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Antagonistic Actions in Vivo of (23S)-25-Dehydro-1-Hydroxyvitamin D_3-26,23-Lactone on Calcium Metabolism Induced by 1,25-Dihydroxyvitamin D₃

Department of Bone and Calcium Metabolism (S.I., M.C., H.M.) and Safety Research Department (D.M.), Teijin Institute for Biomedical Research Instruments, Inc., Tokyo 191-8512, Japan; Department of Environmental Medicine (K.O.), Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka 594-1101, Japan; and Department of Biochemistry and Division of Biomedical Sciences (A.W.N.), University of California, Riverside, California 92521

Address all correspondence and requests for reprints to: Anthony W. Norman, Ph.D., Department of Biochemistry, University of California-Riverside, Riverside, California 92521. E-mail: norman{at}ucrac1.ucr.edu

The vitamin D analog, (23S)-25-dehydro-1-hydroxyvitamin D₃-26,23-lactone (TEI-9647), is an antagonist of the 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells. To clarify whether TEI-9647 could function as an antagonist of 1,25(OH)₂D₃ in vivo, we investigated in vitamin D-deficient (-D) rats the effects of single doses of TEI-9647 on several parameters of calcium metabolism modulated by 1,25(OH)₂D₃. TEI-9647 (50 µg/kg iv) acting alone slightly, but significantly, stimulated intestinal calcium transport (ICA) and bone calcium mobilization (BCM) only at 8 h, but not at 24 h. In contrast, TEI-9647 dose-dependently inhibited ICA and BCM stimulated by an iv dose of 0.25 µg/kg 1,25(OH)₂D₃ after 24 h, but not after 8 h. With respect to serum PTH levels, the administration of either TEI-9647, 50 µg/kg, or 1,25(OH)₂D₃, 0.25 µg/kg, began to decrease the circulating levels by 4 h, which reached a nadir 24 h after administration. But, when TEI-9647 and 1,25(OH)₂D₃ were simultaneously administered to -D rats, the TEI-9647 dose-dependently reversed the inhibition of PTH secretion caused by 1,25(OH)₂D₃, 0.25 µg/kg, at 8 and 24 h after the treatment. In separate experiments, the daily iv administration of 20 µg/kg of TEI-9647 alone to +D rats for 2 weeks resulted in no significant changes in the prevailing serum Ca²⁺ concentration. But doses of 1–20 µg/kg of TEI-9647 in combination with 0.5 µg/kg of 1,25(OH)₂D₃, for 2 weeks, dose-dependently and significantly suppressed the serum calcium concentration increase caused by the 1,25(OH)₂D₃. Collectively, these results show that TEI-9647 acting alone displays in vivo weak agonistic actions, but when administered in combination with 1,25(OH)₂D₃, is a potent antagonist of three genomic-mediated calcium metabolism parameters. We conclude that TEI-9647 can also function as an antagonist of 1,25(OH)₂D₃ in vivo in the rat.

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