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Research ArticleArticle

The Role of Cytochrome P450–Dependent Metabolism in the Regulation of Mouse Hepatic Growth Hormone Signaling Components and Target Genes by 3-Methylcholanthrene

Chunja Lee, Xinxin Ding and David S. Riddick
Drug Metabolism and Disposition February 2013, 41 (2) 457-465; DOI: https://doi.org/10.1124/dmd.112.048835
Chunja Lee
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (C.L., D.S.R.); and Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D.)
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Xinxin Ding
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (C.L., D.S.R.); and Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D.)
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David S. Riddick
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada (C.L., D.S.R.); and Laboratory of Molecular Toxicology, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, Albany, New York (X.D.)
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Abstract

3-Methylcholanthrene (MC) is a readily metabolized aryl hydrocarbon receptor (AHR) agonist. MC 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). To determine if these effects of MC depend on hepatic microsomal P450–mediated activity, we examined biologic responses to MC treatment in liver Cpr–null (LCN) mice with hepatocyte-specific conditional deletion of NADPH-cytochrome P450 oxidoreductase (POR). MC caused mild induction of Por and a hepatic inflammatory marker in wild-type mice, whereas MC caused strong induction of AHR target genes, Cyp1a1, Cyp1a2, and Cyp1b1 in wild-type and LCN mice. Two mouse hepatic STAT5b target genes, Cyp2d9 and major urinary protein 2 (Mup2), were suppressed by MC in wild-type mice, and the CYP2D9 mRNA response was maintained in LCN mice. In wild-type mice only, MC decreased hepatic GH receptor (GHR) mRNA but increased GHR protein levels. There was an apparent impairment of STAT5 phosphorylation by MC in wild-type and LCN mice, but large interanimal variation prevented achievement of statistical significance. In vehicle-treated mice, basal levels of MUP2 mRNA, GHR mRNA, GHR protein, and the activation status of extracellular signal-regulated kinase 2 and Akt were influenced by hepatic Por genetic status. These results indicate that the effects of MC on hepatic GH signaling components and target genes are complex, involving aspects that are both dependent and independent of hepatic microsomal P450–mediated activity.

Footnotes

  • This work was supported by the Canadian Institutes of Health Research [Grant MOP-93759] and National Institutes of Health National Cancer Institute [Grant CA092596].

  • dx.doi.org/10.1124/dmd.112.048835.

  • Received September 5, 2012.
  • Accepted November 20, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleArticle

Responses to 3-Methylcholanthrene in Liver Cpr-Null Mice

Chunja Lee, Xinxin Ding and David S. Riddick
Drug Metabolism and Disposition February 1, 2013, 41 (2) 457-465; DOI: https://doi.org/10.1124/dmd.112.048835

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Research ArticleArticle

Responses to 3-Methylcholanthrene in Liver Cpr-Null Mice

Chunja Lee, Xinxin Ding and David S. Riddick
Drug Metabolism and Disposition February 1, 2013, 41 (2) 457-465; DOI: https://doi.org/10.1124/dmd.112.048835
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