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.
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