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
- 8 February 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Pharmacologica Sinica
- Vol. 42 (11), 1942-1950
- https://doi.org/10.1038/s41401-020-00602-3
Abstract
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.Keywords
This publication has 50 references indexed in Scilit:
- An RNA Alternative to Human Transferrin: A New Tool for Targeting Human CellsMolecular Therapy Nucleic Acids, 2012
- The effect of sphingomyelin synthase 2 (SMS2) deficiency on the expression of drug transporters in mouse brainBiochemical Pharmacology, 2011
- Pravastatin for thioacetamide‐induced hepatic failure and encephalopathyEuropean Journal of Clinical Investigation, 2011
- Structure and function of the blood–brain barrierNeurobiology of Disease, 2010
- Comparison of bidirectional lamivudine and zidovudine transport using MDCK, MDCK–MDR1, and Caco-2 cell monolayersJournal of Pharmaceutical Sciences, 2009
- Liver failure after major hepatic resectionJournal of Hepato-Biliary-Pancreatic Surgery, 2008
- P-glycoprotein-Mediated Active Efflux of the Anti-HIV1 Nucleoside Abacavir Limits Cellular Accumulation and Brain DistributionDrug Metabolism and Disposition, 2007
- Localization of the Human Breast Cancer Resistance Protein (BCRP/ABCG2) in Lipid Rafts/Caveolae and Modulation of Its Activity by Cholesterol in VitroThe Journal of pharmacology and experimental therapeutics, 2007
- P‐Glycoprotein is localized in intermediate‐density membrane microdomains distinct from classical lipid rafts and caveolar domainsThe FEBS Journal, 2005
- An update on the role of brain glutamine synthesis and its relation to cell-specific energy metabolism in the hyperammonemic brain: Further studies using NMR spectroscopyNeurochemistry International, 2005