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

Tom Nijenhuis^*, Bram C. J. van der Eerden, Ulrich Zügel, Andreas Steinmeyer, Harrie Weinans, Joost G. J. Hoenderop^*, Johannes P. T. M. van Leeuwen and René J. M. Bindels^*,1

^* Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; Department of

Internal Medicine and

Orthopedics, Erasmus Medical Centre Rotterdam, The Netherlands; and

Research Business Area Medical Chemistry, Schering AG, Berlin, Germany

¹Correspondence: 286 Cell Physiology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, Nijmegen, NL-6500 HB, The Netherlands. E-mail: r.bindels{at}ncmls.ru.nl

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.—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.