慢性肝损伤对大鼠脑内P-GP及MRP2功能和表达的影响

金实; 姚丹; 刘灿; 王新廷; 张璐璐; 刘晓东

慢性肝损伤对大鼠脑内P-GP及MRP2功能和表达的影响

Effect of chronic liver failure on the function and expression of P-GP and MRP2 in rat brain

摘要

摘要: 研究硫代乙酰胺（TAA）诱导的慢性肝损伤（CLF）对大鼠脑内P-糖蛋白（P-GP）和多药耐药蛋白2（MRP2）的功能和表达的影响。大鼠腹腔注射TAA(200 mg/kg),每周两次，连续给药12周诱导慢性肝损伤模型。最后1次给药后24 h，静脉注射P-GP底物罗丹明123（Rho 123）和长春新碱（VCR），以及MRP2底物溴磺酞钠（BSP），S-(2,4二硝基苯基)-谷胱甘肽（DNP-SG），测定大脑皮层、海马和血浆中底物浓度，计算其脑组织/血浆浓度比；用Western blot测定脑内P-GP和MRP2的蛋白表达。结果显示CLF显著升高Rho123和VCR的脑组织/血浆浓度比，显著降低BSP和DNP-SG脑组织/血浆浓度比。Western blot结果表明CLF显著下调脑内P-GP的蛋白水平，显著上调脑内MRP2的蛋白水平。实验结果表明，慢性肝损伤下调大鼠脑内P-GP的功能和表达，上调MRP2的功能和表达。

Abstract: The purpose of the study was to investigate whether chronic liver failure (CLF) induced by thioacetamide (TAA) affected the function and expression of P-glycoprotein (P-GP) and multidrug resistance-associated protein 2 (MRP2) in rat brain.CLF was induced by ip injection of TAA (200 mg/kg) twice per week for 12 weeks.The rats were used for further experiments 24 h after the last administration.The function of P-GP and MRP2 in rat brain was determined using the brain-to-plasma ratios of corresponding substrates (rhodamine 123,Rho123 and vincristine,VCR for P-GP;Sulfobromophthalein,BSP and dinitrophenyl-S-glutathione,DNP-SG for MRP2);Western blot was applied to determine the expression of P-GP and MRP2 proteins.The results suggested that CLF increased the brain-to-plasma ratios of Rho 123 and VCR,while decreasing those of BSP and DNP-SG.Western blot results showed that CLF decreased brain P-GP levels,while increasing MRP2 levels.In conclusion,CLF may decrease the function and expression of P-GP,while increaseing the function and expression of MRP2.

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