GW4064, an agonist of farnesoid X receptor, represses CYP3A4 expression in human hepatocytes by inducing small heterodimer partner expression.
Farnesoid X receptor (FXR) functions as a regulator of bile acid and lipid homeostasis and is recognized as a promising therapeutic target for metabolic diseases. The biologic function of FXR is mediated in part by a small heterodimer partner (SHP); ligand-activated FXR enhances SHP expression, and SHP in turn represses the activity of multiple transcription factors. This study aimed to investigate the effect of FXR activation on expression of the major drug-metabolizing enzyme CYP3A4. The effects of 3-(2,6-dichlorophenyl)-4-(3'-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), a synthetic agonist of FXR, on the expression and activity of CYP3A4 were examined in primary human hepatocytes by using quantitative real-time polymerase chain reaction and S9 phenotyping. In human hepatocytes, treatment of GW4064 (1 μM) for 48 hours resulted in a 75% decrease in CYP3A4 mRNA expression and a 25% decrease in CYP3A4 activity, accompanied by ∼3-fold increase in SHP mRNA expression. In HepG2 cells, SHP repressed transactivation of CYP3A4 promoter by pregnane X receptor (PXR), constitutive androstane receptor (CAR), and glucocorticoid receptor. Interestingly, GW4064 did not repress expression of CYP2B6, another target gene of PXR and CAR; GW4064 enhanced CYP2B6 promoter activity. In conclusion, GW4064 represses CYP3A4 expression in human hepatocytes, potentially through upregulation of SHP expression and subsequent repression of CYP3A4 promoter activity. Clinically significant drug-drug interaction involving FXR agonists and CYP3A4 substrates may occur.
Department of Pharmacy Practice (H.J.) and Department of Biopharmaceutical Sciences (S.Z., X.P., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
Shu
S
Zhang
Department of Pharmacy Practice (H.J.) and Department of Biopharmaceutical Sciences (S.Z., X.P., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois.
Xian
X
Pan
Department of Pharmacy Practice (H.J.) and Department of Biopharmaceutical Sciences (S.Z., X.P., H.J.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois yjeong@uic.edu.
Hyunyoung
H
Jeong
D002460:Cell Line; D045744:Cell Line, Tumor; D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
D000090702:Constitutive Androstane Receptor; D051544:Cytochrome P-450 CYP3A; D007555:Isoxazoles; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011965:Receptors, Glucocorticoid; D011987:Receptors, Steroid; D000099150:Receptor, Farnesoid X-Activated; C510163:CYP3A4 protein, human; C412815:GW 4064