PT  - JOURNAL ARTICLE
AU  - Kirsten A. Bielefeld
AU  - Chunja Lee
AU  - David S. Riddick
TI  - Regulation of Aryl Hydrocarbon Receptor Expression and Function by Glucocorticoids in Mouse Hepatoma Cells
AID  - 10.1124/dmd.107.019703
DP  - 2008 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 543--551
VI  - 36
IP  - 3
4099  - http://dmd.aspetjournals.org/content/36/3/543.short
4100  - http://dmd.aspetjournals.org/content/36/3/543.full
SO  - Drug Metab Dispos2008 Mar 01; 36
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics