The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4.

Tirona RG, Lee W, Leake BF, Lan LB, Cline CB, Lamba V, Parviz F, Duncan SA, Inoue Y, Gonzalez FJ, Schuetz EG, Kim RB
Nat Med. 2003 9 (2): 220-4

PMID: 12514743 · DOI:10.1038/nm815

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.

MeSH Terms (22)

Animals Base Sequence Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System DNA-Binding Proteins DNA Primers Electrophoretic Mobility Shift Assay Enhancer Elements, Genetic Enzyme Induction Hepatocyte Nuclear Factor 4 Humans Male Mice Mice, Inbred C57BL Phosphoproteins Pregnane X Receptor Receptors, Cytoplasmic and Nuclear Receptors, Steroid Transcription Factors Tumor Cells, Cultured Xenobiotics

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