Our long-term objective is to determine the function of intestinal cytochrome P450 (P450) enzymes in drug metabolism and toxicity. The focus of this proposal is on the characterization of a novel transgenic mouse model for studying the in vivo function of intestinal P450 enzymes in drug/xenobiotic clearance. In preliminary studies, we have generated an intestinal epithelium (IE)-specific NADPH-cytochrome P450 reductase (Cpr) gene knockout mouse model (designated IE-Cpr-null). The gene product of Cpr is the obligatory electron donor to all microsomal P450s. Thus, using the IE-Cpr-null mouse model, we can study the combined roles of IE microsomal P450 enzymes in intestinal xenobiotic metabolism and toxicity. We will use this mouse model to test the central hypothesis that IE P450-mediated drug metabolism can substantially lower the oral bioavailability of numerous drugs/xenobiotics.
In Aim 1, we will further characterize the newly generated IE-Cpr-null mouse, in order to identify its full utility.
In Aim 2, we will directly determine the role of IE CPR/P450s in the first-pass clearance of oral drugs using the IE-Cpr-null mouse model.
In Aim 3, we will test the hypothesis that small intestinal P450-mediated first-pass clearance of ingested dietary or xenobiotic chemicals influences the ability of these chemicals to regulate gene expression in the small intestine and extra-gut organs. Through the proposed studies, we hope to establish the utility of the novel IE-Cpr-null mouse model for identifying those oral drugs/xenobiotics, for which systemic bioavailability (which affects drug efficacy or, alternatively, extent of adverse drug reactions) is substantially influenced by SI P450-mediated first-pass metabolism.

Public Health Relevance

The mutant mouse named IE-Cpr-null will be a powerful tool for determination of the role of intestinal P450 enzymes in limiting the systemic levels of numerous drugs and other foreign chemicals and dietary ingredients. Such knowledge is currently difficult to obtain, and yet is critical for optimizing the effectiveness and safety of numerous clinically important drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM082978-05
Application #
8266547
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$438,313
Indirect Cost
$152,293
Name
Wadsworth Center
Department
Type
DUNS #
153695478
City
Menands
State
NY
Country
United States
Zip Code
12204
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
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
Ahlawat, Sarita; De Jesus, Magdia; Khare, Kedar et al. (2014) Three-dimensional reconstruction of murine Peyer's patches from immunostained cryosections. Microsc Microanal 20:198-205
Zhu, Yi; Ding, Xinxin; Fang, Cheng et al. (2014) Regulation of intestinal cytochrome P450 expression by hepatic cytochrome P450: possible involvement of fibroblast growth factor 15 and impact on systemic drug exposure. Mol Pharmacol 85:139-47
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
Zhang, Peng; Jia, Kunzhi; Fang, Cheng et al. (2013) Dietary regulation of mouse intestinal P450 expression and drug metabolism. Drug Metab Dispos 41:529-35
De Jesus, Magdia; Ahlawat, Sarita; Mantis, Nicholas J (2013) Isolating and immunostaining lymphocytes and dendritic cells from murine Peyer's patches. J Vis Exp :e50167
Riddick, David S; Ding, Xinxin; Wolf, C Roland et al. (2013) NADPH-cytochrome P450 oxidoreductase: roles in physiology, pharmacology, and toxicology. Drug Metab Dispos 41:12-23
Wei, Yuan; Li, Lei; Zhou, Xin et al. (2013) Generation and characterization of a novel Cyp2a(4/5)bgs-null mouse model. Drug Metab Dispos 41:132-40
D'Agostino, Jaime; Ding, Xinxin; Zhang, Peng et al. (2012) Potential biological functions of cytochrome P450 reductase-dependent enzymes in small intestine: novel link to expression of major histocompatibility complex class II genes. J Biol Chem 287:17777-88

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