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Research ArticleArticle

Regulation of Constitutive Mouse Hepatic Cytochromes P450 and Growth Hormone Signaling Components by 3-Methylcholanthrene

Chunja Lee, Janine R. Hutson, Vivien Kok-Fung Tzau and David S. Riddick
Drug Metabolism and Disposition September 2006, 34 (9) 1530-1538; DOI: https://doi.org/10.1124/dmd.106.009936
Chunja Lee
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Janine R. Hutson
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Vivien Kok-Fung Tzau
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David S. Riddick
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Abstract

3-Methylcholanthrene (MC) activates the aryl hydrocarbon receptor and increases expression of cytochrome P450 (P450) enzymes such as CYP1A1. MC also decreases expression of CYP2C11, the major hepatic P450 in male rats that is regulated by pulsatile growth hormone (GH) secretion via a pathway partially dependent on signal transducer and activator of transcription 5b (STAT5b). If disruption of this GH signaling pathway is important for MC's ability to suppress CYP2C11 transcription, we hypothesize that MC suppresses other male-specific genes (e.g., mouse Cyp2d9) regulated by pulsatile GH with STAT5b dependence. We examined the time course of MC's effects on hepatic P450s and GH signaling components in male C57BL/6 mice. P450 content, heme content, and NADPH P450 oxidoreductase activity were induced 2.3-, 1.8-, and 1.3-fold, respectively, by MC. MC dramatically induced CYP1A1 mRNA, protein, and catalytic activity. MC caused a 42% decrease in CYP2D9 protein, a 28% decrease in CYP2D9 mRNA, and a 27% decrease in testosterone 16α-hydroxylation activity. MC caused a pronounced decrease in CYP3A protein; however, there was no apparent change in testosterone 6β-hydroxylation activity, and changes in mRNA levels for CYP3A forms were relatively small. Expression of GH receptor and major urinary protein 2, a gene regulated by GH with STAT5b dependence, was decreased by MC at the mRNA level. These results show that MC suppresses mouse Cyp2d9, a pulsatile GH- and STAT5b-dependent male-specific gene, via a pretranslational mechanism that may involve disrupted GH signaling. Mouse CYP3A protein levels are dramatically decreased by MC via a mechanism that is not yet understood.

Footnotes

  • Supported by the Canadian Institutes of Health Research Grant MOP-42399 (D.S.R.).

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

  • doi:10.1124/dmd.106.009936.

  • ABBREVIATIONS: PAH, polycyclic aromatic hydrocarbon; AHR, aryl hydrocarbon receptor; CIS, cytokine-inducible Src homology 2 domain-containing protein; DRE, dioxin-responsive element; EROD, 7-ethoxyresorufin O-deethylation; GH, growth hormone; GHR, growth hormone receptor; HAH, halogenated aromatic hydrocarbon; JAK2, Janus kinase 2; MC, 3-methylcholanthrene; MUP2, major urinary protein 2; P450, cytochrome P450; RT-PCR, reverse transcriptase-polymerase chain reaction; STAT5, signal transducer and activator of transcription 5; WAP, whey acidic protein.

    • Received February 21, 2006.
    • Accepted June 13, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (9)
Drug Metabolism and Disposition
Vol. 34, Issue 9
1 Sep 2006
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Research ArticleArticle

Regulation of Constitutive Mouse Hepatic Cytochromes P450 and Growth Hormone Signaling Components by 3-Methylcholanthrene

Chunja Lee, Janine R. Hutson, Vivien Kok-Fung Tzau and David S. Riddick
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1530-1538; DOI: https://doi.org/10.1124/dmd.106.009936

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Research ArticleArticle

Regulation of Constitutive Mouse Hepatic Cytochromes P450 and Growth Hormone Signaling Components by 3-Methylcholanthrene

Chunja Lee, Janine R. Hutson, Vivien Kok-Fung Tzau and David S. Riddick
Drug Metabolism and Disposition September 1, 2006, 34 (9) 1530-1538; DOI: https://doi.org/10.1124/dmd.106.009936
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