Inflammation and infection are known to down-regulate the hepatic expression of various cytochrome P450 (CYP) enzymes, and this has important consequences for clinical drug therapy. Our laboratory and others have extensively characterized the acute effects of bacterial lipopolysaccharide (LPS) on basal and drug-induced hepatic CYP expression as a model of bacterial sepsis. In preliminary studies, we found that infection of mice with Citrobacter rodentium, a rodent model of enteropathogenic E.coli (EPEC) infection and of inflammatory bowel disease (IBD) in humans caused relatively selective effects on CYP expression in mouse liver. These effects were found to occur in the absence of a functional toll-like receptor-4 (TLR4), suggesting that they are independent of bacterial LPS. We hypothesize that differential regulation of CYP expression is regulated by multiple host and pathogen factors during C. rodentium infection. Understanding these factors is crucial to predicting clinical drug responses in disease states. We further hypothesize that modulation of CYPs play specific roles in the host response to C. rodentium infection. To address these hypotheses, we will characterize the time course of regulation of hepatic CYP expression in mice infected with C. rodentium and compare it to the progression and resolution of infection and pathology. We will also compare it to a model of chemically-induced IBD. Then, we will define bacterial and host factors involved in CYP regulation during C. rodentium infection, using bacterial and mouse genetics as well as pharmacological approaches. Finally, we will determine whether global or liver-specific modulation of CYP activity can regulate the hepatic, gastrointestinal or systemic responses to C. rodentium infection, using the nonspecific CYP inhibitor 1-aminobenzotriazole, and mice in which the hepatic NADPH-cytochrome P450 reductase (CPR) gene has been selectively deleted.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1-DIG-F (02))
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Serrano, Jose
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Emory University
Schools of Medicine
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Morgan, Edward T; Dempsey, Joseph L; Mimche, Sylvie M et al. (2018) Physiological Regulation of Drug Metabolism and Transport: Pregnancy, Microbiome, Inflammation, Infection, and Fasting. Drug Metab Dispos 46:503-513
Mimche, Patrice N; Brady, Lauren M; Bray, Christian F et al. (2015) The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice. Hepatology 62:900-14
Nyagode, Beatrice A; Williams, Ifor R; Morgan, Edward T (2014) Altered inflammatory responses to Citrobacter rodentium infection, but not bacterial lipopolysaccharide, in mice lacking the Cyp4a10 or Cyp4a14 genes. Inflammation 37:893-907
Merrell, Matthew D; Nyagode, Beatrice A; Clarke, John D et al. (2014) Selective and cytokine-dependent regulation of hepatic transporters and bile acid homeostasis during infectious colitis in mice. Drug Metab Dispos 42:596-602
Mimche, Sylvie M; Nyagode, Beatrice A; Merrell, Matthew D et al. (2014) Hepatic cytochrome P450s, phase II enzymes and nuclear receptors are downregulated in a Th2 environment during Schistosoma mansoni infection. Drug Metab Dispos 42:134-40
Nyagode, Beatrice A; Jahangardi, Roya; Merrell, Matthew D et al. (2014) Selective effects of a therapeutic protein targeting tumor necrosis factor-alpha on cytochrome P450 regulation during infectious colitis: Implications for disease-dependent drug-drug interactions. Pharmacol Res Perspect 2:e00027
Nyagode, Beatrice A; Watkins, William J; Kinloch, Ryan D et al. (2012) Selective modulation of hepatic cytochrome P450 and flavin monooxygenase 3 expression during citrobacter rodentium infection in severe combined immune-deficient mice. Drug Metab Dispos 40:1894-9
Kinloch, Ryan D; Lee, Choon-Myung; van Rooijen, Nico et al. (2011) Selective role for tumor necrosis factor-ýý, but not interleukin-1 or Kupffer cells, in down-regulation of CYP3A11 and CYP3A25 in livers of mice infected with a noninvasive intestinal pathogen. Biochem Pharmacol 82:312-21
Nyagode, Beatrice A; Lee, Choon-Myung; Morgan, Edward T (2010) Modulation of hepatic cytochrome P450s by Citrobacter rodentium infection in interleukin-6- and interferon-{gamma}-null mice. J Pharmacol Exp Ther 335:480-8
Morgan, E T (2009) Impact of infectious and inflammatory disease on cytochrome P450-mediated drug metabolism and pharmacokinetics. Clin Pharmacol Ther 85:434-8

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