Chen Yuan-Hua, Wang Jian-Ping, Wang Hua, Sun Mei-Fang, Wei Ling-Zhen, Wei Wei, Xu De-Xiang
Department of toxicology, Anhui Medical University, Hefei 230032, PR China.
Toxicology. 2005 Aug 1;211(3):242-52. doi: 10.1016/j.tox.2005.03.011.
The cytochrome P450 3A (CYP3A) is a member of the cytochrome P450 monooxygenase superfamily. The multidrug resistance 1 (MDR1) gene belongs to the ATP-binding cassette (ABC) family. Pregnane X receptor (PXR) is a nuclear receptor that regulates its target gene transcription in a ligand-dependent manner. Lipopolysaccharide (LPS)-induced downregulation of PXR, CYP3A and MDR1 in liver has been demonstrated in a series of studies. However, it is not clear whether LPS represses the expression of PXR, CYP3A and MDR1 in placenta. In the present study, we investigated the effects of LPS on the expression of PXR, cyp3a11 and mdr1a in mouse placenta. Pregnant ICR mice were injected intraperitoneally with different doses of LPS (0.1-0.5 mg/kg) on gestational day (gd) 17. Placental PXR, cyp3a11 and mdr1a mRNA levels were determined at 12 h after LPS treatment using RT-PCR. Results showed that LPS significantly downregulated PXR, cyp3a11 and mdr1a mRNA levels in a dose-dependent manner. LPS-induced downregulation of PXR, cyp3a11 and mdr1a mRNA in placenta was significantly attenuated after pregnant mice were pre- and post-treated with alpha-phenyl-N-t-butylnitrone (PBN), a free radical spin trapping agent. Additional experiments revealed that LPS increased lipid peroxidation and proinflammatory cytokine expressions in mouse placenta, all of which were also attenuated by PBN. Furthermore, LPS-induced downregulation of PXR, cyp3a11 and mdr1a mRNA in mouse placenta was prevented by N-acetylcysteine (NAC). NAC also inhibited LPS-initiated lipid peroxidation, GSH depletion and proinflammatory cytokine expressions in mouse placenta. These results indicated that LPS downregulates placental PXR, cyp3a11 and mdr1a mRNA expressions. Reactive oxygen species (ROS) may be involved in LPS-induced downregulation of PXR, cyp3a11 and mdr1a in mouse placenta.
细胞色素P450 3A（CYP3A）是细胞色素P450单加氧酶超家族的成员。多药耐药1（MDR1）基因属于ATP结合盒（ABC）家族。孕烷X受体（PXR）是一种核受体，以配体依赖的方式调节其靶基因转录。一系列研究已证明脂多糖（LPS）可诱导肝脏中PXR、CYP3A和MDR1的下调。然而，LPS是否抑制胎盘组织中PXR、CYP3A和MDR1的表达尚不清楚。在本研究中，我们调查了LPS对小鼠胎盘组织中PXR、cyp3a11和mdr1a表达的影响。在妊娠第17天，对怀孕的ICR小鼠腹腔注射不同剂量的LPS（0.1 - 0.5 mg/kg）。使用RT-PCR在LPS处理后12小时测定胎盘组织中PXR、cyp3a11和mdr1a的mRNA水平。结果显示，LPS以剂量依赖的方式显著下调PXR、cyp3a11和mdr1a的mRNA水平。在用自由基自旋捕获剂α-苯基-N-叔丁基硝酮（PBN）对怀孕小鼠进行预处理和后处理后，LPS诱导的胎盘组织中PXR、cyp3a11和mdr1a mRNA的下调显著减弱。进一步的实验表明，LPS增加了小鼠胎盘组织中的脂质过氧化和促炎细胞因子表达，而这些也被PBN减弱。此外，N-乙酰半胱氨酸（NAC）可防止LPS诱导的小鼠胎盘组织中PXR、cyp3a11和mdr1a mRNA的下调。NAC还抑制了LPS引发的小鼠胎盘组织中的脂质过氧化、谷胱甘肽消耗和促炎细胞因子表达。这些结果表明，LPS下调胎盘组织中PXR、cyp3a11和mdr1a的mRNA表达。活性氧（ROS）可能参与LPS诱导的小鼠胎盘组织中PXR、cyp3a11和mdr1a的下调。
