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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 393-403 |
| Number of pages | 11 |
| Journal | Toxicological Sciences |
| Volume | 117 |
| Issue number | 2 |
| DOIs | |
| State | Published - Jul 15 2010 |
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Keywords
- 2,3,7,8-tetrachlorodibenzo-p-dioxin
- Ah receptor
- Beta-naphthoflavone
- CH223191
- TCDD
ASJC Scopus subject areas
- Toxicology
Cite this
Ch223191 is a ligand-selective antagonist of the Ah (dioxin) receptor. / Zhao, Bin; DeGroot, Danica E.; Hayashi, Ai; He, Guochun; Denison, Michael S.
In: Toxicological Sciences, Vol. 117, No. 2, 15.07.2010, p. 393-403.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Ch223191 is a ligand-selective antagonist of the Ah (dioxin) receptor
AU - Zhao, Bin
AU - DeGroot, Danica E.
AU - Hayashi, Ai
AU - He, Guochun
AU - Denison, Michael S.
PY - 2010/7/15
Y1 - 2010/7/15
N2 - 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.
AB - 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.
KW - 2,3,7,8-tetrachlorodibenzo-p-dioxin
KW - Ah receptor
KW - Beta-naphthoflavone
KW - CH223191
KW - TCDD
UR - http://www.scopus.com/inward/record.url?scp=77956911339&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77956911339&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfq217
DO - 10.1093/toxsci/kfq217
M3 - Article
C2 - 20634293
AN - SCOPUS:77956911339
VL - 117
SP - 393
EP - 403
JO - Toxicological Sciences
JF - Toxicological Sciences
SN - 1096-6080
IS - 2
ER -