Perinatal lipopolysaccharide exposure downregulates pregnane X receptor and Cyp3a11 expression in fetal mouse liver.
Perinatal lipopolysaccharide exposure downregulates pregnane X receptor and Cyp3a11 expression in fetal mouse liver.
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DOI：
10.1093/toxsci/kfi239
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发表时间：
2005-09
期刊：
影响因子：
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通讯作者：
De-xiang Xu;Yuan-Hua Chen;Jianping Wang;Meifang Sun;Hua Wang;Ling‐Zhen Wei;Wei Wei-Wei
中科院分区：
文献类型：
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作者：
De-xiang Xu;Yuan-Hua Chen;Jianping Wang;Meifang Sun;Hua Wang;Ling‐Zhen Wei;Wei Wei-Wei
孕烷X受体(PXR)是核受体超家族的一员，以配体依赖的方式调节细胞色素P450 3A(CyP3A)基因转录。脂多糖(LPS)诱导成年小鼠肝脏PXR和cyp3a11表达下调的研究已有报道。在本研究中，我们研究了母体脂多糖暴露对胎鼠肝脏PXR和cyp3a11表达的影响。于妊娠第17天给妊娠ICR小鼠腹腔注射不同剂量的内毒素(0.1，约0.5 mg/kg)，用RT-PCR方法检测PXR和cyp3a11基因的表达水平。本研究以红霉素N-脱甲基酶(ERND)活性作为细胞色素P3A表达的指标。结果表明，内毒素可明显下调胎肝PXR、cyp3a11基因表达水平和ERND活性，并呈剂量依赖关系。自由基自旋捕捉剂α-苯基-N-叔丁基硝酮(PBN)可减弱脂多糖对妊娠小鼠PXR和cyp3a11基因表达及ERND活性的影响。此外，实验还发现，内毒素可显著增加胎肝中的脂质过氧化反应，PBN预处理也可减轻这一作用。此外，母体给予N-乙酰半胱氨酸(NAC)可阻止内毒素诱导的PXR和cyp3a11基因表达及ERND活性的下调。母体给予NAC也能抑制脂多糖诱导的胎肝脂质过氧化和GSH耗竭。然而，母体内毒素治疗并不影响胎儿肝脏中亚硝酸盐和硝酸盐的浓度。相应地，诱导型一氧化氮合酶(INOS)的选择性抑制剂氨基胍对内毒素诱导的胎肝PXR和cyp3a11表达及ERND活性的下调没有影响。这些结果表明，母鼠脂多糖暴露可下调胎鼠肝脏中PXR和cyp3a11的表达。ROS可能参与了内毒素对胎鼠肝脏PXR和cyp3a11表达的下调。
The pregnane X receptor (PXR) is a member of the nuclear receptor superfamily that regulates cytochrome P450 3A (CYP3A) gene transcription in a ligand-dependent manner. Lipopolysaccharide (LPS)-induced downregulation on PXR and cyp3a11 in adult mouse liver has been well characterized. In this study, we investigated the effects of maternal LPS exposure on PXR and cyp3a11 expression in fetal mouse liver. Pregnant ICR mice were injected intraperitoneally with different doses of LPS (0.1 approximately 0.5 mg/kg) on gestational day (GD) 17. PXR and cyp3a11 mRNA levels were determined using RT-PCR. Erythromycin N-demethylase (ERND) activity was used as an indicator of CYP3A expression in this study. Results showed that LPS significantly downregulated PXR and cyp3a11 mRNA levels and ERND activity in fetal liver in a dose-dependent manner. LPS-induced downregulation of PXR and cyp3a11 mRNA expression and ERND activity was attenuated after pregnant mice were pretreated with alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Additional experiment revealed that LPS significantly increased lipid peroxidation in fetal liver, which was also attenuated by PBN pretreatment. Furthermore, LPS-induced downregulation of PXR and cyp3a11 mRNA expression and ERND activity was prevented by maternal pretreatment with N-acetylcysteine (NAC). Maternal pretreatment with NAC also inhibited LPS-initiated lipid peroxidation and GSH depletion in fetal liver. However, maternal LPS treatment did not affect nitrite plus nitrate concentration in fetal liver. Correspondingly, aminoguanidine, a selective inhibitor of inducible nitric oxide synthase (iNOS), has no effect on LPS-induced downregulation of PXR and cyp3a11 expression and ERND activity in fetal liver. These results indicated that maternal LPS exposure downregulates PXR and cyp3a11 in fetal mouse liver. Reactive oxygen species (ROS) may be involved in LPS-induced downregulation of PXR and cyp3a11 in fetal mouse liver.