Binding of highly concentrated maxacalcitol to the nuclear vitamin D receptors of parathyroid cells

Kazuhiro Shiizaki, Naohiko Hayakawa, Ikuo Imazeki, Ikuji Hatamura, Tadashi Okada, Shigeo Negi, Toshifumi Sakaguchi, Takashi Shigematsu, Tadao Akizawa

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6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1078-1086
Number of pages9
JournalNephrology Dialysis Transplantation
Volume22
Issue number4
DOIs
Publication statusPublished - Apr 1 2007

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Keywords

  • 22-oxacalcitriol
  • 5/6 nephrectomy
  • Parathyroid gland
  • Renal osteodistrophy
  • Secondary hyperparathyroidism
  • Vitamin D receptor

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Shiizaki, K., Hayakawa, N., Imazeki, I., Hatamura, I., Okada, T., Negi, S., ... Akizawa, T. (2007). Binding of highly concentrated maxacalcitol to the nuclear vitamin D receptors of parathyroid cells. Nephrology Dialysis Transplantation, 22(4), 1078-1086. https://doi.org/10.1093/ndt/gfl713