Ramzi Shawahna1,2,3, Kayathiri Ganeshamoorthy4,5,6, Luo Huilong1,2, Jean-Michel Scherrmann1,2, Pierre-Olivier Couraud4,5,6, Xavier Declèves7,8. 1. Inserm, U1144, Paris, 75006, France. 2. Faculté de Pharmacie, Inserm UMR-S1144, Université Paris Descartes, 4 Avenue de L'observatoire, 75006, Paris, France. 3. Department of Physiology, Pharmacology, and Toxicology, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine. 4. Inserm U1016, Institut Cochin, Paris, France. 5. CNRS, UMR 8104, Paris, France. 6. Université Paris Descartes Sorbonne Paris Cité, Paris, France. 7. Inserm, U1144, Paris, 75006, France. xavier.decleves@parisdescartes.fr. 8. Faculté de Pharmacie, Inserm UMR-S1144, Université Paris Descartes, 4 Avenue de L'observatoire, 75006, Paris, France. xavier.decleves@parisdescartes.fr.
Abstract
BACKGROUND AND OBJECTIVES: Lithium chloride (LiCl) has been shown to improve the tightness of brain endothelial cell monolayers in vitro by inhibition of the GSK-3β enzyme, activation of the Wnt/beta-catenin pathway and regulation of tight junction (TJ) protein expression. However, the effect of LiCl on the drug transporters and drug-metabolizing enzymes has not been addressed so far. The hCMEC/D3 cell line is a validated in vitro BBB model expressing transporters and drug-metabolizing enzymes (phase 1 and 2). The present study was conducted to compare the mRNAs levels corresponding to several BBB endothelial markers in hCMEC/D3 cells with and without incubation in LiCl. METHODS: We used quantitative real-time polymerase chain reaction (qRT-PCR) to quantify the mRNA expression of 5 tight junction (TJ) proteins, 4 adhesion proteins, 5 solute carriers, 7 ATP-binding cassette (ABC) transporters, 8 cytochrome P450 (CYP) and 17 phase 2 conjugation enzymes in hCMEC/D3 cells with and without incubation in LiCl. RESULTS: Our study showed that LiCl treatment for 6 days at a concentration of 10 mM induced the TJ protein claudin-3, the ABC transporter BCRP/ABCG2, the cytochrome P-450 CYP1A1 and the glutathione-S-transferase GSTM3, while the other selected markers were not significantly affected. CONCLUSIONS: Our findings provide new insights into the effects of lithium on some drug transporters and drug-metabolizing enzymes in the BBB that may have consequences in pharmacotherapy.
BACKGROUND AND OBJECTIVES:Lithium chloride (LiCl) has been shown to improve the tightness of brain endothelial cell monolayers in vitro by inhibition of the GSK-3β enzyme, activation of the Wnt/beta-catenin pathway and regulation of tight junction (TJ) protein expression. However, the effect of LiCl on the drug transporters and drug-metabolizing enzymes has not been addressed so far. The hCMEC/D3 cell line is a validated in vitro BBB model expressing transporters and drug-metabolizing enzymes (phase 1 and 2). The present study was conducted to compare the mRNAs levels corresponding to several BBB endothelial markers in hCMEC/D3 cells with and without incubation in LiCl. METHODS: We used quantitative real-time polymerase chain reaction (qRT-PCR) to quantify the mRNA expression of 5 tight junction (TJ) proteins, 4 adhesion proteins, 5 solute carriers, 7 ATP-binding cassette (ABC) transporters, 8 cytochrome P450 (CYP) and 17 phase 2 conjugation enzymes in hCMEC/D3 cells with and without incubation in LiCl. RESULTS: Our study showed that LiCl treatment for 6 days at a concentration of 10 mM induced the TJ protein claudin-3, the ABC transporter BCRP/ABCG2, the cytochrome P-450 CYP1A1 and the glutathione-S-transferaseGSTM3, while the other selected markers were not significantly affected. CONCLUSIONS: Our findings provide new insights into the effects of lithium on some drug transporters and drug-metabolizing enzymes in the BBB that may have consequences in pharmacotherapy.
Authors: Joseph C Lim; Katarzyna D Kania; Hasini Wijesuriya; Sangeeta Chawla; Jaswinder K Sethi; Lukasz Pulaski; Ignacio A Romero; Pierre O Couraud; Babette B Weksler; Stephen B Hladky; Margery A Barrand Journal: J Neurochem Date: 2008-07-04 Impact factor: 5.372
Authors: Yulian Zhou; Yanshu Wang; Max Tischfield; John Williams; Philip M Smallwood; Amir Rattner; Makoto M Taketo; Jeremy Nathans Journal: J Clin Invest Date: 2014-08-01 Impact factor: 14.808