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J. Biol. Chem., Vol. 277, Issue 1, 209-217, January 4, 2002
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From INSERM U128, IFR24, Campus CNRS, 1919 Route de Mende,
34293 Montpellier, France
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 (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
glucocorticoid-responsive element imperfect palindrome at
1662/1676, and a DR4 motif at 1803/1818 recognized and
transactivated by human glucocorticoid receptor and by hCAR and
pregnane X receptor, 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/pregnane X
receptor activation.
To whom correspondence should be addressed. Tel.: 33-4-6761-3363;
Fax: 33-4-6752-3681; E-mail:
maurel@u128.crbm.cnrs-mop.fr.
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