scholarly journals Beyond the aryl hydrocarbon receptor: Pathway interactions in the hepatotoxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds

2017 ◽  
Vol 2 ◽  
pp. 36-41 ◽  
Author(s):  
Kelly A. Fader ◽  
Timothy R. Zacharewski
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Aryl Hydrocarbon ◽  
Tetrachlorodibenzo P Dioxin ◽  
Related Compounds

scholarly journals Transformation of the aryl hydrocarbon receptor to a DNA-binding form is accompanied by release of the 90 kDa heat-shock protein and increased affinity for 2,3,7,8-tetrachlorodibenzo-p-dioxin

1993 ◽  
Vol 294 (1) ◽  
pp. 95-101 ◽  
Author(s):  
E C Henry ◽  
T A Gasiewicz
Keyword(s):  
Heat Shock ◽  
Dna Binding ◽  
Heat Shock Protein ◽  
Aryl Hydrocarbon Receptor ◽  
Incubation Temperature ◽  
Binding Affinities ◽  
Aryl Hydrocarbon ◽  
Molecular Events ◽  
Binding Forms ◽  
Tetrachlorodibenzo P Dioxin

The binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the aryl hydrocarbon receptor (AhR) elicits a sequence of poorly defined molecular events that ultimately yield a heteromeric transformed AhR that is active as a transcription factor. We have previously developed a model of the ligand-initiated transformation of the AhR to the DNA-binding state based on characterization of several forms of the AhR with respect to their physicochemical properties and DNA-binding affinities. The present studies were designed to determine whether, and at what stage, this process of transformation alters the receptor's affinity for TCDD. In rat hepatic cytosol, approx. 10% of the TCDD specifically bound to the AhR rapidly dissociated (t1/2 approximately 1 h), while the remainder was only slowly dissociable (t1/2 approximately 70 h). The isolated DNA-binding forms of the receptor (monomeric and transformed) bound TCDD very tightly (t1/2 > 100 h), whereas TCDD was dissociable from the non-DNA-binding receptor form(s). A lower incubation temperature (0-4 degrees C) and the presence of molybdate partially stabilized the non-DNA-binding fraction of the TCDD.receptor complex and also enhanced TCDD dissociation in crude cytosol. Immunoprecipitation of the different AhR forms with an anti-AhR antibody and immunoblotting with antibody to the 90 kDa heat-shock protein (hsp90) demonstrated that hsp90 was associated with the unoccupied receptor complex as well as with a fraction of the non-DNA-binding TCDD.receptor complex; isolated DNA-binding forms did not contain detectable hsp90. We conclude that while hsp90 remains associated with the AhR, TCDD is readily dissociable; following release of hsp90, however, TCDD becomes very tightly bound, and remains so upon completion of transformation.

Aryl-hydrocarbon Receptor-Deficient Mice Are Resistant to 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Induced Toxicity

1996 ◽  
Vol 140 (1) ◽  
pp. 173-179 ◽  
Author(s):  
Pedro M. Fernandez-Salguero ◽  
David M. Hilbert ◽  
Stuart Rudikoff ◽  
Jerrold M. Ward ◽  
Frank J. Gonzalez
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Aryl Hydrocarbon ◽  
Tetrachlorodibenzo P Dioxin ◽  
Deficient Mice
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