title: 1α,25-Dihydroxyvitamin D3-liganded vitamin D receptor increases expression and transport activity of P-glycoprotein in isolated rat brain capillaries and human and rat brain microvessel endothelial cells.
abstract: Induction of the multidrug resistance protein 1 (MDR1)/P-glycoprotein (P-gp) by the vitamin D receptor (VDR) was investigated in isolated rat brain capillaries and rat (RBE4) and human (hCMEC/D3) brain microvessel endothelial cell lines. Incubation of isolated rat brain capillaries with 10 nM of the VDR ligand, 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] for 4 h increased P-gp protein expression fourfold. Incubation with 1,25(OH)(2)D(3) for 4 or 24 h increased P-gp transport activity (specific luminal accumulation of NBD-CSA, the fluorescent P-gp substrate) by 25-30%. In RBE4 cells, Mdr1b mRNA was induced in a concentration-dependent manner by exposure to 1,25(OH)(2)D(3). Concomitantly, P-gp protein expression increased 2.5-fold and was accompanied by a 20-35% reduction in cellular accumulation of the P-gp substrates, rhodamine 6G (R6G), and HiLyte Fluor 488-labeled human amyloid beta 1-42 (hAβ(42)). In hCMEC/D3 cells, a 3 day exposure to 100 nM 1,25(OH)(2)D(3) increased MDR1 mRNA expression (40%) and P-gp protein (threefold); cellular accumulation of R6G and hAβ(42) was reduced by 30%. Thus, VDR activation up-regulates Mdr1/MDR1 and P-gp protein in isolated rat brain capillaries and rodent and human brain microvascular endothelia, implicating a role for VDR in increasing the brain clearance of P-gp substrates, including hAβ(42), a plaque-forming precursor in Alzheimer's disease.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Durk
authors.forename: Gary N Y
authors.initials: GN
authors.lastname: Chan
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Campos
authors.forename: John C
authors.initials: JC
authors.lastname: Peart
authors.forename: Edwin C Y
authors.initials: EC
authors.lastname: Chow
authors.forename: Eason
authors.initials: E
authors.lastname: Lee
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Cannon
authors.forename: Reina
authors.initials: R
authors.lastname: Bendayan
authors.forename: David S
authors.initials: DS
authors.lastname: Miller
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology* / Q000378:metabolism / Q000502:physiology; D001921:Brain / Q000098:blood supply* / Q000166:cytology; D002117:Calcitriol / Q000378:metabolism* / Q000502:physiology*; D002460:Cell Line; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008297:Male; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008024:Ligands; D018167:Receptors, Calcitriol; D002117:Calcitriol