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Research ArticleArticle

Selective Modulation of Hepatic Cytochrome P450 and Flavin Monooxygenase 3 Expression during Citrobacter rodentium Infection in Severe Combined Immune-Deficient Mice

Beatrice A. Nyagode, William J. Watkins, Ryan D. Kinloch and Edward T. Morgan
Drug Metabolism and Disposition October 2012, 40 (10) 1894-1899; DOI: https://doi.org/10.1124/dmd.112.046557
Beatrice A. Nyagode
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
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William J. Watkins
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
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Ryan D. Kinloch
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
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Edward T. Morgan
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia
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Abstract

The profile of selective modulation of hepatic cytochrome P450 (P450) gene expression caused by infection with the murine intestinal pathogen Citrobacter rodentium has been well characterized in multiple genetic backgrounds; yet, the mechanisms underlying this modulation are still not entirely understood. Although several studies have addressed the roles of cytokines from the innate immune system, the influence of the adaptive immune system is not known. To address this deficiency, we used mice harboring the severe combined immune deficiency (SCID) spontaneous mutation, which lack mature T and B lymphocytes and are unable to mount an acquired immune response. Female C57BL/6 (B6) and SCID mice were infected orally with C. rodentium and assessed for bacterial colonization/translocation and P450 and flavin monooxygenase-3 (Fmo3) expression levels after 7 days. SCID mice showed similar patterns of colonic bacterial colonization and a similar degree of colonic mucosal hypertrophy compared with infected B6 mice, but SCID mice displayed 6-fold greater bacterial translocation to the liver. In the SCID mice, Cyp4a10 and Cyp2b9 down-regulations were partially and fully blocked, respectively, whereas the regulation of other P450s and Fmo3 was similar in both strains. In the C3H genetic background, the SCID mutation also blocked the down-regulation of Cyp3a11, Cyp3a25, Cyp2d22, and Cyp2c29. The results clearly dissociate bacterial translocation to the liver from hepatic drug-metabolizing enzyme regulation and suggest a possible role of T cells, T-cell cytokines, or other proteins regulated by such cytokines in the selective regulation of a limited subset of hepatic P450 enzymes during C. rodentium infection.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK072372].

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

    http://dx.doi.org/10.1124/dmd.112.046557.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    CR
    Citrobacter rodentium
    Fmo
    flavin monooxygenase
    TLR
    Toll-like receptor
    TNF
    tumor necrosis factor
    IL
    interleukin
    IFNγ
    interferon-γ
    SCID
    severe combined immune deficiency
    RAG
    recombination activating gene
    PBS
    phosphate-buffered saline
    WT
    wild type
    Th
    T helper
    KGF
    keratinocyte growth factor.

  • Received May 3, 2012.
  • Accepted June 27, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (10)
Drug Metabolism and Disposition
Vol. 40, Issue 10
1 Oct 2012
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Research ArticleArticle

REGULATION OF CYTOCHROMES P450 IN SCID MICE

Beatrice A. Nyagode, William J. Watkins, Ryan D. Kinloch and Edward T. Morgan
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1894-1899; DOI: https://doi.org/10.1124/dmd.112.046557

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Research ArticleArticle

REGULATION OF CYTOCHROMES P450 IN SCID MICE

Beatrice A. Nyagode, William J. Watkins, Ryan D. Kinloch and Edward T. Morgan
Drug Metabolism and Disposition October 1, 2012, 40 (10) 1894-1899; DOI: https://doi.org/10.1124/dmd.112.046557
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