title: 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.
authors.affiliation: Laboratory of Molecular, State University of New York at Albany, NY, USA. zhangq@wadsworth.org
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Kunzhi
authors.initials: K
authors.lastname: Jia
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.forename: Xin
authors.initials: X
authors.lastname: Zhou
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhang
mesh_terms: D000821:Animal Feed; D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004032:Diet; D005260:Female; D006900:Hydroxylation; D007422:Intestines / Q000187:drug effects / Q000201:enzymology*; D007527:Isoenzymes; D007555:Isoxazoles / Q000494:pharmacology; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008862:Microsomes, Liver / Q000201:enzymology; D008874:Midazolam / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009251:NADPH-Ferrihemoprotein Reductase / Q000172:deficiency / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D013379:Substrate Specificity; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D003577:Cytochrome P-450 Enzyme System; D007527:Isoenzymes; D007555:Isoxazoles; D008874:Midazolam; D009251:NADPH-Ferrihemoprotein Reductase; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064