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Molecular pharmacokinetic studies of drug transport in endotoxemia

内毒素血症药物转运的分子药代动力学研究

基本信息

批准号：
15590484
负责人：
HASEGAWA Takaaki
金额：
$ 1.98万
依托单位：
Aichi Medical University (2004)Nagoya University (2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

First, the effect of pioglitazone, a potent PPAR-γ ligand, on the endotoxin-induced reduction of cytochrome P450 (CYP) was investigated. Second, the role of TNF-α in the down-regulation of hepatic P-glycoprotein and CYP3A2 and CYP2C11 by endotoxin was investigated using TNF-α-knockout mice. Third, the differential effects of endotoxin derived from various gram-negative bacteria on the expression of hepatic CYP3A2, CYP2C11, P-glycoprotein and Mrp2 were investigated.1. Pretreatment with a potent PPAR-γ ligand, pioglitazone, significantly protected the endotoxin-induced decreases the protein levels of CYP3A2, but not CYP2C11, with no biochemical and histopathological changes in the liver. Also, it significantly protected endotoxin-induced overexpression of iNOS in the liver, but not the overproduction of NO in plasma. It is unlikely that the protective effect of pioglitazone against endotoxin-induced decreases in the protein levels of CYP3A2 in the liver is due to the inhibition of the ov … More erproduction of NO.2. Endotoxin had no effect the expression of P-glycoprotein in TNF-α-knockout mice, suggesting that TNF-α plays a pivotal role in the down-regulation of P-glycoprotein by endotoxin. Endotoxin-induced decreases in the expression of CYP3A2 and CYP2C11 in TNF-α-knockout mice were significantly greater than wild-type mice. These results suggest that TNF-α plays a key role in endotoxin-induced down-regulation of hepatic P-glycoprotein, as well as plays a protective role in the regulation of hepatic CYP3A2 and CYP2C11 against endotoxin-induced acute inflammatory.3. The down-regulation of CYP3A2 by K pneumonia and E. coli endotoxin was greater than that by P. aeruginosa endotoxin. But that of CYP2C11 by all three different endotoxin was almost the same. Both K pneumonia and P. aeruginosa endotoxin significantly down-regulated P-glycoprotein, but did not down-regulate Mrp2. E. coli endotoxin had no effect on the expression of either P-glycoprotein or Mrp2. These results suggest that endotoxin has a differential effect on the protein levels of hepatic CYP3A2 and P-glycoprotein, probably due to bacterial source-differences in the production of some proinflammatory mediators Less

首先，研究了吡格列酮（一种有效的PPAR-γ配体）对内毒素诱导的细胞色素P450（CYP）还原的影响。第二，使用TNF-α基因敲除小鼠研究TNF-α在内毒素下调肝脏P-糖蛋白和CYP 3A 2和CYP 2C 11中的作用。第三，研究了不同革兰氏阴性菌来源的内毒素对肝脏CYP 3A 2、CYP 2C 11、P-糖蛋白和Mrp 2表达的不同影响.用有效的PPAR-γ配体吡格列酮预处理可显著保护内毒素诱导的CYP 3A 2蛋白水平降低，但不能保护CYP 2C 11蛋白水平降低，肝脏中无生化和组织病理学变化。此外，它显着保护内毒素诱导的iNOS在肝脏中的过度表达，但不是在血浆中NO的过度产生。吡格列酮对内毒素诱导的肝脏CYP 3A 2蛋白水平降低的保护作用不太可能是由于抑制过氧化氢酶， ...更多信息生产NO.2。内毒素对TNF-α基因敲除小鼠P-糖蛋白表达无影响，提示TNF-α在内毒素下调P-糖蛋白表达中起重要作用。TNF-α敲除小鼠中内毒素诱导的CYP 3A 2和CYP 2C 11表达降低显著大于野生型小鼠。提示TNF-α在内毒素诱导的肝脏P-糖蛋白表达下调中起关键作用，并在调节肝脏CYP 3A 2和CYP 2C 11对抗内毒素诱导的急性炎症中起保护作用.肺炎克雷伯菌和大肠杆菌对CYP 3A 2的下调作用。大肠杆菌内毒素的作用大于铜绿假单胞菌内毒素。而三种内毒素对CYP 2C 11的影响几乎相同。肺炎克雷伯菌和铜绿假单胞菌内毒素均显著下调P-糖蛋白，但不下调Mrp 2。E.大肠杆菌内毒素对P-糖蛋白和Mrp 2的表达均无影响。这些结果表明，内毒素对肝脏CYP 3A 2和P-糖蛋白的蛋白水平有不同的影响，这可能是由于细菌来源-某些促炎介质产生的差异。