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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Selective and Cytokine-Dependent Regulation of Hepatic Transporters and Bile Acid Homeostasis during Infectious Colitis in Mice

Matthew D. Merrell, Beatrice A. Nyagode, John D. Clarke, Nathan J. Cherrington and Edward T. Morgan
Drug Metabolism and Disposition April 2014, 42 (4) 596-602; DOI: https://doi.org/10.1124/dmd.113.055525
Matthew D. Merrell
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (M.D.M., B.A.N., E.T.M.); Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (J.D.C, N.J.C.)
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Beatrice A. Nyagode
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (M.D.M., B.A.N., E.T.M.); Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (J.D.C, N.J.C.)
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John D. Clarke
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (M.D.M., B.A.N., E.T.M.); Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (J.D.C, N.J.C.)
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Nathan J. Cherrington
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (M.D.M., B.A.N., E.T.M.); Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (J.D.C, N.J.C.)
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Edward T. Morgan
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia (M.D.M., B.A.N., E.T.M.); Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona (J.D.C, N.J.C.)
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Abstract

Various disease models have been shown to alter hepatic drug-metabolizing enzyme (DME) and transporter expression and to induce cholestasis through altered enzyme and transporter expression. Previously, we detailed the regulation of hepatic DMEs during infectious colitis caused by Citrobacter rodentium infection. We hypothesized that this infection would also modulate hepatic drug transporter expression and key genes of bile acid (BA) synthesis and transport. Mice lacking Toll-like receptor 4 (TLR4), interleukin-6 (IL-6), or interferon-gamma (IFNγ) and appropriate wild-type animals were orally infected with C. rodentium and sacrificed 7 days later. In two wild-type strains, drug transporter mRNA expression was significantly decreased by infection for Slc22a4, Slco1a1, Slco1a4, Slco2b1, and Abcc6, whereas the downregulation of Abcc2, Abcc3, and Abcc4 were strain-dependent. In contrast, mRNA expressions of Slco3a1 and Abcb1b were increased in a strain-dependent manner. Expression of Abcb11, Slc10a1, the two major hepatic BA transporters, and Cyp7a1, the rate-limiting enzyme of BA synthesis, was also significantly decreased in infected animals. None of the above effects were caused by bacterial lipopolysaccharide, since they still occurred in the absence of functional TLR4. The downregulation of Slc22a4 and Cyp7a1 was absent in IFNγ-null mice, and the downregulation of Slco1a1 was abrogated in IL-6-null mice, indicating in vivo roles for these cytokines in transporter regulation. These data indicate that C. rodentium infection modulates hepatic drug processing through alteration of transporter expression as well as DMEs. Furthermore, this infection downregulates important genes of BA synthesis and transport and may increase the risk for cholestasis.

Footnotes

    • Received October 22, 2013.
    • Accepted December 30, 2013.
  • This work was supported by grants from the National Institutes of Health [DK072372, HD062489, AI083927] and National Institute of Environmental Health Sciences [ES012870, ES007091].

  • dx.doi.org/10.1124/dmd.113.055525.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (4)
Drug Metabolism and Disposition
Vol. 42, Issue 4
1 Apr 2014
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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Drug Transporter Expression during C. rodentium Infection

Matthew D. Merrell, Beatrice A. Nyagode, John D. Clarke, Nathan J. Cherrington and Edward T. Morgan
Drug Metabolism and Disposition April 1, 2014, 42 (4) 596-602; DOI: https://doi.org/10.1124/dmd.113.055525

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Research ArticleSpecial Section on Transporters in Toxicity and Disease

Drug Transporter Expression during C. rodentium Infection

Matthew D. Merrell, Beatrice A. Nyagode, John D. Clarke, Nathan J. Cherrington and Edward T. Morgan
Drug Metabolism and Disposition April 1, 2014, 42 (4) 596-602; DOI: https://doi.org/10.1124/dmd.113.055525
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