Received for publication November 12, 2007.
Revised December 13, 2007.
Accepted for publication December 14, 2007.

Regulation of aryl hydrocarbon receptor expression and function by glucocorticoids in mouse hepatoma cells

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 AHR’s role 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 RU486, suggesting GR involvement. This small magnitude increase in AHR levels was functionally significant; pre-treatment 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-kb of the mouse Ahr 5'-flanking region and promoter was induced approximately 2.5-fold by DEX when co-transfected 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.

Key words: Ah receptor, cytochrome P450 regulation, gene regulation, nuclear receptors, polycyclic aromatic hydrocarbons, polycyclic halogenated hydrocarbons, steroids, toxicology, transcriptional regulation