Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Artikel
Titel:
Dual effect of dexamethasone on CYP3A4 gene expression in human hepatocytes : Sequential role of glucocorticoid receptor and pregnane X receptor
:
Sequential role of glucocorticoid receptor and pregnane X receptor
Beschreibung:
<jats:p>Although <jats:italic>CYP3A</jats:italic> induction by dexamethasone has been extensively documented, its mechanism is still unclear because both the role of the glucocorticoid receptor and the ability of dexamethasone to activate the human pregnane X receptor have been questioned. In an attempt to resolve this problem, we investigated the response of <jats:italic>CYP3A4</jats:italic> to dexamethasone (10 n<jats:sc>m</jats:sc>–100 µ<jats:sc>m</jats:sc>) in primary human hepatocytes and HepG2 cells, using a variety of methods: kinetic analysis of <jats:italic>CYP3A4</jats:italic> and tyrosine aminotransferase expression, effects of RU486 and cycloheximide, ligand binding assay, cotransfection of HepG2 cells with <jats:italic>CYP3A4</jats:italic> reporter gene constructs and vectors expressing the glucocorticoid receptor, pregnane X receptor or constitutively activated receptor. In contrast to rifampicin (monophasic induction), dexamethasone produces a biphasic induction of <jats:italic>CYP3A4</jats:italic> mRNA consisting of a low‐dexamethasone component (nmol concentrations) of low amplitude (factor of 3–4) followed by a high‐dexamethasone component (supramicromolar concentrations) of high amplitude (factor of 15–30). We show that the low‐dexamethasone component results from the glucocorticoid receptor‐mediated expression of pregnane X receptor and/or constitutively activated receptor which, in turn, are able to transactivate <jats:italic>CYP3A4</jats:italic> in a xenobiotic‐independent manner. At supramicromolar concentrations (>10 µ<jats:sc>m</jats:sc>), dexamethasone binds to and activates pregnane X receptor thus producing the high‐dexamethasone component of <jats:italic>CYP3A4</jats:italic> induction. We conclude that, in contrast to the other xenobiotic inducers of <jats:italic>CYP3A4</jats:italic>, glucocorticoids play a dual role in CYP3A4 expression, first by controlling the expression of PXR and CAR under physiological conditions (submicromolar concentrations) through the classical glucocorticoid receptor pathway, and second by activating the pregnane X receptor under bolus or stress conditions (supramicromolar concentrations).</jats:p>