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The orphan nuclear receptor HNF4α determines PXR- and CAR-mediated xenobiotic induction of CYP3A4

Abstract

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-4α (HNF4α; 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 HNF4α binding and thereby permits PXR- and CAR-mediated gene activation. Fetal mice with conditional deletion of Hnf4α had reduced or absent expression of CYP3A. Furthermore, adult mice with conditional hepatic deletion of Hnf4α had reduced basal and inducible expression of CYP3A. These data identify HNF4α as an important regulator of coordinate nuclear-receptor–mediated response to xenobiotics.

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Figure 1: Effect of HNF4α on CYP3A4 promoter activity.
Figure 2: Gene expression in genetically altered mice.

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Acknowledgements

We thank G. Gervasini for preparing the human VDR expression plasmid; M. Pontoglio (Institut Pasteur), G.I. Bell (The University of Chicago) and M. Hara (The University of Chicago) for providing Hnf1α-knockout mice; and G.R. Wilkinson and D.M. Roden (Vanderbilt University) for helpful discussions. This work was supported in part by United States Public Health Service Grants GM54724 (R.B.K.), GM31304 (R.B.K.), ES08658 (E.G.S) and GM60346 (E.G.S).

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Correspondence to Richard B. Kim.

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Tirona, R., Lee, W., Leake, B. et al. The orphan nuclear receptor HNF4α determines PXR- and CAR-mediated xenobiotic induction of CYP3A4. Nat Med 9, 220–224 (2003). https://doi.org/10.1038/nm815

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