Park Shinhee, Cheng Sunny Lihua, Cui Julia Yue
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98105, USA.
Acta Pharm Sin B. 2016 Sep;6(5):475-491. doi: 10.1016/j.apsb.2016.07.004. Epub 2016 Aug 2.
Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3) is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs) in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type and mice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice, mRNA was down-regulated by TCPOBOP in liver and duodenum. mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012), TCPOBOP up-regulated many DPGs (, and ) in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs of and were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs were CAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical.
肠道负责许多经口摄入化学物质的生物转化。已知组成型雄烷受体（CAR/Nr1i3）可上调肝脏中许多编码药物代谢酶和转运蛋白的基因（药物加工基因/DPGs），但关于其在肠道中的作用了解较少。60日龄的野生型小鼠和[此处原文缺失具体小鼠类型]小鼠每天接受一次CAR配体TCPOBOP或赋形剂，持续4天。在野生型小鼠中，TCPOBOP使肝脏和十二指肠中的[此处原文缺失具体基因名称]mRNA下调。[此处原文缺失具体小鼠类型]小鼠以节段特异性方式改变了许多DPGs的基础肠道表达。与肝脏数据一致（Aleksunes和Klaassen，2012年），TCPOBOP以CAR依赖的方式上调了小肠特定节段中的许多DPGs（[此处原文缺失具体基因名称]、[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]）。然而，[此处原文缺失具体基因名称]和[此处原文缺失具体基因名称]的mRNA先前已知在肝脏中被TCPOBOP上调，但在肠道中未发生改变。有趣的是，许多已知的CAR靶基因在结肠中表达最高，而结肠中CAR的表达最低，这表明还有其他调节因子参与调节它们的表达。总之，CAR调节肠道中许多DPGs的基础表达，尽管许多肝脏中CAR靶向的DPGs在肠道中也是CAR靶点，但肝脏和肠道中CAR的药理激活并不相同。
