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The novel vitamin D analog ZK191784 as an intestine‐ specific vitamin D antagonist
Author(s) -
Nijenhuis Tom,
Eerden Bram C. J.,
Zügel Ulrich,
Steinmeyer Andreas,
Weinans Harrie,
Hoenderop Joost G. J.,
Leeuwen Johannes P. T. M.,
Bindels René J. M.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.05-5515fje
Subject(s) - trpv6 , medicine , endocrinology , calbindin , chemistry , transcellular , calcium metabolism , reabsorption , homeostasis , vitamin d and neurology , calcitriol receptor , hypercalciuria , paracellular transport , calcium , excretion , kidney , biology , biochemistry , membrane , permeability (electromagnetism)
Vitamin D [1,25(OH) 2 D 3 ] plays a crucial role in Ca 2+ homeostasis by stimulating Ca 2+ (re)absorption and bone turnover. The 1,25(OH) 2 D 3 analog ZK191784 was recently developed to dissociate the therapeutic immunomodulatory activity from the hypercalcemic side effects of 1,25(OH) 2 D 3 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 Ca 2+ homeostasis and the regulation of Ca 2+ transport proteins in wild‐type (WT) mice and mice lacking the renal epithelial Ca 2+ channel TRPV5 (TRPV5‐/‐). The latter display hypercalciuria, hypervitaminosis D, increased intestinal expression of the epithelial Ca 2+ channel TRPV6, the Ca 2+ ‐binding protein calbindin‐D 9K , and intestinal Ca 2+ hyperabsorption. ZK191784 normalized the Ca 2+ hyperabsorption and the expression of intestinal Ca 2+ transport proteins in TRPV5‐/‐ mice. Furthermore, the compound decreased intestinal Ca 2+ absorption in WT mice and reduced 1,25(OH) 2 D 3 ‐dependent 45 Ca 2+ uptake by Caco‐2 cells, substantiating a 1,25(OH) 2 D 3 ‐antagonistic action of ZK191784 in the intestine. ZK191784 increased renal TRPV5 and calbindin‐D 28K expression and decreased urine Ca 2+ excretion in WT mice. Both 1,25(OH) 2 D 3 and ZK191784 enhanced transcellular Ca 2+ transport in primary cultures of rabbit connecting tubules and cortical collecting ducts, indicating a 1,25(OH) 2 D 3 ‐agonistic effect in kidney. ZK191784 enhanced bone TRPV6 mRNA levels and 1,25(OH) 2 D 3 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) 2 D 3 ligand displaying a unique tissue‐specific profile when administered in vivo . Because ZK191784 acts as an intestine‐specific 1,25(OH) 2 D 3 antagonist, this compound will be associated with less hypercalcemic side effects compared with the 1,25(OH) 2 D 3 analogs currently used in clinical practice.—Nijenhuis, T., van der Eerden, B. C. J., Zügel, U., Steinmeyer, A., Weinans, H., Hoenderop, J. G. J., van Leeuwen, J. P. T. M., Bindels, R. J. M. The novel vitamin D analog ZK191784 as an intestine‐specific vitamin D antagonist. FASEB J. 20, E1589 –E1598 (2006)