands within its ligand-binding cavity.
“More recent studies have reported that the ligand binding promiscuity of a given AHR may result from differential binding of structurally diverse ligands within the AHR ligand-binding cavity (11-14), similar to the mechanisms responsible for pregnane X receptor ligand binding promiscuity (15,16).”
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- Authors
- Zhao, B., DeGroot, D. E., Hayashi, A., He, G., & Denison, M. S.
- Affiliations
- Chinese Academy of Sciences (CN)
- University of California, Davis (US)
- State Key Laboratory of Environmental Chemistry and Ecotoxicology (CN)
- Corresponding author
- Denison, Michael S.
- Venue
- Toxicological Sciences
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-07-15
- Volume
- 117
- Issue
- 2
- Pages
- 393-403
- ISSN
- 1096-0929 (ISSN-L)
- 1096-6080
- PMC
- PMC2940411
- OpenAlex
- W2109440685
- Cited by
- 312
- References
- 51
- Citations by year
- 2026: 22 · 2025: 22 · 2024: 15 · 2023: 25 · 2022: 34 · 2021: 36 · 2020: 32 · 2019: 26 · 2018: 21 · 2017: 11 · 2016: 9 · 2015: 9 · 2014: 15 · 2013: 13 · 2012: 8
- FWCI
- 8.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Toxicological Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Center for Eco-Environmental Sciences OpenIR (Chinese Academy of Sciences) (submittedVersion)
- Funders
- University of Louisville
- University of California, Davis
- National Institute of Environmental Health Sciences (P42ES004699, R01ES007685, ES012498, ES007685, ES004699, R01ES012498)
- Topics
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Toxic Organic Pollutants Impact
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Physical Sciences › Environmental Science › Health, Toxicology and Mutagenesis › Effects and risks of endocrine disrupting chemicals
- Keywords
- aryl hydrocarbon receptor, CH223191, halogenated aromatic hydrocarbons, polycyclic aromatic hydrocarbons, 2,3,7,8-tetrachlorodibenzo-p-dioxin, flavonoids, indirubin
- MeSH terms
- Polychlorinated Dibenzodioxins, Animals, Azo Compounds, Cell Line, Environmental Pollutants, Enzyme Inhibitors, Guinea Pigs, Humans, Ligands, Male, Protein Binding, Pyrazoles, Structure-Activity Relationship, Signal Transduction, Gene Expression, Receptors, Aryl Hydrocarbon, beta-Naphthoflavone, Mice, Rats
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