CH223191 is a ligand-selective antagonist of the Ah (Dioxin) receptor.
Toxicol Sci
; 117(2): 393-403, 2010 Oct.
Article
in En
| MEDLINE
| ID: mdl-20634293
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Pyrazoles
/
Azo Compounds
/
Receptors, Aryl Hydrocarbon
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Toxicol Sci
Journal subject:
TOXICOLOGIA
Year:
2010
Document type:
Article
Affiliation country: