Lipopolysaccharide and cecal ligation/puncture differentially affect the subcellular distribution of the pregnane X receptor but consistently cause suppression of its target genes CYP3A.

Abstract

The repressed expression of cytochrome P450 (CYP) enzymes in septic patients contributes significantly to therapeutic failures. Mice treated with sepsis-inducing agent lipopolysaccharide (LPS) sequentially express reduced mRNA levels of the pregnane X receptor (PXR) and its target genes Cyp3a(s), suggesting that reduction of Cyp expression is associated with the repression of PXR. The present study was undertaken to determine whether septic rats induced by LPS and cecal ligation/puncture (CLP) express reduced levels of rat PXR protein and whether the subcellular distribution of PXR is altered in septic conditions. Rats were treated with LPS (55 vs. 1 mg/kg) or underwent CLP, and the expression of CYP3A and PXR was determined. In LPS-treated rats, the expression of CYP3A enzymes was consistently decreased regardless of the doses used. In contrast, high dose and repeated low dose of LPS caused significant decreases on the nuclear PXR, whereas the opposite was true with the cytosolic PXR. When rats were administered with only a single low dose of LPS, both nuclear and cytosolic PXR levels were significantly increased. In the CLP model, rats undergoing CLP for 30 h expressed significantly lower levels of CYP3A but the PXR levels were not significantly altered. In addition, when rats were treated with dexamethasone, a significant induction of CYP3A was detected. However, such an induction was markedly antagonized by the treatment with LPS. The differential changes on the levels of the nuclear PXR and CYP3A between LPS and CLP models suggest that PXR plays negligible roles in the constitutive expression of CYP3A. The antagonism of LPS against dexamethasone-mediated CYP3A induction suggests that endotoxemia minimizes the inducibility of PXR target genes.