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

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。

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.