Molecular pharmacokinetic studies of drug transport in endotoxemia

首先，研究了有效的PPAR-γ配体吡格列酮对内毒素诱导的细胞色素P450(CyP)还原的影响。其次，利用肿瘤坏死因子-α基因敲除小鼠，研究了肿瘤坏死因子-α在内毒素下调肝脏P-糖蛋白、细胞色素P3A2和细胞色素P450_2C11基因表达中的作用。第三，研究不同革兰氏阴性杆菌来源的内毒素对肝脏细胞色素P3A2、细胞色素P2C11、P糖蛋白和MRP2表达的影响。预先给予有效的PPAR-γ配体吡格列酮可显著保护内毒素诱导的肝脏细胞色素P3A2的蛋白水平下降，但不影响细胞色素P450受体C11的蛋白水平，而肝脏的生化和组织病理学变化不明显。此外，它还能显著保护内毒素诱导的肝脏iNOS过度表达，但不能保护血浆中NO的过度产生。吡格列酮对内毒素诱导的肝脏细胞色素P3A2蛋白水平降低的保护作用不太可能是通过抑制OV…起作用的。2号的更多错误生产。内毒素对肿瘤坏死因子-α基因敲除小鼠P-糖蛋白表达无影响，提示肿瘤坏死因子-α在内毒素下调P-糖蛋白表达中起关键作用。内毒素诱导的肿瘤坏死因子α基因敲除小鼠细胞色素P3A2和细胞色素P450 2 C11的表达下降幅度明显大于野生型小鼠。这些结果提示，肿瘤坏死因子-α在内毒素诱导的肝脏P-糖蛋白下调中起关键作用，并且在调节肝脏细胞色素P3A2和细胞色素P450-C11对内毒素诱导的急性炎症具有保护作用。肺炎克雷伯菌和大肠杆菌内毒素对细胞色素P3A2的下调作用大于铜绿假单胞菌内毒素。但三种不同内毒素对细胞色素P450 2C11的抑制作用基本相同。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MRP2。大肠杆菌内毒素对P-糖蛋白和MRP2的表达均无影响。这些结果表明，内毒素对肝脏细胞色素P3A2和P-糖蛋白的蛋白水平有不同的影响，可能是由于细菌来源--某些促炎介质产生的差异较少

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