Nature Medicine9, 220 - 224 (2003)
Published online: 6 January 2003; | doi:10.1038/nm815
The orphan nuclear receptor HNF4 determines PXR- and CAR-mediated xenobiotic induction of CYP3A4
Rommel G. Tirona1, Wooin Lee1, Brenda F. Leake1, Lu-Bin Lan4, Cynthia Brimer Cline4, Vishal Lamba4, Fereshteh Parviz2, Stephen A. Duncan2, Yusuke Inoue3, Frank J. Gonzalez3, Erin G. Schuetz4
& Richard B. Kim1
1
Division of Clinical Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
2
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
3
Laboratory of Metabolism, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland, USA
4
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
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 toxicity1. Currently available studies indicate that the ligand-activated nuclear receptors pregnane X receptor (PXR; NR1I2) and constitutive androstane receptor (CAR; NR1I3) regulate CYP3A4 expression2,
3. However, in cell-based reporter assays, CYP3A4 promoter activity was most pronounced in liver-derived cells and minimal or modest in non-hepatic cells2, indicating that a liver-specific factor is required for physiological transcriptional response. Here we show that the orphan nuclear receptor hepatocyte nuclear factor-4 (HNF4; 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 HNF4 binding and thereby permits PXR- and CAR-mediated gene activation. Fetal mice with conditional deletion of Hnf4 had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of Hnf4 had reduced basal and inducible expression of CYP3A. These data identify HNF4 as an important regulator of coordinate nuclear-receptor−mediated response to xenobiotics.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
determines PXR- and CAR-mediated xenobiotic induction of CYP3A4
(HNF4
had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of Hnf4
