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

• Published in: Journal of neurochemistry Vol. 123; no. 6; pp. 944 - 953
• Main Authors: Durk, Matthew R., Chan, Gary N.Y., Campos, Christopher R., Peart, John C., Chow, Edwin C. Y., Lee, Eason, Cannon, Ronald E., Bendayan, Reina, Miller, David S., Pang, K. Sandy
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.12.2012; Wiley-Blackwell
• Subjects: 1α,25‐dihydroxyvitamin D3 and vitamin D receptor; 25-dihydroxyvitamin D3 and vitamin D receptor; Adult and adolescent clinical studies; amyloid beta; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1 - physiology; Biological and medical sciences; blood brain barrier; Blood-Brain Barrier - cytology; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - physiology; Brain - blood supply; Brain - cytology; Calcitriol - metabolism; Calcitriol - physiology; Cell Line; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humans; Ligands; Male; Medical sciences; Neurology; Organic mental disorders. Neuropsychology; P-glycoprotein; Protein Transport - physiology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rats; Rats, Sprague-Dawley; Receptors, Calcitriol - metabolism; Receptors, Calcitriol - physiology; Up-Regulation - physiology; Endothelial cell; Rat; Alzheimer disease; Biological transport; Central nervous system; P Glycoprotein; Vitamin; Activation; Encephalon; Degenerative disease; Biological receptor; Human; Nervous system diseases; Induction; Rodentia; and vitamin D receptor; Protein; amyloid beta; Cerebral disorder; Resistance; Substrate; P-glycoprotein; blood brain barrier; Vertebrata; Mammalia; Cell line; Central nervous system disease; 1 α,25-dihydroxyvitamin D
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12041

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 D3 [1,25(OH)2D3] for 4 h increased P‐gp protein expression fourfold. Incubation with 1,25(OH)2D3 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)2D3. 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 (hAβ42). In hCMEC/D3 cells, a 3 day exposure to 100 nM 1,25(OH)2D3 increased MDR1 mRNA expression (40%) and P‐gp protein (threefold); cellular accumulation of R6G and hAβ42 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 hAβ42, a plaque‐forming precursor in Alzheimer's disease. 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 Exposure of rat (RBE4) and human (hCMEC/D3) brain microvessel endothelial cells to 1α,25‐dihydroxyvitamin D3, the active ligand of the vitamin D receptor, resulted in upregualtion of the multidrug resistance protein 1 (MDR1) and its gene product, P‐glycoprotein (P‐gp) and reduced the cellular accumulation of rhodamine 6G (R6G) and human amyloid‐beta 1‐42 (hAβ42), a putative precursor of plaques in Alzheimer's disease. P‐gp efflux function was susceptible to inhibition by PSC833.