title: Resveratrol suppresses the inducible expression of CYP3A4 through the pregnane X receptor.
abstract: The pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is activated by a number of clinically prescribed drugs and herbal extracts. The inducible expression of several important cytochrome P450 (CYP450) enzymes has been shown to be regulated by the activation of PXR in the liver. In the current study, reporter gene-transfected cells were used to identify potential antagonists of PXR. Here, we showed that resveratrol (RES), a natural polyphenolic compound could significantly suppress the rifampicin-induced PXR transactivation of the CYP3A4 promoter. Treatment of hPXR-over-expressed cells with RES reduced the rifampicin-inducible expression of CYP3A4 in a concentration-dependent manner. Moreover, the induction of mRNA and protein expression of CYP3A11 by pregnenolone 16α-carbonitrile was also significantly reduced when RES was applied in primary cultures of mouse hepatocytes. Taking together, these findings suggest that RES can attenuate the PXR-mediated induction of CYP3A enzyme. Therefore, it would be possible for RES to antagonize the elevation in CYP3A-mediated drug metabolism by identified PXR activators.
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, China.
authors.forename: Rongrong
authors.initials: R
authors.lastname: Deng
authors.forename: Chenshu
authors.initials: C
authors.lastname: Xu
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.forename: Yongtao
authors.initials: Y
authors.lastname: Wang
authors.forename: Xunian
authors.initials: X
authors.lastname: Zhou
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Lu
authors.initials: L
authors.lastname: Niu
authors.forename: Mengjia
authors.initials: M
authors.lastname: Ying
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Huichang
authors.initials: H
authors.lastname: Bi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051544:Cytochrome P-450 CYP3A / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008807:Mice, Inbred BALB C; D000077297:Pregnane X Receptor; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D011987:Receptors, Steroid / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000077185:Resveratrol; D012293:Rifampin / Q000037:antagonists & inhibitors; D013267:Stilbenes / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D008565:Membrane Proteins; C000625853:Nr1i2 protein, mouse; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D013267:Stilbenes; D011285:Pregnenolone Carbonitrile; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D000077185:Resveratrol; D012293:Rifampin