title: The novel vitamin D analog ZK191784 as an intestine-specific vitamin D antagonist.
abstract: Vitamin D [1,25(OH)2D3] plays a crucial role in Ca2+ homeostasis by stimulating Ca2+ (re)absorption and bone turnover. The 1,25(OH)2D3 analog ZK191784 was recently developed to dissociate the therapeutic immunomodulatory activity from the hypercalcemic side effects of 1,25(OH)2D3 and contains a structurally modified side chain characterized by a 22,23-double bond, 24R-hydroxy group, 25-cyclopropyl ring, and 5-butyloxazole unit. We investigated the effect of ZK191784 on Ca2+ homeostasis and the regulation of Ca2+ transport proteins in wild-type (WT) mice and mice lacking the renal epithelial Ca2+ channel TRPV5 (TRPV5-/-). The latter display hypercalciuria, hypervitaminosis D, increased intestinal expression of the epithelial Ca2+ channel TRPV6, the Ca2+-binding protein calbindin-D(9K), and intestinal Ca2+ hyperabsorption. ZK191784 normalized the Ca2+ hyperabsorption and the expression of intestinal Ca2+ transport proteins in TRPV5-/- mice. Furthermore, the compound decreased intestinal Ca2+ absorption in WT mice and reduced 1,25(OH)2D3-dependent 45Ca2+ uptake by Caco-2 cells, substantiating a 1,25(OH)2D3-antagonistic action of ZK191784 in the intestine. ZK191784 increased renal TRPV5 and calbindin-D(28K) expression and decreased urine Ca2+ excretion in WT mice. Both 1,25(OH)2D3 and ZK191784 enhanced transcellular Ca2+ transport in primary cultures of rabbit connecting tubules and cortical collecting ducts, indicating a 1,25(OH)2D3-agonistic effect in kidney. ZK191784 enhanced bone TRPV6 mRNA levels and 1,25(OH)2D3 as well as ZK191784 stimulated secretion of the bone formation marker osteocalcin in rat osteosarcoma cells, albeit to a different extent. In conclusion, ZK191784 is a synthetic 1,25(OH)2D3 ligand displaying a unique tissue-specific profile when administered in vivo. Because ZK191784 acts as an intestine-specific 1,25(OH)2D3 antagonist, this compound will be associated with less hypercalcemic side effects compared with the 1,25(OH)2D3 analogs currently used in clinical practice.
authors.affiliation: Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen, NL-6500 HB, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: Nijenhuis
authors.forename: Bram C J
authors.initials: BC
authors.lastname: van der Eerden
authors.forename: Ulrich
authors.initials: U
authors.lastname: Zügel
authors.forename: Andreas
authors.initials: A
authors.lastname: Steinmeyer
authors.forename: Harrie
authors.initials: H
authors.lastname: Weinans
authors.forename: Joost G J
authors.initials: JG
authors.lastname: Hoenderop
authors.forename: Johannes P T M
authors.initials: JP
authors.lastname: van Leeuwen
authors.forename: René J M
authors.initials: RJ
authors.lastname: Bindels
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000172:deficiency / Q000378:metabolism* / Q000502:physiology; D006706:Homeostasis / Q000187:drug effects*; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity; D011817:Rabbits; D050916:TRPV Cation Channels / Q000172:deficiency / Q000502:physiology; D014807:Vitamin D / Q000037:antagonists & inhibitors*
chemical_list: D015220:Calcium Channels; D050916:TRPV Cation Channels; C492240:Trpv5 protein, mouse; C470666:ZK 191784; D014807:Vitamin D; D002117:Calcitriol; D002118:Calcium