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Research ArticleArticle

The Aryl Hydrocarbon Receptor Pathway and the Response to 3-Methylcholanthrene Are Altered in the Liver of Adrenalectomized Rats

Anne K. Mullen Grey and David S. Riddick
Drug Metabolism and Disposition January 2011, 39 (1) 83-91; DOI: https://doi.org/10.1124/dmd.110.035584
Anne K. Mullen Grey
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada
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David S. Riddick
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada
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Abstract

The aryl hydrocarbon receptor (AHR) is activated by 3-methylcholanthrene (MC), a polycyclic aromatic hydrocarbon, and environmental contaminants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin. Adrenalectomized (ADX) rats have decreased hepatic AHR protein and lower levels of MC-induced CYP1B1 mRNA. To further characterize the effects of decreased AHR protein and the response to MC in ADX rats, we measured AHR-mediated responses in the liver of sham-operated (SHAM) and ADX rats, 6 and 54 h after MC treatment. CYP1A2 mRNA was suppressed by 46 to 60% 4 days after ADX in vehicle-treated animals. AHR mRNA was induced 4-fold 6 h after MC in SHAM rats, but no induction was observed in ADX rats. The MC-induced 7-ethoxyresorufin O-deethylation (EROD) activity in ADX rats was 35% of the activity in the MC-treated SHAM group at 6 h. At 54 h after treatment, the induction of EROD activity by MC was more pronounced in ADX rats than at 6 h. To assess the overall capacity for hepatic P450-mediated metabolism, we measured NADPH-cytochrome P450 oxidoreductase (POR) activity. POR activity was decreased by 50% after ADX. We have shown that the response to MC in ADX rats is suppressed for some, but not all, AHR-mediated responses and that reduced POR activity after ADX could contribute to a decreased capacity for P450-dependent metabolism. The current study contributes to our understanding of how adrenal-dependent factors modulate the AHR pathway and the response to MC in vivo.

Footnotes

    • Received July 20, 2010.
    • Accepted September 28, 2010.
  • This work was supported by the Canadian Institutes of Health Research [Grant MOP-93759] (to D.S.R.). A.K.M.G. was the recipient of an Ontario Graduate Scholarship and a Peterborough K. M. Hunter Graduate Studentship.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/dmd.110.035584.

  • ABBREVIATIONS:

    AHR
    aryl hydrocarbon receptor
    DME
    drug-metabolizing enzyme
    P450
    cytochrome P450
    TCDD
    2,3,7,8-tetrachlorodibenzo-p-dioxin
    MC
    3-methylcholanthrene
    POR
    NADPH-cytochrome P450 oxidoreductase
    ADX
    adrenalectomy or adrenalectomized
    SHAM
    sham-operated
    EROD
    7-ethoxyresorufin O-deethylation
    RT
    reverse transcriptase
    PCR
    polymerase chain reaction
    ECL
    enhanced chemiluminescence
    ANOVA
    analysis of variance
    DEX
    dexamethasone
    TAT
    tyrosine aminotransferase
    GR
    glucocorticoid receptor.

  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (1)
Drug Metabolism and Disposition
Vol. 39, Issue 1
1 Jan 2011
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Research ArticleArticle

The Aryl Hydrocarbon Receptor Pathway and the Response to 3-Methylcholanthrene Are Altered in the Liver of Adrenalectomized Rats

Anne K. Mullen Grey and David S. Riddick
Drug Metabolism and Disposition January 1, 2011, 39 (1) 83-91; DOI: https://doi.org/10.1124/dmd.110.035584

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Research ArticleArticle

The Aryl Hydrocarbon Receptor Pathway and the Response to 3-Methylcholanthrene Are Altered in the Liver of Adrenalectomized Rats

Anne K. Mullen Grey and David S. Riddick
Drug Metabolism and Disposition January 1, 2011, 39 (1) 83-91; DOI: https://doi.org/10.1124/dmd.110.035584
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