7-Ketocholesterol Is an Endogenous Modulator for the Arylhydrocarbon Receptor

We have identified 7-ketocholesterol (7-KC) as an endogenous modulator that inhibits transactivation by the arylhydrocarbon receptor (AhR) through competitive binding against xenobiotic ligands. 7-KC binds AhR and displaces labeled dioxin (2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD)). IC50 is 5 × 10−...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-02, Vol.276 (5), p.3054-3059
Main Authors: Savouret, Jean-Francois, Antenos, Monica, Quesne, Monique, Xu, Jing, Milgrom, Edwin, Casper, Robert Frederick
Format: Article
Language:English
Subjects:
Animals
Cytochrome P-450 CYP1A1 - metabolism
Humans
Hydroxysteroid Dehydrogenases - metabolism
Ketocholesterols - metabolism
Ketocholesterols - physiology
Polychlorinated Dibenzodioxins - pharmacology
Rats
Receptors, Aryl Hydrocarbon - genetics
Receptors, Aryl Hydrocarbon - metabolism
Teratogens - pharmacology
Transcriptional Activation - drug effects
Transcriptional Activation - physiology
Tumor Cells, Cultured
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Summary:We have identified 7-ketocholesterol (7-KC) as an endogenous modulator that inhibits transactivation by the arylhydrocarbon receptor (AhR) through competitive binding against xenobiotic ligands. 7-KC binds AhR and displaces labeled dioxin (2,3,7,8-tetrachlorodibenzo(p)dioxin (TCDD)). IC50 is 5 × 10−7min vivo and 7 × 10−6min vitro. These figures are consistent with its concentration in human blood plasma and tissues. Association with 7-KC prevents AhR binding to DNA. 7-KC blocks the TCDD-mediated transactivation of stably expressed reporter gene constructs in T47-D cells as well as the expression of the endogenous CYP 1A1 gene in HepG2 cells and in primary porcine aortic endothelial cells. Injection of 7-KC to rats blocks the induction of CYP 1A1 messenger RNA and protein in endothelial cells from myocardial blood vessels. The differential sensitivity of mammalian species to toxic effects of AhR ligands, especially dioxin (TCDD), correlates with the expression of 7-hydroxycholesterol dehydrogenase, which synthesizes 7-KC from 7-hydroxycholesterol. The documented involvement of AhR ligands in cardiovascular diseases through lipid peroxidation and endothelium dysfunction can now be examined in the context of displacement of this protective modulator.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M005988200