title: 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.affiliation: Division of Nephrology and Blood Purification Medicine, Wakayama Medical University, Wakayama 641-0012, Japan. shiizaki@wakayama-med.ac.jp
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Shiizaki
authors.forename: Naohiko
authors.initials: N
authors.lastname: Hayakawa
authors.forename: Ikuo
authors.initials: I
authors.lastname: Imazeki
authors.forename: Ikuji
authors.initials: I
authors.lastname: Hatamura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Okada
authors.forename: Shigeo
authors.initials: S
authors.lastname: Negi
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Shigematsu
authors.forename: Tadao
authors.initials: T
authors.lastname: Akizawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology; D002117:Calcitriol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D004195:Disease Models, Animal; D006962:Hyperparathyroidism, Secondary / Q000188:drug therapy; D007267:Injections; D008297:Male; D010280:Parathyroid Glands / Q000166:cytology / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000502:physiology; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014511:Uremia / Q000378:metabolism; D014807:Vitamin D / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D010281:Parathyroid Hormone; D018167:Receptors, Calcitriol; D014807:Vitamin D; D002117:Calcitriol; C051883:maxacalcitol; D002118:Calcium