Antagonistic Actions in Vivo of (23S)-25-Dehydro-1alpha-Hydroxyvitamin D(3-)26,23-Lactone on Calcium Metabolism Induced by 1alpha,25-Dihydroxyvitamin D(3).
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.
Ishizuka
S
S
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.
Miura
D
D
Ozono
K
K
Chokki
M
M
Mimura
H
H
Norman
A W
AW
D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism*; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002136:Calcium, Dietary; D004386:Duodenum / Q000502:physiology / Q000503:physiopathology; D018922:HL-60 Cells; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000502:physiology / Q000503:physiopathology; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood*; D014808:Vitamin D Deficiency / Q000378:metabolism* / Q000503:physiopathology
D002136:Calcium, Dietary; D010281:Parathyroid Hormone; C400545:TEI 9647; D014807:Vitamin D; D002117:Calcitriol; D002118:Calcium