Department of Pharmacology and Toxicology

Permanent URI for this communityhttps://hdl.handle.net/1807/25349

The Department of Pharmacology and Toxicology offers training in pharmacology and toxicology to both undergraduate and graduate students who may subsequently go on to exciting research, regulatory and administrative careers in academic, industrial and healthcare provision settings.

Current areas of research investigation in the Department include Receptor Pharmacology, Signal Transduction Pathways, Neuropharmacology, Drug Addiction Studies, Drug Metabolism and Pharmacokinetics, Pharmacogenetics, Cardiovascular Pharmacology, Clinical Pharmacology, Behavioural Pharmacology, Immunopharmacology, Endocrine Pharmacology and Molecular Toxicology.

News

Department of Pharmacology and Toxicology

Browse

Browsing Department of Pharmacology and Toxicology by Subject "aryl hydrocarbon receptor"

Filter results by typing the first few letters
Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Aryl hydrocarbon receptor-dependence of dioxin's effects on constitutive mouse hepatic cytochromes P450 and growth hormone signaling components
    (NRC Research Press, 2012-09-14) Lee, Chunja ; Riddick, David S.
    The aryl hydrocarbon receptor (AHR) has physiological roles in the absence of exposure to exogenous ligands and mediates adaptive and toxic responses to the environmental pollutant, 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD). A readily metabolized AHR agonist, 3-methylcholanthrene, disrupts expression of mouse hepatic growth hormone (GH) signaling components and suppresses cytochrome P450 2D9 (Cyp2d9), a male-specific gene controlled by pulsatile GH via signal transducer and activator of transcription 5b (STAT5b). Using TCDD as an essentially non-metabolized AHR agonist and Ahr -/- mice as the preferred model to determine the AHR-dependence of biological responses, we now show that two mouse hepatic STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), are suppressed by TCDD in an AHR-dependent manner. TCDD also decreased hepatic mRNA levels for GH receptor, Janus kinase 2, and STAT5a/b with AHR-dependence. Without inducing selected hepatic inflammatory markers, TCDD caused AHR-dependent induction of Cyp1a1 and NADPH-cytochrome P450 oxidoreductase (Por) and suppression of Cyp3a11. In vehicle-treated mice, basal mRNA levels for CYP2D9, CYP3A11, POR, serum amyloid protein P, and MUP2 were influenced by Ahr genetic status. We conclude that AHR activation per se leads to dysregulation of hepatic GH signaling components and suppression of some, but not all, STAT5b target genes.
  • Thumbnail Image
    Item
    Glucocorticoid and adrenalectomy effects on the rat aryl hydrocarbon receptor pathway depend on the dosing regimen and post-surgical time
    (Elsevier, 2009-07-16) Grey, Anne K. Mullen ; Riddick, David S.
    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 four 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 – 1.5 mg/kg) induced hepatic AHR nuclear translocator (ARNT) mRNA by up to 9-fold at 3 and 6 h 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.
  • Thumbnail Image
    Item
    Loss of hepatic aryl hydrocarbon receptor protein in adrenalectomized rats does not involve altered levels of the receptor's cytoplasmic chaperones
    (NRC Research Press, 2013-08-16) Lee, Chunja ; Grey, Anne K. Mullen ; Riddick, David S.
    The aryl hydrocarbon receptor (AHR) plays physiological roles and mediates adaptive and toxic responses to environmental pollutants. Adrenalectomized rats display decreased hepatic AHR protein levels, with no change in mRNA, and selectively impaired induction of cytochrome P450 1B1. This was similar to reported phenotypes for mice with hepatocyte-specific conditional deletion of AHR-interacting protein (AIP), a chaperone protein of the cytoplasmic AHR complex. In the current study, we demonstrated that adrenalectomy (ADX) and acute dexamethasone (DEX) treatment do not alter hepatic AIP mRNA or protein levels. Also, hepatic protein levels of the 90-kDa heat shock protein and p23 were not altered by ADX or acute DEX treatment. These results suggest that the loss of rat hepatic AHR protein following ADX cannot be explained by changes in the levels of the receptor’s cytoplasmic chaperone proteins.