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

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-3H-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.

• Authors: Kazuhiro Shiizaki, Naohiko Hayakawa, Ikuo Imazeki, Ikuji Hatamura, Tadashi Okada, Shigeo Negi, Toshifumi Sakaguchi, Takashi Shigematsu, Tadao Akizawa
• Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association (Nephrol Dial Transplant) Vol. 22 Issue 4 Pg. 1078-86 (Apr 2007) ISSN: 0931-0509 [Print] England
• PMID: 17234669 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Parathyroid Hormone
• Receptors, Calcitriol
• Vitamin D
• Calcitriol
• maxacalcitol
• Calcium

Topics

• Animals
• Antineoplastic Agents (administration & dosage, metabolism)
• Apoptosis (physiology)
• Calcitriol (administration & dosage, analogs & derivatives, metabolism)
• Calcium (pharmacology)
• Disease Models, Animal
• Hyperparathyroidism, Secondary (drug therapy)
• Injections
• Male
• Parathyroid Glands (cytology, metabolism)
• Parathyroid Hormone (physiology)
• Protein Binding
• Rats
• Rats, Sprague-Dawley
• Receptors, Calcitriol (metabolism)
• Uremia (metabolism)
• Vitamin D (pharmacology)