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Rapid CommunicationShort Communication

Dietary Regulation of Mouse Intestinal P450 Expression and Drug Metabolism

Peng Zhang, Kunzhi Jia, Cheng Fang, Xin Zhou, Xinxin Ding and Qing-Yu Zhang
Drug Metabolism and Disposition February 2013, 41 (2) 529-535; DOI: https://doi.org/10.1124/dmd.112.049403
Peng Zhang
Laboratory of Molecular Toxicology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, New York
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Kunzhi Jia
Laboratory of Molecular Toxicology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, New York
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Cheng Fang
Laboratory of Molecular Toxicology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, New York
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Xin Zhou
Laboratory of Molecular Toxicology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, New York
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Xinxin Ding
Laboratory of Molecular Toxicology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, New York
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Qing-Yu Zhang
Laboratory of Molecular Toxicology, Division of Environmental Health Sciences, Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York at Albany, New York
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Abstract

The study was originally designed to test the hypothesis that the compensatory increase in intestinal P450 (cytochrome P450) expression in the intestinal epithelium-specific P450 reductase (CPR) knockout (IE-Cpr-null) mice was attributable to decreased metabolism of putative P450 inducers present in the diet. Thus, we determined the impact of a dietary change from regular rodent chow to a synthetic diet devoid of phytochemicals on the expression of P450 enzymes in the small intestine (SI) and liver of wild-type (WT) and IE-Cpr-null mice. The dietary change diminished expression of CYP1A, 2B, 2C, and 3A in SI and CYP2B, 2C, and 3A in liver of both WT and IE-Cpr-null mice. However, the compensatory increase in SI P450 expression still occurred in IE-Cpr-null, compared with WT, mice, on the synthetic diet. The diet change–induced decrease in P450 expression was accompanied by decreases in microsomal midazolam-hydroxylase activity in vitro and first-pass clearance of midazolam in vivo in WT mice. Further studies showed that the dietary change, but not Cpr deletion, caused large decreases in bile acid (BA) levels in plasma, liver, SI, and intestinal content and that treatment of WT mice on the synthetic diet with GW4064, a farnesoid-X-receptor agonist, restored the levels of CYP3A expression in both liver and SI to those seen in mice fed with regular chow. Taken together, these results highlight the vital role of diet in maintaining adequate expression of major drug-metabolizing P450s and their associated drug-metabolizing activities in the digestive tract and suggest potential involvement of BA signaling in the regulatory mechanisms.

Footnotes

  • This study was supported in part by the National Institutes of Health National Institute of General Medical Sciences [Grant GM082978].

  • dx.doi.org/10.1124/dmd.112.049403.

  • Received October 4, 2012.
  • Accepted November 16, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Rapid CommunicationShort Communication

Dietary Regulation of Intestinal P450 Expression

Peng Zhang, Kunzhi Jia, Cheng Fang, Xin Zhou, Xinxin Ding and Qing-Yu Zhang
Drug Metabolism and Disposition February 1, 2013, 41 (2) 529-535; DOI: https://doi.org/10.1124/dmd.112.049403

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Rapid CommunicationShort Communication

Dietary Regulation of Intestinal P450 Expression

Peng Zhang, Kunzhi Jia, Cheng Fang, Xin Zhou, Xinxin Ding and Qing-Yu Zhang
Drug Metabolism and Disposition February 1, 2013, 41 (2) 529-535; DOI: https://doi.org/10.1124/dmd.112.049403
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