Lipopolysaccharide downregulates the expressions of intestinal pregnane X receptor and cytochrome P450 3a11.

The pregnane X receptor is a member of the nuclear receptor superfamily, which heterodimerize with the retinoid X receptor, and is an important regulator of cytochrome P450 3A (CYP3A). Lipopolysaccharide (LPS)-induced downregulation of pregnane X receptor and its target gene cyp3a11 has been well characterized in mouse liver. In the present study, we investigated the effects of LPS on the expressions of pregnane X receptor and its target gene cyp3a11 in mouse intestine. Mice were injected intraperitoneally with different doses of LPS (0.1-5.0 mg/kg). Intestinal pregnane X receptor, retinoid X receptor alphalpha and cyp3a11 mRNA were determined using reverse transcription polymerase chain reaction (RT-PCR). Erythromycin N-demethylase (ERND) activity was used as an indicator of CYP3A expression. Results showed that LPS significantly downregulated the expressions of intestinal pregnane X receptor and its heterodimer retinoid X receptor alpha in a dose-dependent manner. Furthermore, LPS repressed the upregulation of cyp3a11 mRNA and ERND catalytic activity in mice pretreated with pregnane X receptor ligand dexamethasone. Additional experiment showed that LPS significantly increased the level of intestinal thiobarbituric acid-reactive substance, which was attenuated by oral administration with either N-acetylcysteine or ascorbic acid. Correspondingly, oral administration with either N-acetylcysteine or ascorbic acid significantly attenuated LPS-induced downregulation of intestinal pregnane X receptor and retinoid X receptor alphalpha. In addition, these antioxidants prevented the repressive effect of LPS on dexamethasone-inducible cyp3a11 mRNA and ERND activity in mouse intestine. Taken together, these results indicate that LPS suppresses the expressions of pregnane X receptor and its target gene cyp3a11 in mouse intestine. LPS-induced downregulation of pregnane X receptor and cyp3a11 in mouse intestine is mediated, at least in part, by oxidative stress.