The novel vitamin D analog ZK191784 as an intestine-specific vitamin D antagonist

Vitamin D [1,25(OH) D-2(3)] plays a crucial role in Ca2+ homeostasis by stimulating Ca2+ (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 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)(2)D-3-dependent Ca-45(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 Ca2+ excretion in WT mice. Both 1,25(OH)(2)D-3 and ZK191784 enhanced transcellular Ca2+ 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.