Ishizuka S, Miura D, Ozono K, Chokki M, Mimura H, Norman A W
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.
Endocrinology. 2001 Jan;142(1):59-67. doi: 10.1210/endo.142.1.7925.
The vitamin D analog, (23S)-25-dehydro-1alpha-hydroxyvitamin D(3)-26,23-lactone (TEI-9647), is an antagonist of the 1alpha,25-dihydroxyvitamin D(3) [1alpha,25(OH)(2)D(3)] nuclear receptor (VDR)-mediated differentiation of human leukemia (HL-60) cells. To clarify whether TEI-9647 could function as an antagonist of 1alpha,25(OH)(2)D(3) 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 1alpha,25(OH)(2)D(3). TEI-9647 (50 microgram/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 microgram/kg 1alpha,25(OH)(2)D(3) after 24 h, but not after 8 h. With respect to serum PTH levels, the administration of either TEI-9647, 50 microgram/kg, or 1alpha,25(OH)(2)D(3), 0.25 microgram/kg, began to decrease the circulating levels by 4 h, which reached a nadir 24 h after administration. But, when TEI-9647 and 1alpha,25(OH)(2)D(3) were simultaneously administered to -D rats, the TEI-9647 dose-dependently reversed the inhibition of PTH secretion caused by 1alpha,25(OH)(2)D(3), 0.25 microgram/kg, at 8 and 24 h after the treatment. In separate experiments, the daily iv administration of 20 microgram/kg of TEI-9647 alone to +D rats for 2 weeks resulted in no significant changes in the prevailing serum Ca(2+) concentration. But doses of 1-20 microgram/kg of TEI-9647 in combination with 0.5 microgram/kg of 1alpha,25(OH)(2)D(3), for 2 weeks, dose-dependently and significantly suppressed the serum calcium concentration increase caused by the 1alpha,25(OH)(2)D(3). Collectively, these results show that TEI-9647 acting alone displays in vivo weak agonistic actions, but when administered in combination with 1alpha,25(OH)(2)D(3), is a potent antagonist of three genomic-mediated calcium metabolism parameters. We conclude that TEI-9647 can also function as an antagonist of 1alpha,25(OH)(2)D(3) in vivo in the rat.
维生素D类似物（23S）-25-脱氢-1α-羟基维生素D3-26,23-内酯（TEI-9647）是1α,25-二羟基维生素D3[1α,25(OH)2D3]核受体（VDR）介导的人白血病（HL-60）细胞分化的拮抗剂。为了阐明TEI-9647在体内是否能作为1α,25(OH)2D3的拮抗剂，我们在维生素D缺乏（-D）大鼠中研究了单剂量TEI-9647对由1α,25(OH)2D3调节的钙代谢若干参数的影响。单独作用的TEI-9647（50微克/千克静脉注射）仅在8小时时轻微但显著地刺激肠道钙转运（ICA）和骨钙动员（BCM），但在24小时时未出现这种情况。相反，在24小时后，TEI-9647剂量依赖性地抑制了静脉注射0.25微克/千克1α,25(OH)2D3所刺激的ICA和BCM，但在8小时后未出现这种抑制作用。关于血清甲状旁腺激素（PTH）水平，给予50微克/千克的TEI-9647或0.25微克/千克的1α,25(OH)2D3后，4小时开始降低循环水平，给药后24小时达到最低点。但是，当将TEI-9647和1α,25(OH)2D3同时给予-D大鼠时，在治疗后8小时和24小时，TEI-9647剂量依赖性地逆转了由0.25微克/千克1α,25(OH)2D3引起的PTH分泌抑制。在单独的实验中，每天给+D大鼠静脉注射20微克/千克的TEI-9647，持续2周，对当时的血清Ca2+浓度没有显著影响。但是，1 - 20微克/千克的TEI-9647与0.5微克/千克的1α,25(OH)2D3联合使用2周，剂量依赖性且显著地抑制了由1α,25(OH)2D3引起的血清钙浓度升高。总体而言，这些结果表明，单独作用的TEI-9647在体内表现出微弱的激动作用，但与1α,25(OH)2D3联合给药时，是三种基因组介导的钙代谢参数的有效拮抗剂。我们得出结论，TEI-9647在大鼠体内也可作为1α,25(OH)2D3的拮抗剂。
