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

Qing Yu Zhang, Cheng Fang, Jin Zhang, Deborah Dunbar, Laurence Kaminsky, Xinxin Ding

Research output: Contribution to journalArticle

40 Citations (Scopus)

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 -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.

Original languageEnglish (US)
Pages (from-to)651-657
Number of pages7
JournalDrug Metabolism and Disposition
Volume37
Issue number3
DOIs
StatePublished - Mar 1 2009
Externally publishedYes

Fingerprint

Intestinal Mucosa
Nifedipine
Knockout Mice
Cytochrome P-450 Enzyme System
Oxidoreductases
Small Intestine
Cytochrome P-450 CYP1A1
Cardiopulmonary Resuscitation
Cytochrome P-450 CYP3A
Gene Knockout Techniques
Xenobiotics
Biological Availability
Kidney
Lung
Liver
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

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. / Zhang, Qing Yu; Fang, Cheng; Zhang, Jin; Dunbar, Deborah; Kaminsky, Laurence; Ding, Xinxin.

In: Drug Metabolism and Disposition, Vol. 37, No. 3, 01.03.2009, p. 651-657.

Research output: Contribution to journalArticle

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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 -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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