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

通过生物膜的药物转运功能及其在内毒素血症中的生理作用的研究

基本信息

批准号：
13672417
负责人：
HASEGAWA Takaaki
金额：
$ 2.3万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13672417/
关键词：
endotoxin membrane transport transporters P-glycoprotein blood-brain barrier cytokines 生体膜輸送機構 TNF-α

项目摘要

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.

本研究的结果如下： 1．细胞因子和介质，如TNF-α、IL-1和PAF在内毒素诱导的CYP含量和CYP3A2和2C11蛋白水平降低中的参与似乎很小。2．一些喹诺酮类抗菌药物增加了P-糖蛋白依赖性抗癌药物耐药细胞中P-糖蛋白底物阿霉素的细胞内积累，表明它们可以逆转肿瘤的抗癌药物耐药性。它们通过P-糖蛋白介导的转运系统排泄到胆汁中。3．内毒素不改变葡萄糖醛酸化活性，但由于Mrp2-和/或P-糖蛋白介导的肝胆转运系统和肾脏处理受损而降低司帕沙星及其葡萄糖醛酸苷。4．注射内毒素后6 h,肝脏和肾脏中Mdrla mRNA表达量下降,并恢复至对照水平。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的胆汁和肾脏排泄，这可能是由于血浆TNF-α水平增加所致。5．内毒素不会引起脑毛细血管的组织病理学变化，并且对小鼠脑毛细血管的完整性和阿霉素跨血脑屏障（BBB）的转运没有影响。内毒素不改变脑内P-糖蛋白的功能和表达。尽管大脑中 P-糖蛋白水平降低，但 P-糖蛋白功能可能足以转运阿霉素。6。志贺样毒素II损害BBB功能和阿霉素跨BBB转运，同时诱导P-糖蛋白上调，这与内毒素注射的结果不同。内毒素和志贺样毒素II之间的差异可能是由于细胞因子产生含量的差异所致。