The in vivo activities of microsomal cytochrome P450 (P450) enzymes in the intestine toward endogenous compounds are not well studied and their potential impact on normal intestinal function or disease risk is poorly understood. Many P450 enzymes are expressed in the intestine, where they potentially play important roles in maintaining homeostasis of endogenous compounds and influence the susceptibility to intestinal injury induced by drugs and other xenobiotics. Our broad, long-term objective is to determine the metabolic and biological functions of intestinal P450 enzymes and P450 reductase (CPR, required for activities of all microsomal P450s), particularly concerning their impact on disease risks, including susceptibility to adverse drug responses. Studies of the current funding cycle have provided clear evidence for a major role of intestinal P450 in controlling systemic bioavailability of a number of clinically important oral drugs and ingested xenobiotics, and in drug-induced intestinal toxicity. In preliminary studies on intestinal epithelium (IE)-specific Cpr null (IECN) mice, we discovered a role of intestinal CPR/P450 in modulating sensitivity of the colon toward dextran sulphate sodium (DSS)-induced colitis, a widely used animal model of human inflammatory bowel disease (IBD). These findings led to the current proposal, to identify the mechanistic link between intestinal CPR/P450 and inflammatory responses of the colon in an animal model of experimental colitis (Aim 1), and to explore more broadly the capacity of mouse and human intestinal CPR/P450 enzymes in the production or degradation of endogenous compounds in the intestine (Aim 2).
In Aim 1, we will test the hypothesis that the hypersensitivity of the colon in IECN mice to DSS-induced colitis is mainly due to a loss of abilit of the IE cells to increase production of corticosterone (CC) in response to DSS-induced inflammation, and that a global decrease in CPR expression, as expected in human individuals with CPR deficiency, and as represented in a Cpr-low mouse model, also leads to decreases in intestinal CPR-dependent CC synthesis, and consequently increased vulnerability to experimental colitis.
In Aim 2, we will use a unique metabolomics approach to search for additional endogenous compounds, potentially including novel metabolites, that are produced or degraded by intestinal microsomal CPR/P450, and whose tissue levels are impacted by the loss (or decrease) of IE CPR. We will also characterize the ability of human intestinal microsomes to catalyze the synthesis or degradation of the various identified endogenous compounds; the results are expected to provide valuable information concerning human relevance of the findings from our animal studies.
The proposed studies, which will yield fundamental knowledge regarding cytochrome P450 enzymes' roles in the synthesis or degradation of endogenous compounds in the intestine, will aid future studies of the impact of genetic polymorphisms and xenobiotic exposures on the homeostasis, biological function, and disease links of the identified compounds. The outcome may identify additional risk factors as well as new therapeutic targets/approaches for inflammatory bowel diseases and other diseases of the digestive system.
|Li, Lei; Bao, Xiaochen; Zhang, Qing-Yu et al. (2017) Role of CYP2B in Phenobarbital-Induced Hepatocyte Proliferation in Mice. Drug Metab Dispos 45:977-981|
|Sheng, Jonathan; Wang, Yi; Turesky, Robert J et al. (2016) Novel Transgenic Mouse Model for Studying Human Serum Albumin as a Biomarker of Carcinogenic Exposure. Chem Res Toxicol 29:797-809|
|Xie, Fang; Ding, Xinxin; Zhang, Qing-Yu (2016) An update on the role of intestinal cytochrome P450 enzymes in drug disposition. Acta Pharm Sin B 6:374-383|
|Levinson, Kara J; Giffen, Samantha R; Pauly, Michael H et al. (2015) Plant-based production of two chimeric monoclonal IgG antibodies directed against immunodominant epitopes of Vibrio cholerae lipopolysaccharide. J Immunol Methods 422:111-7|
|Zhu, Yi; Xie, Fang; Ding, Liang et al. (2015) Intestinal epithelium-specific knockout of the cytochrome P450 reductase gene exacerbates dextran sulfate sodium-induced colitis. J Pharmacol Exp Ther 354:10-7|
|Turesky, Robert J; Konorev, Dmitri; Fan, Xiaoyu et al. (2015) Effect of Cytochrome P450 Reductase Deficiency on 2-Amino-9H-pyrido[2,3-b]indole Metabolism and DNA Adduct Formation in Liver and Extrahepatic Tissues of Mice. Chem Res Toxicol 28:2400-10|
|Levinson, Kara J; De Jesus, Magdia; Mantis, Nicholas J (2015) Rapid effects of a protective O-polysaccharide-specific monoclonal IgA on Vibrio cholerae agglutination, motility, and surface morphology. Infect Immun 83:1674-83|
|Megaraj, Vandana; Ding, Xinxin; Fang, Cheng et al. (2014) Role of hepatic and intestinal p450 enzymes in the metabolic activation of the colon carcinogen azoxymethane in mice. Chem Res Toxicol 27:656-62|
|De Jesus, Magdia; Ostroff, Gary R; Levitz, Stuart M et al. (2014) A population of Langerin-positive dendritic cells in murine Peyer's patches involved in sampling ?-glucan microparticles. PLoS One 9:e91002|
|Ahlawat, Sarita; Xie, Fang; Zhu, Yi et al. (2014) Mice deficient in intestinal epithelium cytochrome P450 reductase are prone to acute toxin-induced mucosal damage. Sci Rep 4:5551|
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