TY - JOUR
T1 - Binding of highly concentrated maxacalcitol to the nuclear vitamin D receptors of parathyroid cells
AU - Shiizaki, Kazuhiro
AU - Hayakawa, Naohiko
AU - Imazeki, Ikuo
AU - Hatamura, Ikuji
AU - Okada, Tadashi
AU - Negi, Shigeo
AU - Sakaguchi, Toshifumi
AU - Shigematsu, Takashi
AU - Akizawa, Tadao
N1 - Funding Information:
Acknowledgements. This study was funded by Chugai Pharmaceutical Co. Ltd, Tokyo, Japan and was carried out in Wakayama Medical University, Japan and Chugai Pharmaceutical Co. Ltd, Japan.
PY - 2007/4/1
Y1 - 2007/4/1
N2 - Background. Injection of maxacalcitol (OCT) directly into the parathyroid gland (PTG) is a clinically safe and effective treatment for advanced secondary hyperparathyroidism (A-SHPT) resistant to conventional medical treatment. In the present study, the degree of nuclear localization of directly injected OCT in parathyroid cells (PTC) was investigated by microautoradiography (mARG) in a model of A-SHPT. Methods. The 5/6 nephrectomized Sprague-Dawley rats were fed a high-phosphate and low-calcium diet for 8 weeks and consequently the level of vitamin D receptor (VDR) in their PTC severely decreased. The bilateral PTG were surgically exposed and only the left gland were directly injected with 3H-OCT (DI-3H-OCT). The time course of the changes in both radioactivity and localization of 3H-OCT in the bilateral glands was analysed using a bioimaging analyser system and mARG, respectively. A very high dose of unlabelled calcitriol was administered intravenously (IV-1,25D3) prior to DI-3H-OCT, as a competitive study. Results. Peak radioactivity levels in the directly injected and intact PTG occured immediately and 1 h, respectively, after DI-3 H-OCT, and the difference was about 50-fold higher in the treated gland. The of mARG showed a marked concentration of silver grains in the nuclei of PTC in the gland treated with DI-3H-OCT and that concentration was significantly suppressed by IV-1,25D3. Conclusions. Direct injection of OCT into the PTG enables the administration of the highly concentrated drug for specific binding to nuclear vitamin D binding sites, including VDR of PTC, which markedly suppresses the parathyroid hormone, improves the response to calcium and vitamin D and induces apoptosis in PTC.
AB - Background. Injection of maxacalcitol (OCT) directly into the parathyroid gland (PTG) is a clinically safe and effective treatment for advanced secondary hyperparathyroidism (A-SHPT) resistant to conventional medical treatment. In the present study, the degree of nuclear localization of directly injected OCT in parathyroid cells (PTC) was investigated by microautoradiography (mARG) in a model of A-SHPT. Methods. The 5/6 nephrectomized Sprague-Dawley rats were fed a high-phosphate and low-calcium diet for 8 weeks and consequently the level of vitamin D receptor (VDR) in their PTC severely decreased. The bilateral PTG were surgically exposed and only the left gland were directly injected with 3H-OCT (DI-3H-OCT). The time course of the changes in both radioactivity and localization of 3H-OCT in the bilateral glands was analysed using a bioimaging analyser system and mARG, respectively. A very high dose of unlabelled calcitriol was administered intravenously (IV-1,25D3) prior to DI-3H-OCT, as a competitive study. Results. Peak radioactivity levels in the directly injected and intact PTG occured immediately and 1 h, respectively, after DI-3 H-OCT, and the difference was about 50-fold higher in the treated gland. The of mARG showed a marked concentration of silver grains in the nuclei of PTC in the gland treated with DI-3H-OCT and that concentration was significantly suppressed by IV-1,25D3. Conclusions. Direct injection of OCT into the PTG enables the administration of the highly concentrated drug for specific binding to nuclear vitamin D binding sites, including VDR of PTC, which markedly suppresses the parathyroid hormone, improves the response to calcium and vitamin D and induces apoptosis in PTC.
KW - 22-oxacalcitriol
KW - 5/6 nephrectomy
KW - Parathyroid gland
KW - Renal osteodistrophy
KW - Secondary hyperparathyroidism
KW - Vitamin D receptor
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U2 - 10.1093/ndt/gfl713
DO - 10.1093/ndt/gfl713
M3 - Article
C2 - 17234669
AN - SCOPUS:34047191422
SN - 0931-0509
VL - 22
SP - 1078
EP - 1086
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 4
ER -