Dietary Regulation of Mouse Intestinal P450 Expression and Drug Metabolism

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.

Cryopreserved Human Intestinal Mucosal Epithelium: A Novel In Vitro Experimental System for the Evaluation of Enteric Drug Metabolism, Cytochrome P450 Induction, and Enterotoxicity

“…Additional ongoing activities in our laboratory include the collection of CHIM from additional donors for the development of a CHIM bank for use in experimentation and for research into genetic and environmental factors affecting enteric drug-metabolizing enzyme activities (Hoensch et al, 1975;Pantuck et al, 1976;Zhang et al, 2013). We will continue to optimize conditions to prolong the life span of CHIM for enzyme induction and enterotoxicity studies, fully realizing that this may be difficult due to the limited life span of mature enterocytes in vivo.…”

An update on the role of intestinal cytochrome P450 enzymes in drug disposition

“…Potential dietary regulation of intestinal drug metabolism is also illustrated by the effects of a synthetic diet on intestinal P450 expression and function 67 . When mice maintained on a regular laboratory chow diet were fed a synthetic (albeit nutritionally balanced) diet devoid of phytochemicals, they exhibited diminished intestinal expression of CYP1A, 2B, 2C, and 3A and hepatic expression of CYP2B, 2C, and 3A.…”

“…Hepatic P450 expression was not induced in the IECN mouse except for a slight induction of CYP1A1 and CYP1A2, the former was present at very low levels. The IECN mouse has been used to demonstrate the critical role of intestinal P450 enzymes in the in vivo metabolism and disposition of a number of xenobiotic compounds, including nifedipine, lovastatin, and midazolam 66 , 67 , 74 , 78 , 79 . As depicted in Fig.…”

Comparison of CYP Induction by <i>Coleus forskohlii</i> Extract and Recovery in the Small Intestine and Liver of Mice

“…25) Moreover, CYP was induced by multiple compounds in CFE. 37) Further study is needed to clarify the different mechanisms of CYP induction between the liver and intestine in regards to transcriptional factors and specific compounds in CFE.…”