The aryl hydrocarbon (dioxin) receptor (AhR) is a ligand-dependent basic helix-loop-helix-Per-Arnt-Sim (PAS)–containing transcription factor that responds to exogenous and endogenous chemicals with the induction/repression of expression of a diverse battery of genes in a wide range of species and tissues. CH-223191 is a preferential inhibitor of TCDD-induced AhR-dependent gene expression in various species. The relative inhibitory potency (IC50) of CH-223191 against TCDD-dependent gene induction in each cell line was 1.1 μM for guinea pig cells, 1.5 μM for mouse cells, 3.1 μM for rat cells, and 0.2 μM for human cells. Co-incubation of yAHAYc6 cells with CH-223191 dramatically reduced TCDD-dependent nuclear accumulation of yAhR (yellow fluorescent protein (YFP)-AhR chimera). The ability of 10 μM CH-223191 to significantly inhibit induction by the dihalogen-substituted flavonoid AY9 in rat hepatoma cells indicates this concentration of CH-223191 appears to have a preference for halogen-substituted AhR agonists [1]. It is noteworthy that CH-223191 potently prevented TCDD-elicited cytochrome P450 induction, liver toxicity, and wasting syndrome in mice [2].
作用机制
CH223191 could bind to the AhR outside of the ligand–binding domain and act as an allosteric modulator.
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