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Dietary Regulation of Mouse Intestinal P450 Expression and Drug Metabolism
Author(s) -
Zhang QingYu,
Zhang Peng,
Jia Kunzhi,
Fang Cheng,
Zhou Xin,
Ding Xinxin
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1180.6
Subject(s) - drug metabolism , medicine , endocrinology , cytochrome p450 , cholesterol 7 alpha hydroxylase , enterohepatic circulation , metabolism , in vivo , small intestine , biology , midazolam , pharmacology , bile acid , sedation , microbiology and biotechnology
To determine the impact of dietary changes on intestinal P450 expression and drug metabolism, we studied wild‐type (WT) and intestinal epithelium (IE)‐specific P450 reductase (CPR) knockout (IE‐ Cpr ‐null) mice, fed either with a regular chow or with a synthetic diet devoid of phytochemicals. A change from regular chow to the synthetic diet diminished expression of CYP1A, 2B, 2C, and 3A in the small intestine (SI), and of CYP2B, 2C, and 3A in liver, of both WT and IE‐ Cpr ‐null mice; it also decreased microsomal midazolam‐hydroxylase activity in vitro and first‐pass clearance of midazolam in vivo. However, compensatory increase in SI P450 expression still occurred in IE‐ Cpr ‐null, compared to WT, mice, on the synthetic diet. The dietary change, but not Cpr deletion, caused large decreases in bile acid (BA) levels in plasma, liver, SI, and intestinal content. Furthermore, the diet change in WT mice led to increases in SI expression of FGF15, an enterohepatic regulator of hepatic BA synthesis, and a decrease in hepatic expression of CYP7A1, a key enzyme in BA synthesis. These results highlight the vital role of diet in maintaining adequate expression of major drug‐metabolizing P450s in the digestive tract, and suggest potential involvement of FGF15 and BA signaling in the regulatory mechanisms. (Supported in part by NIH grant GM082978)