Lipopolysaccharide downregulates the expressions of intestinal pregnane X receptor and cytochrome P450 3a11.
Lipopolysaccharide downregulates the expressions of intestinal pregnane X receptor and cytochrome P450 3a11.
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DOI：
10.1016/j.ejphar.2006.02.029
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发表时间：
2006-04
影响因子：
5
通讯作者：
De-xiang Xu;Jianping Wang;Meifang Sun;Yuan-Hua Chen;Wei Wei-Wei
中科院分区：
文献类型：
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作者：
De-xiang Xu;Jianping Wang;Meifang Sun;Yuan-Hua Chen;Wei Wei-Wei
孕烷X受体是核受体超家族的成员，与类视黄醇X受体异二聚化，是细胞色素P450 3A （CYP3A）的重要调节因子。脂多糖（LPS）诱导的妊娠X受体及其靶基因cyp3a11的下调已经在小鼠肝脏中得到了很好的表征。在本研究中，我们研究了LPS对小鼠肠内妊娠X受体及其靶基因cyp3a11表达的影响。小鼠腹腔注射不同剂量的LPS （0.1 ~ 5.0mg/kg）。采用逆转录聚合酶链反应（RT-PCR）检测肠道孕烷X受体、类维甲酸X受体α α α和cyp3a11 mRNA。以红霉素n -去甲基化酶（ERND）活性作为CYP3A表达的指标。结果显示，LPS显著下调肠道孕烷X受体及其异二聚体类视黄醇X受体α的表达，并呈剂量依赖性。此外，LPS抑制妊娠X受体配体地塞米松预处理小鼠的cyp3a11 mRNA上调和ERND催化活性。另外的实验表明，LPS显著增加了肠道硫代巴比妥酸反应物质的水平，而口服n -乙酰半胱氨酸或抗坏血酸均能减弱该反应物质的水平。相应地，口服n -乙酰半胱氨酸或抗坏血酸均可显著减弱lps诱导的肠道孕烷X受体和类维甲酸X受体α α α α的下调。此外，这些抗氧化剂可以阻止LPS对小鼠肠道中地塞米松诱导的cyp3a11 mRNA和ERND活性的抑制作用。综上所述，LPS可抑制小鼠肠内妊娠X受体及其靶基因cyp3a11的表达。lps诱导的小鼠肠中妊娠X受体和cyp3a11的下调至少部分是由氧化应激介导的。
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 (0.1–5.0mg/kg). Intestinal pregnane X receptor, retinoid X receptor αlpha 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 αlpha. 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.