TY - JOUR
T1 - The novel vitamin D analog ZK191784 as an intestine-specific vitamin D antagonist
AU - Nijenhuis, Tom
AU - Van Der Eerden, Bram C.J.
AU - Zügel, Ulrich
AU - Steinmeyer, Andreas
AU - Weinans, Harrie
AU - Hoenderop, Joost G.J.
AU - Van Leeuwen, Johannes P.T.M.
AU - Bindels, René J.M.
N1 - © FASEB
PY - 2006/10
Y1 - 2006/10
N2 - 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-D9K, 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 Ca 2+ absorption in WT mice and reduced 1,25(OH)2D 3-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)2D 3-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.
AB - 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-D9K, 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 Ca 2+ absorption in WT mice and reduced 1,25(OH)2D 3-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)2D 3-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.
UR - http://www.scopus.com/inward/record.url?scp=33845615322&partnerID=8YFLogxK
UR - https://www.researchgate.net/publication/6783149_The_novel_vitamin_D_analog_ZK191784_as_an_intestine-specific_vitamin_D_antagonist
U2 - 10.1096/fj.05-5515fje
DO - 10.1096/fj.05-5515fje
M3 - Article
C2 - 17012263
SN - 0892-6638
VL - 20
SP - E1589-E1598
JO - FASEB Journal
JF - FASEB Journal
IS - 12
ER -