Bile duct ligation causes opposite impacts on the expression and function of BCRP and P-gp in rat brain partly via affecting membrane expression of ezrin/radixin/moesin proteins  

作　　者：Tong Wu Yun Sheng Yuan-yuan Qin Wei-min Kong Meng-meng Jin Han-yu Yang Xiao-ke Zheng Chang Dai Ming Liu Xiao-dong Liu Li Liu 

机构地区：[1]Center of Drug Metabolism and Pharmacokinetics,School of Pharmacy,China Pharmaceutical University,Nanjing 210009,China

出　　处：《Acta Pharmacologica Sinica》2021年第11期1942-1950,共9页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Nos.81872930,82073922,81673505);the"Double First-Class"University Project(CPU2018GY22).

摘　　要：Breast cancer resistance protein(BCRP)and P-glycoprotein(P-gp)are co-located at blood–brain barrier(BBB)cells,preventing their substrates from entering brain.Accumulating evidence demonstrates that liver failure impairs P-gp and BCRP expression and function in the brain.In the current study,we investigated how liver failure influenced the expression and function of brain BCRP and P-gp in rats subjected to bile duct ligation(BDL).The function of BCRP,P-gp and BBB integrity was assessed using distribution of prazosin,rhodamine 123 and fluorescein,respectively.We showed that BDL significantly decreased BCRP function,but increased P-gp function without affecting BBB integrity.Furthermore,we found that BDL significantly downregulated the expression of membrane BCRP and upregulated the expression of membrane P-gp protein in the cortex and hippocampus.In human cerebral microvascular endothelial cells,NH4Cl plus unconjugated bilirubin significantly decreased BCRP function and expression of membrane BCRP protein,but upregulated P-gp function and expression of membrane P-gp protein.The decreased expression of membrane BCRP protein was linked to the decreased expression of membrane radixin protein,while the increased expression of membrane P-gp protein was related to the increased location of membrane ezrin protein.Silencing ezrin impaired membrane location of P-gp,whereas silencing radixin impaired membrane location of BCRP protein.BDL rats showed the increased expression of membrane ezrin protein and decreased expression of membrane radixin protein in the brain.We conclude that BDL causes opposite effects on the expression and function of brain BCRP and P-gp,attributing to the altered expression of membrane radixin and ezrin protein,respectively,due to hyperbilirubinemia and hyperammonemia.

关 键 词：liver failure breast cancer resistance protein P-GLYCOPROTEIN blood-brain barrier ERM proteins 

分 类 号：R657.4[医药卫生—外科学]