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.
Xu
De-Xiang
DX
Department of toxicology, Anhui Medical University, Hefei, 230032, PR China. xudex@mail.hf.ah.cn
Wang
Jian-Ping
JP
Sun
Mei-Fang
MF
Chen
Yuan-Hua
YH
Wei
Wei
W
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D002384:Catalysis / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007421:Intestine, Small / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D000077297:Pregnane X Receptor; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D011987:Receptors, Steroid / Q000235:genetics*; D047490:Retinoid X Receptor alpha / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D047490:Retinoid X Receptor alpha; D003907:Dexamethasone; C496508:Cyp3a11 protein, mouse; D051544:Cytochrome P-450 CYP3A; D001205:Ascorbic Acid; D000111:Acetylcysteine