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Papers In Press, published online ahead of print October 25, 2001
J. Biol. Chem, 10.1074/jbc.M107228200
Submitted on July 30, 2001
Revised on October 24, 2001
Accepted on October 24, 2001

Transcriptional regulation of CYP2C9 gene:role of glucocorticoid receptor and constitutive androstane receptor

Sabine Gerbal-Chaloin, Martine Daujat, Jean-Marc Pascussi, Lydiane Pichard-Garcia, Marie-Jose Vilarem, and Patrick J. P. Maurel

IFR24, INSERM U128, Montpellier 34293

Corresponding Author: maurel{at}falbala.crbm.cnrs-mop.fr

Although cytochrome P450 2C9 (CYP2C9) is a major CYP expressed in the adult human liver, its mechanism of regulation is poorly known. In previous work, we have shown that CYP2C9 is inducible in primary human hepatocytes by xenobiotics including dexamethasone, rifampicin and phenobarbital. The aim of this work was to investigate the molecular mechanism(s) controlling the inducible expression of CYP2C9. Deletional analysis of CYP2C9 regulatory region (+21 to –2088) in the presence of various hormone nuclear receptors suggested the presence of two functional response elements, a Glucocorticoid Receptor-responsive element (GR, –1648/–1684) and a Constitutive Androstane Receptor-responsive element (CAR, –1783/–1856). Each of these were characterized by co-transfection experiments, directed mutagenesis, gel shift assays, and response to specific antagonists RU486 and androstanol. By these experiments we located a GRE imperfect palindrome at -1662/-1676, and a DR4 motif at -1803/-1818 recognized and transactivated by hGR and by hCAR and Pregnane X Receptor (PXR), respectively. Identification of these functional elements provides rational mechanistic basis for CYP2C9 induction by dexamethasone (submicromolar concentrations), and by phenobarbital and rifampicin, respectively. CYP2C9 appears therefore to be a primary glucocorticoid-responsive gene, which in addition, may be induced by xenobiotics through CAR/PXR activation.


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