Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery

We have developed an in vitro system to easily examine the affinity for vitamin D receptor (VDR) and CYP24A1-mediated metabolism as two methods of assessing vitamin D derivatives. Vitamin D derivatives with high VDR affinity and resistance to CYP24A1-mediated metabolism could be good therapeutic age...

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Autores principales:	Kaori Yasuda, Miyu Nishikawa, Hiroki Mano, Masashi Takano, Atsushi Kittaka, Shinichi Ikushiro, Toshiyuki Sakaki
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	vitamin D vitamin D receptor split luciferase-based biosensor CYP24A1-dependent metabolism CYP27B1 rickets Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/04cd20e66f75432db5ef07d3d6fde473
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spelling	oai:doaj.org-article:04cd20e66f75432db5ef07d3d6fde4732021-11-11T17:16:13ZDevelopment of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery10.3390/ijms2221118391422-00671661-6596https://doaj.org/article/04cd20e66f75432db5ef07d3d6fde4732021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11839https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067We have developed an in vitro system to easily examine the affinity for vitamin D receptor (VDR) and CYP24A1-mediated metabolism as two methods of assessing vitamin D derivatives. Vitamin D derivatives with high VDR affinity and resistance to CYP24A1-mediated metabolism could be good therapeutic agents. This system can effectively select vitamin D derivatives with these useful properties. We have also developed an in vivo system including a <i>Cyp27b1-</i>gene-deficient rat (a type I rickets model), a <i>Vdr</i>-gene-deficient rat (a type II rickets model), and a rat with a mutant <i>Vdr</i> (R270L) (another type II rickets model) using a genome editing method. For <i>Cyp27b1</i>-gene-deficient and <i>Vdr</i> mutant (R270L) rats, amelioration of rickets symptoms can be used as an index of the efficacy of vitamin D derivatives. <i>Vdr-</i>gene-deficient rats can be used to assess the activities of vitamin D derivatives specialized for actions not mediated by VDR. One of our original vitamin D derivatives, which displays high affinity VDR binding and resistance to CYP24A1-dependent metabolism, has shown good therapeutic effects in <i>Vdr</i> (R270L) rats, although further analysis is needed.Kaori YasudaMiyu NishikawaHiroki ManoMasashi TakanoAtsushi KittakaShinichi IkushiroToshiyuki SakakiMDPI AGarticlevitamin Dvitamin D receptorsplit luciferase-based biosensorCYP24A1-dependent metabolismCYP27B1ricketsBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11839, p 11839 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	vitamin D vitamin D receptor split luciferase-based biosensor CYP24A1-dependent metabolism CYP27B1 rickets Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	vitamin D vitamin D receptor split luciferase-based biosensor CYP24A1-dependent metabolism CYP27B1 rickets Biology (General) QH301-705.5 Chemistry QD1-999 Kaori Yasuda Miyu Nishikawa Hiroki Mano Masashi Takano Atsushi Kittaka Shinichi Ikushiro Toshiyuki Sakaki Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery
description	We have developed an in vitro system to easily examine the affinity for vitamin D receptor (VDR) and CYP24A1-mediated metabolism as two methods of assessing vitamin D derivatives. Vitamin D derivatives with high VDR affinity and resistance to CYP24A1-mediated metabolism could be good therapeutic agents. This system can effectively select vitamin D derivatives with these useful properties. We have also developed an in vivo system including a <i>Cyp27b1-</i>gene-deficient rat (a type I rickets model), a <i>Vdr</i>-gene-deficient rat (a type II rickets model), and a rat with a mutant <i>Vdr</i> (R270L) (another type II rickets model) using a genome editing method. For <i>Cyp27b1</i>-gene-deficient and <i>Vdr</i> mutant (R270L) rats, amelioration of rickets symptoms can be used as an index of the efficacy of vitamin D derivatives. <i>Vdr-</i>gene-deficient rats can be used to assess the activities of vitamin D derivatives specialized for actions not mediated by VDR. One of our original vitamin D derivatives, which displays high affinity VDR binding and resistance to CYP24A1-dependent metabolism, has shown good therapeutic effects in <i>Vdr</i> (R270L) rats, although further analysis is needed.
format	article
author	Kaori Yasuda Miyu Nishikawa Hiroki Mano Masashi Takano Atsushi Kittaka Shinichi Ikushiro Toshiyuki Sakaki
author_facet	Kaori Yasuda Miyu Nishikawa Hiroki Mano Masashi Takano Atsushi Kittaka Shinichi Ikushiro Toshiyuki Sakaki
author_sort	Kaori Yasuda
title	Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery
title_short	Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery
title_full	Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery
title_fullStr	Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery
title_full_unstemmed	Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery
title_sort	development of in vitro and in vivo evaluation systems for vitamin d derivatives and their application to drug discovery
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/04cd20e66f75432db5ef07d3d6fde473
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Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery

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