title: Temporal changes in tissue 1α,25-dihydroxyvitamin D3, vitamin D receptor target genes, and calcium and PTH levels after 1,25(OH)2D3 treatment in mice.
abstract: The vitamin D receptor (VDR) maintains a balance of plasma calcium and 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], its natural active ligand, by directly regulating the calcium ion channel (TRPV6) and degradation enzyme (CYP24A1), and indirectly regulating the parathyroid hormone (PTH) for feedback regulation of the synthetic enzyme CYP27B1. Studies that examined the intricate relationships between plasma and tissue 1,25(OH)2D3 levels and changes in VDR target genes and plasma calcium and PTH are virtually nonexistent. In this study, we investigated temporal correlations between tissue 1,25(OH)2D3 concentrations and VDR target genes in ileum and kidney and plasma calcium and PTH concentrations in response to 1,25(OH)2D3 treatment in mice (2.5 μg/kg ip, singly or q2d × 4). After a single ip dose, plasma 1,25(OH)2D3 peaked at ∼0.5 h and then decayed biexponentially, falling below basal levels after 24 h and then returning to baseline after 8 days. Upon repetitive ip dosing, plasma, ileal, renal, and bone 1,25(OH)2D3 concentrations rose and decayed in unison. Temporal profiles showed increased expressions of ileal Cyp24a1 and renal Cyp24a1, Mdr1/P-gp, and VDR but decreased renal Cyp27b1 mRNA after a time delay in VDR activation. Increased plasma calcium and attenuated PTH levels and increased ileal and renal Trpv6 expression paralleled the changes in tissue 1,25(OH)2D3 concentrations. Gene changes in the kidney were more sustained than those in intestine, but the magnitudes of change for Cyp24a1 and Trpv6 were lower than those in intestine. The data revealed that 1,25(OH)2D3 equilibrates with tissues rapidly, and VDR target genes respond quickly to exogenously administered 1,25(OH)2D3.
authors.affiliation: Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Edwin C Y
authors.initials: EC
authors.lastname: Chow
authors.forename: Holly P
authors.initials: HP
authors.lastname: Quach
authors.forename: Reinhold
authors.initials: R
authors.lastname: Vieth
authors.forename: K Sandy
authors.initials: KS
authors.lastname: Pang
mesh_terms: D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D015153:Blotting, Western; D002117:Calcitriol / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002118:Calcium / Q000097:blood / Q000378:metabolism*; D015220:Calcium Channels / Q000096:biosynthesis / Q000235:genetics; D025461:Feedback, Physiological / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010281:Parathyroid Hormone / Q000378:metabolism*; D010758:Phosphorus / Q000097:blood; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D050916:TRPV Cation Channels / Q000096:biosynthesis / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase; D014815:Vitamins / Q000378:metabolism* / Q000494:pharmacology*
chemical_list: D015220:Calcium Channels; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D050916:TRPV Cation Channels; C446923:Trpv6 protein, mouse; D014815:Vitamins; D010758:Phosphorus; D013250:Steroid Hydroxylases; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002117:Calcitriol; D002118:Calcium
keywords: 1α,25-dihydroxyvitamin D3; 1α-hydroxylase; 24-hydroxylase cytochrome P-450; 25-hydroxyvitamin D3; Cyp24a1; Cyp27b1; TRPV6; member 6; subfamily V; transient receptor potential cation channel; vitamin D receptor