Selective and Cytokine-Dependent Regulation of Hepatic Transporters and Bile Acid Homeostasis during Infectious Colitis in Mice
| Autor: | Edward T. Morgan, John D. Clarke, Matthew D. Merrell, Nathan J. Cherrington, Beatrice A. Nyagode |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
medicine.drug_class Pharmaceutical Science ABCC4 Biology Pharmacology Cholesterol 7 alpha-hydroxylase Bile Acids and Salts Mice Citrobacter Cholestasis Downregulation and upregulation Internal medicine medicine Animals Homeostasis Special Section on Transporters in Toxicity and Disease Mice Inbred C3H SLC10A1 Bile acid Multidrug resistance-associated protein 2 Enterobacteriaceae Infections Transporter Colitis medicine.disease Mice Inbred C57BL Endocrinology Gene Expression Regulation Liver biology.protein Cytokines Female Carrier Proteins |
| Zdroj: | Drug Metabolism and Disposition. 42:596-602 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.113.055525 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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