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An Intestinal Epithelium-specific Cytochrome P450 (P450) Reductase-knockout Mouse Model: Direct Evidence for a Role of Intestinal P450s in First-pass Clearance of Oral Nifedipine

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Specialty Pharmacology
Date 2008 Dec 6
PMID 19056912
Citations 30
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Abstract

To determine the in vivo function of intestinal cytochrome P450 (P450) enzymes, we have generated an intestinal epithelium (IE)-specific P450 reductase gene (Cpr) knockout mouse model (designated IE-Cpr-null). In the IE-Cpr-null mouse, CPR expression was abolished in IE cells; however, CPR expression was not altered in other tissues examined. The loss of CPR expression in the small intestine (SI) led to increased expression of several P450 proteins examined, including CYP1A1, CYP2B, CYP2C, and CYP3A. It is interesting to note that the expression of CYP1A1 was also increased in the liver, kidney, and lung of the IE-Cpr-null mice compared with wild-type (WT) littermates, a result strongly supporting the notion that SI metabolism of putative dietary CYP1A1 inducers can influence the systemic bioavailability of these inducers. The rates of SI microsomal metabolism of nifedipine (NFP) in the IE-Cpr-null mice were approximately 10% of the rates in WT littermates, despite the compensatory expression of multiple P450 enzymes in the SI. Furthermore, the area under the concentration-time curve (AUC) values for blood NFP (dosed at 10 mg/kg) levels were 1.6-fold higher in IE-Cpr-null mice than in WT littermates when NFP was given orally; in contrast, the AUC values were comparable for the two strains when NFP was given intravenously. This result directly showed that P450-catalyzed NFP metabolism in the SI plays an important role in the first-pass clearance of oral NFP. Our findings indicate that the IE-Cpr-null mouse model can be used to study the in vivo function of intestinal P450 enzymes in the clearance of oral drugs and other xenobiotics.

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References
1.
Chen Y, Liu Y, Su T, Ren X, Shi L, Liu D . Immunoblot analysis and immunohistochemical characterization of CYP2A expression in human olfactory mucosa. Biochem Pharmacol. 2003; 66(7):1245-51. DOI: 10.1016/s0006-2952(03)00476-3. View

2.
Paine M, Hart H, Ludington S, Haining R, Rettie A, Zeldin D . The human intestinal cytochrome P450 "pie". Drug Metab Dispos. 2006; 34(5):880-6. PMC: 2222892. DOI: 10.1124/dmd.105.008672. View

3.
Suzuki H, Sugiyama Y . Role of metabolic enzymes and efflux transporters in the absorption of drugs from the small intestine. Eur J Pharm Sci. 2000; 12(1):3-12. DOI: 10.1016/s0928-0987(00)00178-0. View

4.
Fang C, Gu J, Xie F, Behr M, Yang W, Abel E . Deletion of the NADPH-cytochrome P450 reductase gene in cardiomyocytes does not protect mice against doxorubicin-mediated acute cardiac toxicity. Drug Metab Dispos. 2008; 36(8):1722-8. PMC: 2575052. DOI: 10.1124/dmd.108.021881. View

5.
Weng Y, Fang C, Turesky R, Behr M, Kaminsky L, Ding X . Determination of the role of target tissue metabolism in lung carcinogenesis using conditional cytochrome P450 reductase-null mice. Cancer Res. 2007; 67(16):7825-32. DOI: 10.1158/0008-5472.CAN-07-1006. View