RT Journal Article SR Electronic T1 GW4064, an Agonist of Farnesoid X Receptor (FXR), Represses CYP3A4 Expression in Human Hepatocytes JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.114.062836 DO 10.1124/dmd.114.062836 A1 Shu Zhang A1 Xian Pan A1 Hyunyoung Jeong YR 2015 UL http://dmd.aspetjournals.org/content/early/2015/02/27/dmd.114.062836.abstract AB 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 biological function of FXR is in part mediated by small heterodimer partner (SHP); ligand-activated FXR enhances SHP expression, and SHP in turn represses activity of multiple transcription factors. The objective of this study is to investigate the effect of FXR activation on the expression of the major drug-metabolizing enzyme, cytochrome P450 (CYP) 3A4. The effects of GW4064, a synthetic agonist of FXR, on expression and activity of CYP3A4 were examined in primary human hepatocytes by using quantitative real-time PCR and S9 phenotyping. In human hepatocytes, treatment of GW4064 (1 μM) for 48 hours resulted in 75% decrease in CYP3A4 mRNA expression and 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 (GR). Interestingly, GW4064 did not repress expression of CYP2B6, another target gene of PXR and CAR; GW4064 was shown to enhance 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.