Cytochrome P450 (P450) enzymes play crucial roles in the clearance of drugs from the circulation, and therefore changes in their activities can significantly influence the therapeutic and adverse effects of a drug on an individual. Infectious and inflammatory diseases cause the down-regulation of many P450s and other drug metabolizing enzymes in the liver, causing impairment of drug clearances. In mice infected with C. rodentium, a model of E. Coli food poisoning in humans, a number of P450 enzymes in the liver are moderately down-regulated. However, CYP4A enzymes are more profoundly affected, as is another drug metabolizing enzyme, i.e. flavin monooxygenase 3 (FMO3). Preliminary evidence suggests that one or more bacterially secreted factors regulate hepatic CYP4A expression in an endotoxin-independent manner. CYP4As have important roles in fatty acid metabolism, control of blood pressure and in oxidative stress. Therefore, it is important to understand how human CYP4A11 is regulated during infection, and to understand whether on not CYP4A regulation is a defensive or adaptive response of the host, or if the invading bacterium could be regulating CYP4As to its own advantage. To address these questions, the regulation of CYP4A11 will be studied in the livers and kidneys of CYP4A11 transgenic mice during C. rodentium infection. This will be complemented by studies in cultured human hepatocytes and in CYP4A11 transgenic mouse hepatocytes, on CYP4A11 regulation by inflammatory cytokines and bacterial products. Transcriptional and proteomic profiling will be used to assess the effects of infection on global gene expression in the liver and to elucidate signaling networks involved in CYP4A and FMO3 down-regulation by factors secreted by bacteria. To identify these factor(s) we will screen known mutants and, if necessary, an enteropathogenic E. coli transposon insertion library to identify mutants that fail to down-regulate these enzymes. This approach will be complemented by biochemical characterization and partial purification of the factor(s). To elucidate the role of CYP4A enzymes in the host response to C. rodentium infection, or as targets of the bacterium's strategy for propagation and survival, the effects will be studied of Cyp4A10-/- and Cyp4A14-/- gene deletion on the pathologies associated with C. rodentium infection.

Public Health Relevance

This project will investigate the effects of a model of food poisoning on enzymes in the liver and kidneys called CYP4A enzymes, which are important in fat metabolism and also in oxidative damage to the tissues. The questions of whether the human enzyme levels are changed by infection in the same way as the mouse enzymes;how the liver responds to factors secreted by bacteria;and why these changes happen during infection, will be studied. This project will increase our understanding of how liver metabolism changes during infection or inflammation, and may discover new strategies to treat infectious and inflammatory diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072372-08
Application #
8431436
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Serrano, Jose
Project Start
2005-09-01
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$356,801
Indirect Cost
$126,607
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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; 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
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
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
Chaluvadi, Madhusudana R; Nyagode, Beatrice A; Kinloch, Ryan D et al. (2009) TLR4-dependent and -independent regulation of hepatic cytochrome P450 in mice with chemically induced inflammatory bowel disease. Biochem Pharmacol 77:464-71
Chaluvadi, Madhusudana R; Kinloch, Ryan D; Nyagode, Beatrice A et al. (2009) Regulation of hepatic cytochrome P450 expression in mice with intestinal or systemic infections of citrobacter rodentium. Drug Metab Dispos 37:366-74
Zhang, Jun; Chaluvadi, Madhusudana R; Reddy, Rob et al. (2009) Hepatic flavin-containing monooxygenase gene regulation in different mouse inflammation models. Drug Metab Dispos 37:462-8

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