Abstract
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates most biological responses to 2,3, 7,8-tetrachlorodibenzo-p-dioxin (TCDD) and related aromatic hydrocarbons. Although the role of the AHR in control of drug metabolism and endocrine disruption is partly understood, we know little about the regulation of the AHR itself by endocrine factors. Our work with hypophysectomized rats suggested that hepatic AHR protein level is positively regulated by pituitary-dependent factors. A current hypothesis is that adrenal glucocorticoids elevate AHR expression and enhance responsiveness to AHR agonists. Dexamethasone (DEX) at concentrations that activate the glucocorticoid receptor (GR) increased AHR mRNA, protein, and TCDD-binding by approximately 50% in Hepa-1 mouse hepatoma cells. This response was blocked by the GR antagonist 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one (RU486), suggesting GR involvement. This small magnitude increase in AHR levels was functionally significant; pretreatment of Hepa-1 cells with DEX caused a 75% increase in the maximum induction of an AHR-activated luciferase reporter plasmid by TCDD. A luciferase reporter under control of the proximal 2.5 kilobases of the mouse Ahr 5′-flanking region and promoter was induced approximately 2.5-fold by DEX when cotransfected with a mouse GR expression plasmid. This is the first demonstration that glucocorticoids increase AHR levels in hepatoma cells via a GR-dependent transcriptional mechanism, suggesting a novel aspect of cross-talk between the AHR and the GR.
Footnotes
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This work was supported by the Canadian Institutes of Health Research Grant MOP-42399 (D.S.R.). K.A.B. was the recipient of a Postgraduate Scholarship from the Natural Sciences and Engineering Research Council of Canada.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.019703.
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ABBREVIATIONS: AHR, aryl hydrocarbon receptor; HAH, halogenated aromatic hydrocarbon; TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin; PAH, polycyclic aromatic hydrocarbon; MC, 3-methylcholanthrene; DRE, dioxin-responsive element; CORT, corticosterone; EROD, 7-ethoxyresorufin O-deethylation; DEX, dexamethasone; GRE, glucocorticoid-responsive element; GR, glucocorticoid receptor; DMSO, dimethylsulfoxide; RU486, 17β-hydroxy-11β-[4-dimethylamino phenyl]-17α-[1-propynyl]estra-4,9-dien-3-one; RT, reverse transcriptase; PCR, polymerase chain reaction; TAT, tyrosine aminotransferase; bp, base pairs; TSA, trichostatin A; ANOVA, analysis of variance; PXR, pregnane X receptor.
- Received November 9, 2007.
- Accepted December 14, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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