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.
CH-223191 细胞实验
Cell Line
Concentration
Treated Time
Description
References
DLD1 colon cancer cells
10 µM
2 days
Reduced the proliferation of colon cancer cells
Genes Dev. 2019 Sep 1;33(17-18):1236-1251.
EL-4 cells
10 μM
24 h
CH223191 almost offset alpinetin-mediated increase of CYP1A1 expression
Cell Death Dis. 2018 Aug 30;9(9):890.
Hs578T cells
10 μM
48 h
Reduced ALDH1 activity and decreased the percentage of ALDHhigh cells
BMC Biol. 2016 Mar 16;14:20.
SUM149 cells
10 μM
48 h
Reduced ALDH1 activity and decreased the percentage of ALDHhigh cells
BMC Biol. 2016 Mar 16;14:20.
Caco-2 cells
10 μM
24 h
Inhibit AHR activity to study its effect on IL10R1 expression
Mucosal Immunol. 2017 Sep;10(5):1133-1144.
CD8 T cells
30 μM
72 h
To evaluate the effect of CH-223191 on IFN γ production in CD8 T cells. Results showed that CH-223191 significantly suppressed IFN γ production.
CH-223191 suppressed the GFP expression induced by BaP and FICZ, indicating that CH-223191 is an AHR antagonist.
Int J Mol Sci. 2023 Oct 12;24(20):15116.
CD4+ T cells
10 μM
72 h
CH223191 almost completely abolished alpinetin-promoted Treg differentiation
Cell Death Dis. 2018 Aug 30;9(9):890.
CH-223191 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6 mice
Obesity model
Oral
10 mg/kg
Once daily, starting 1 week before administration of vehicle or PCB-77 and continued throughout the study
To investigate the effect of CH-223191 on PCB-77-induced glucose and insulin intolerance, results showed that CH-223191 blocked these effects of PCB-77.
Environ Health Perspect. 2013 Jan;121(1):105-10.
Mice
Tiparp-/- or WT mice
Intraperitoneal injection
10 mg/kg
Days 1 and 3
CH223191 cotreatment reduced 3MC-induced ALT activity and epididymal adipose tissue loss, but did not completely prevent 3MC-induced chylous ascites.
Int J Mol Sci. 2019 May 10;20(9):2312
Mice
Tet2ΔV A V mice
Intraperitoneal injection
300 μg/mouse
5 days per week for 5 weeks
To evaluate the effect of CH-223191 on AIH-like pathology. Results showed that CH-223191 significantly suppressed the development of AIH-like pathology.
To test the inhibitory effect of CH-223191 on TCDD-induced atherosclerotic plaque formation, results showed that CH-223191 significantly reduced TCDD-induced atherosclerotic plaque formation.
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