Dexamethasone induces pregnane X receptor and retinoid X receptor-alpha expression in human hepatocytes: Synergistic increase of CYP3A4 induction by pregnane X receptor activators

In this report we show that submicromolar concentrations of dexamethasone e nhance pregnane X receptor (PXR) activator-mediated CYP3A4 gene expression in cultured human hepatocytes. Because this result is only observed after 2 4 h of cotreatment and is inhibited by pretreatment with cycloheximide, we further investigated which factor(s), induced by dexamethasone, might be re sponsible for this effect. We report that dexamethasone increases both reti noid X receptor-alpha (RXR alpha) and PXR mRNA expression in cultured human hepatocytes, whereas PXR activators such as rifampicin and clotrimazole do not. Accumulation of RXR alpha and PXR mRNA reaches a maximum at a concent ration of 100 nM dexamethasone after treatment for 6 to 12 h and is greatly diminished by RU486. A similar pattern of expression is observed with tyro sine aminotransferase mRNA. Moreover, the effect of dexamethasone on PXR mR NA accumulation seems to be through direct action on the glucocorticoid rec eptor (GR) because the addition of cycloheximide has no effect, and dexamet hasone does not affect the degradation of PXR mRNA. Furthermore, dexamethas one induces the accumulation of a RXR alpha-immunoreactive protein and incr eases the nuclear level of RXR alpha:PXR heterodimer as shown by gel shift assays with a CYP3A4 ER6 PXRE probe. This accumulation of latent PXR and RX R alpha in the nucleus of hepatocytes explains the synergistic effect obser ved with dexamethasone and PXR activators together on CYP3A4 induction. The se results reveal the existence of functional cross talk between the GR and PXR, and may explain some controversial aspects of the role of the GR in C YP3A4 induction.