Modulation of P-glycoprotein activity by glial factors and retinoic acid in an immortalized rat brain microvessel endothelial cell line.
P-glycoprotein (P-gp), a product of the multidrug-resistant (mdr) genes, is expressed in the endothelial cells of the blood-brain barrier (BBB). Effects of glial factors and retinoic acid (RA) on P-gp activity and level were investigated in the immortalized rat brain endothelial cell line RBE4, which expressed immunodetectable P-gp associated with a decrease in accumulation of the P-gp substrates, vinblastine and colchicine. When RBE4 cells were cultured either in the presence of C6-conditioned medium or on C6- or astrocyte-extracellular matrix, intracellular vinblastine and colchicine concentrations were decreased. When the cells were treated with RA, increases in P-gp activities were correlated with increases in P-gp levels. Effects of simultaneous treatments with glial factors and RA were studied in RBE4 cells cultured on astrocyte-extracellular matrix and were shown to be additive on P-gp activity and level. RBE4 cells may serve as a useful in vitro model for basic research on P-gp regulation at the level of the BBB.
El Hafny
B
B
INSERM U 26, Unité de Neuro-Pharmaco-Nutrition, Hôpital Fernand Widal, Paris, France.
Chappey
O
O
Piciotti
M
M
Debray
M
M
Boval
B
B
Roux
F
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000187:drug effects; D002460:Cell Line; D003078:Colchicine / Q000032:analysis; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D005910:Glioma / Q000378:metabolism; D008833:Microcirculation / Q000378:metabolism; D051381:Rats; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000032:analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D017077:Culture Media, Conditioned; D014212:Tretinoin; D014747:Vinblastine; D016572:Cyclosporine; D003078:Colchicine