The signal transduction pathways involved in hepatic cytochrome P450 regulation in the rat during a lipopolysaccharide-induced model of central nervous system inflammation
The signal transduction pathways involved in hepatic cytochrome P450 regulation in the rat during a lipopolysaccharide-induced model of central nervous system inflammation
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DOI：
10.1124/dmd.105.004564
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发表时间：
2005-10-01
影响因子：
3.9
通讯作者：
Renton, KW
中科院分区：
文献类型：
--
作者：
Abdulla, D;Goralski, KB;Renton, KW
众所周知，中枢神经系统 (CNS) 的炎症和感染状况通过细胞色素 P450 (P450) 的变化来差异调节肝脏药物代谢。然而，导致这种监管的途径仍然未知。我们提供了证据，描述了在建立的中枢神经系统炎症大鼠模型中，使用脂多糖（LPS）直接注射（静脉注射）到侧脑室中肝脏 P450 基因表达下调的信号转导途径。静脉注射后，脑细胞因子水平升高，肝脏中肿瘤坏死因子α和κBα抑制剂（IκBα）的表达增加。 LPS 的施用，表明大脑和肝脏中存在炎症反应。 CNS 炎症后 CYP2D1/5、CYP2B1/2 和 CYP1A1 的表达下调。使用电迁移率位移测定法检查了几种转录因子 [B 细胞中 kappa 增强子的核因子 (NF-kappa B)、激活蛋白-1、cAMP 反应元件结合蛋白、CCAAT 增强子结合蛋白 (C/EBP)] 与 P450 启动子区域上的反应元件的结合。 NF-kappa B 和 C/EBP 分别与 CYP2D5 和 CYP2B1 启动子区域的结合增加，表明它们在炎症反应过程中这两种异构体的调节中发挥重要作用。还提供的证据表明 LPS 从 CNS 快速转移到外周可能是肝脏中 P450 下调的原因。
It is well known that inflammatory and infectious conditions of the central nervous system (CNS) differentially regulate hepatic drug metabolism through changes in cytochrome P450 ( P450); however, the pathways leading to this regulation remain unknown. We provide evidence delineating a signal transduction pathway for hepatic P450 gene expression down-regulation in an established rat model of CNS inflammation using lipopolysaccharide (LPS) injected (i.c.v.) directly into the lateral cerebral ventricle. Brain cytokine levels were elevated, and the expression of tumor necrosis factor alpha and inhibitor of kappa B alpha (I kappa B alpha)were increased in the liver following the i.c.v. administration of LPS, indicating the presence of an inflammatory response in the brain and liver. The expression of CYP2D1/5, CYP2B1/2, and CYP1A1 was down-regulated following CNS inflammation. The binding of several transcription factors [ nuclear factor of the kappa enhancer in B cells (NF-kappa B), activator protein-1, cAMP response element binding protein, CCAAT-enhancer binding protein (C/EBP)] to responsive elements on P450 promoter regions was examined using electromobility shift assays. Binding of both NF-kappa B and C/EBP to the promoter regions of CYP2D5 and CYP2B1, respectively, was increased, indicating that they play an important role in the regulation of these two isoforms during inflammatory responses. Evidence is also provided suggesting that the rapid transfer of LPS from the CNS into the periphery likely accounts for the down-regulation of P450s in the liver.