Investigation of drug transport function through biological membranes and physiological role in endotoxemia

本研究得到的结果如下：1。细胞因子和介质，如TNF-α、IL-1和PAF，参与内毒素诱导的CYP含量和CYP3A2和2C11蛋白水平的降低似乎很小。一些喹诺酮类抗菌剂增加了p -糖蛋白依赖的抗癌耐药细胞内多柔比星（p -糖蛋白的底物）的积累，表明它们可以逆转肿瘤的抗癌耐药。它们通过p -糖蛋白介导的转运系统排泄到胆汁中。内毒素没有改变葡萄糖醛酸化的活性，但由于Mrp2-和/或p -糖蛋白介导的肝胆转运系统和肾脏处理的损伤，降低了斯帕沙星及其葡萄糖醛酸。内毒素注射后6 h，肝脏和肾脏中Mdrla mRNA的表达下降，恢复到对照水平。内毒素通过降低Mdrla的表达来减少p -糖蛋白介导的罗丹明-123的胆道和肾脏排泄，这可能是由于血浆TNF-α水平升高所致。内毒素不会引起小鼠脑毛细血管的组织病理学改变，对小鼠脑毛细血管完整性和阿霉素通过血脑屏障（BBB）的转运没有影响。内毒素未改变p -糖蛋白的功能和表达。尽管脑内p -糖蛋白水平下降，但p -糖蛋白的功能可能足以运输阿霉素。志贺样毒素II损害血脑屏障功能和阿霉素在血脑屏障中的转运，同时诱导p -糖蛋白上调，这与内毒素注射的结果不同。内毒素与志贺样毒素的差异可能与细胞因子含量的差异有关。

Results obtained from this research are represented as follows :1. The involvement of cytokines and mediators, such TNF-α, IL-1 and PAF, in endotoxin-induced decreases in the content of CYP and protein levels of CYP3A2 and 2C11 appears to be small.2. Some quinolone antimicrobial agents increased the intracellular accumulation of doxorubicin, a substrate of P-glycoprotein, in P-glycoprotein-dependent anticancer drug resistant cells, suggesting that they can reverse anticancer drug resistance of tumors. They are excreted into the bile by a P-glycoprotein-mediated transport system.3. Endotoxin did not change the activity of glucuronidation, but decreased sparfloxacin and its glucuronide due to impairment of Mrp2- and/or P-glycoprotein-mediated hepatobiliary transport systems and renal handling.4. The expression of Mdrla mRNA in both liver and kidney decreased 6 h after endotoxin injection and returned to control level. Endotoxin decreased P-glycoprotein-mediated biliary and renal excretion of rhodamine-123 by decreasing the expression of Mdrla, which is likely due to increased plasma TNF-α levels.5. Endotoxin did not induce histopathological changes in the brain capillaries, and had no effect on the brain capillary integrity and doxorubicin transport across the blood-brain barrier (BBB) in mice. Endotoxin did not change the function and expression of P-glycoprotein in the brain. It is likely that P-glycoprotein function might be sufficient to transport doxorubicin despite of decreased levels of P-glycoprotein in the brain.6. Shiga-like toxin II impairs the BBB function and doxorubicin transport across the BBB, while induces upregulation of P-glycoprotein, which are different from results by endotoxin injection. The discrepancy between endotoxin and Shiga-like toxin II may be explained by the difference in the contents of cytokine production.