Tirona Rommel G, Lee Wooin, Leake Brenda F, Lan Lu-Bin, Cline Cynthia Brimer, Lamba Vishal, Parviz Fereshteh, Duncan Stephen A, Inoue Yusuke, Gonzalez Frank J, Schuetz Erin G, Kim Richard B
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Nat Med. 2003 Feb;9(2):220-4. doi: 10.1038/nm815. Epub 2003 Jan 6.
The drug metabolizing enzyme cytochrome P450 3A4 (CYP3A4) is thought to be involved in the metabolism of nearly 50% of all the drugs currently prescribed. Alteration in the activity or expression of this enzyme seems to be a key predictor of drug responsiveness and toxicity. Currently available studies indicate that the ligand-activated nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) regulate CYP3A4 expression. However, in cell-based reporter assays, CYP3A4 promoter activity was most pronounced in liver-derived cells and minimal or modest in non-hepatic cells, indicating that a liver-specific factor is required for physiological transcriptional response. Here we show that the orphan nuclear receptor hepatocyte nuclear factor-4alpha (HNF4alpha; HNF4A) is critically involved in the PXR- and CAR-mediated transcriptional activation of CYP3A4. We identified a specific cis-acting element in the CYP3A4 gene enhancer that confers HNF4alpha binding and thereby permits PXR- and CAR-mediated gene activation. Fetal mice with conditional deletion of Hnf4alpha had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of Hnf4alpha had reduced basal and inducible expression of CYP3A. These data identify HNF4alpha as an important regulator of coordinate nuclear-receptor-mediated response to xenobiotics.
药物代谢酶细胞色素P450 3A4（CYP3A4）被认为参与了目前所开处方中近50%药物的代谢。该酶活性或表达的改变似乎是药物反应性和毒性的关键预测指标。现有研究表明，配体激活的核受体孕烷X受体（PXR；NR1I2）和组成型雄甾烷受体（CAR；NR1I3）调节CYP3A4的表达。然而，在基于细胞的报告基因检测中，CYP3A4启动子活性在肝源性细胞中最为显著，而在非肝细胞中则最小或适度，这表明生理转录反应需要一种肝脏特异性因子。在此我们表明，孤儿核受体肝细胞核因子-4α（HNF4α；HNF4A）在PXR和CAR介导的CYP3A4转录激活中起关键作用。我们在CYP3A4基因增强子中鉴定出一个特定的顺式作用元件，该元件赋予HNF4α结合能力，从而允许PXR和CAR介导的基因激活。条件性缺失Hnf4α的胎鼠CYP3A的表达降低或缺失。此外，条件性肝脏缺失Hnf4α的成年小鼠CYP3A的基础表达和诱导表达均降低。这些数据表明HNF4α是核受体介导的对外源化合物协同反应的重要调节因子。
