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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.
AuthorsTom Nijenhuis, Bram C J van der Eerden, Ulrich Zügel, Andreas Steinmeyer, Harrie Weinans, Joost G J Hoenderop, Johannes P T M van Leeuwen, René J M Bindels
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 20 Issue 12 Pg. 2171-3 (Oct 2006) ISSN: 1530-6860 [Electronic] United States
PMID17012263 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Calcium Channels
  • TRPV Cation Channels
  • Trpv5 protein, mouse
  • ZK 191784
  • Vitamin D
  • Calcitriol
  • Calcium
Topics
  • Animals
  • Calcitriol (administration & dosage, analogs & derivatives, pharmacokinetics, pharmacology)
  • Calcium (metabolism)
  • Calcium Channels (deficiency, metabolism, physiology)
  • Homeostasis (drug effects)
  • Intestinal Absorption
  • Intestinal Mucosa (metabolism)
  • Mice
  • Mice, Knockout
  • Organ Specificity
  • Rabbits
  • TRPV Cation Channels (deficiency, physiology)
  • Vitamin D (antagonists & inhibitors)

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