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.

L-Kynurenine/Aryl Hydrocarbon Receptor Pathway Mediates Brain Damage After Experimental Stroke

“…After in vivo experimental stroke by permanent MCAO, 2 different AhR antagonists, TMF 14 and CH, 15 were neuroprotective. The antagonism of AhR (with TMF) was also beneficial when ischemia was followed by recanalization (transient MCAO).…”

Effects of AhR ligands on the production of immunoglobulins in purified mouse B cells

“…However, special attention should be paid to this interpretation. Recently, it was reported that CH223191 is a ligand-selective antagonist of AhR, and preferentially inhibits the ability of some classes of AhR agonists (TCDD and related HAHs), but not others (PAHs, flavonoids or indirubin), to activate the AhR and AhR signal transduction (26). However, the important point to note is that this AhR agonist had the ability to suppress the production of several immunoglobulins.…”

The Aryl Hydrocarbon Receptor is a Critical Regulator of Tissue Factor Stability and an Antithrombotic Target in Uremia

“…A minor nuclear fraction indicated basal activation. Both IS and uremic serum induced AHR nuclear translocation within 20 minutes (Figure 1, B and C), an effect abrogated by a novel AHR antagonist, CB7993113, developed by our group 18 and CH223191, a well established AHR antagonist 19 ( Figure 1C, Supplemental Figure 5). …”