Zhang Shu, Pan Xian, Jeong Hyunyoung
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.
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
Drug Metab Dispos. 2015 May;43(5):743-8. doi: 10.1124/dmd.114.062836. Epub 2015 Feb 27.
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.
法尼醇X受体（FXR）作为胆汁酸和脂质稳态的调节因子，被认为是代谢性疾病一个有前景的治疗靶点。FXR的生物学功能部分由小异二聚体伴侣（SHP）介导；配体激活的FXR增强SHP表达，而SHP反过来抑制多种转录因子的活性。本研究旨在探讨FXR激活对主要药物代谢酶CYP3A4表达的影响。通过定量实时聚合酶链反应和S9表型分析，检测了FXR的合成激动剂3-(2,6-二氯苯基)-4-(3'-羧基-2-氯芪-4-基)氧甲基-5-异丙基异恶唑（GW4064）对原代人肝细胞中CYP3A4表达和活性的影响。在人肝细胞中，用GW4064（1 μM）处理48小时导致CYP3A4 mRNA表达下降75%，CYP3A4活性下降25%，同时SHP mRNA表达增加约3倍。在HepG2细胞中，SHP抑制孕烷X受体（PXR）、组成型雄烷受体（CAR）和糖皮质激素受体对CYP3A4启动子的反式激活。有趣的是，GW4064并未抑制PXR和CAR的另一个靶基因CYP2B6的表达；GW4064增强了CYP2B6启动子活性。总之，GW4064可能通过上调SHP表达并随后抑制CYP3A4启动子活性来抑制人肝细胞中CYP3A4的表达。涉及FXR激动剂和CYP3A4底物的具有临床意义的药物相互作用可能会发生。
