Glucocorticoid and adrenalectomy effects on the rat aryl hydrocarbon receptor pathway depend on the dosing regimen and post-surgical time.
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that mediates the effects of aromatic hydrocarbons, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene (MC); the prototypical response is induction of drug-metabolizing enzymes. Factors that regulate AHR levels in vivo are poorly understood and it is also not clear how AHR levels affect aromatic hydrocarbon responsiveness. Our interest in pituitary-dependent regulation of AHR levels was prompted by two findings from our laboratory: (1) hypophysectomized rats have reduced hepatic levels of AHR protein; and (2) glucocorticoids increase AHR expression and aromatic hydrocarbon responsiveness in rodent hepatoma cells. To study whether adrenalectomy and glucocorticoids contribute to hormone-dependent regulation of the hepatic AHR pathway, male adrenalectomized (ADX) or SHAM-ADX rats were treated with dexamethasone (DEX) or vehicle. AHR protein was depleted by 50-60% at 4 days after ADX, but was not altered by DEX treatment. To assess whether the observed AHR depletion affected aromatic hydrocarbon responsiveness, the induction of hepatic cytochrome P450 1B1 (CYP1B1) mRNA by MC was measured as an AHR-mediated adaptive response. MC-induced hepatic CYP1B1 mRNA was reduced by 50% in ADX rats relative to SHAM-ADX. Exogenous glucocorticoid treatment (DEX - 1.5mg/kg) induced hepatic AHR nuclear translocator (ARNT) mRNA by up to 9-fold at 3 and 6h after dosing, with no corresponding change in ARNT protein levels. These data demonstrate that: (1) adrenal-dependent factors contribute to the physiological maintenance of hepatic AHR protein levels; (2) the depletion of hepatic AHR protein in ADX rats coincided with a diminished adaptive response to MC; and (3) exogenous glucocorticoid treatment increases hepatic ARNT mRNA levels regardless of adrenal status. This model is useful for studying the mechanisms of AHR and ARNT regulation and for further characterization of the impact of AHR protein depletion on the response to aromatic hydrocarbons in vivo.
Mullen Grey
Anne K
AK
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
Riddick
David S
DS
D000315:Adrenalectomy; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D015696:Gene Products, tat; D005938:Glucocorticoids; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003907:Dexamethasone; D001189:Aryl Hydrocarbon Hydroxylases; C585499:Cyp1b1 protein, rat; D065633:Cytochrome P-450 CYP1B1