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Volume 22
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10.3390/ijms222111839
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Review

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

by
Kaori Yasuda
1,
Miyu Nishikawa
2,
Hiroki Mano
1,
Masashi Takano
3,
Atsushi Kittaka
3,
Shinichi Ikushiro
2 and
Toshiyuki Sakaki
1,*
1
Department of Pharmaceutical Engineering, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu 939-0398, Toyama, Japan
2
Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu 939-0398, Toyama, Japan
3
Faculty of Pharmaceutical Sciences, Teikyo University, Tokyo 173-8605, Japan
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(21), 11839; https://doi.org/10.3390/ijms222111839
Submission received: 1 September 2021 / Revised: 25 October 2021 / Accepted: 26 October 2021 / Published: 31 October 2021
(This article belongs to the Special Issue Novel Strategies in the Development of New Therapies, Drug Substances and Drug Carriers)
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Abstract

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 Cyp27b1-gene-deficient rat (a type I rickets model), a Vdr-gene-deficient rat (a type II rickets model), and a rat with a mutant Vdr (R270L) (another type II rickets model) using a genome editing method. For Cyp27b1-gene-deficient and Vdr mutant (R270L) rats, amelioration of rickets symptoms can be used as an index of the efficacy of vitamin D derivatives. Vdr-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 Vdr (R270L) rats, although further analysis is needed.
Keywords: vitamin D; vitamin D receptor; split luciferase-based biosensor; CYP24A1-dependent metabolism; CYP27B1; rickets; genome editing vitamin D; vitamin D receptor; split luciferase-based biosensor; CYP24A1-dependent metabolism; CYP27B1; rickets; genome editing

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MDPI and ACS Style

Yasuda, K.; Nishikawa, M.; Mano, H.; Takano, M.; Kittaka, A.; Ikushiro, S.; Sakaki, T. Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery. Int. J. Mol. Sci. 2021, 22, 11839. https://doi.org/10.3390/ijms222111839

AMA Style

Yasuda K, Nishikawa M, Mano H, Takano M, Kittaka A, Ikushiro S, Sakaki T. Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery. International Journal of Molecular Sciences. 2021; 22(21):11839. https://doi.org/10.3390/ijms222111839

Chicago/Turabian Style

Yasuda, Kaori, Miyu Nishikawa, Hiroki Mano, Masashi Takano, Atsushi Kittaka, Shinichi Ikushiro, and Toshiyuki Sakaki. 2021. "Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery" International Journal of Molecular Sciences 22, no. 21: 11839. https://doi.org/10.3390/ijms222111839

APA Style

Yasuda, K., Nishikawa, M., Mano, H., Takano, M., Kittaka, A., Ikushiro, S., & Sakaki, T. (2021). Development of In Vitro and In Vivo Evaluation Systems for Vitamin D Derivatives and Their Application to Drug Discovery. International Journal of Molecular Sciences, 22(21), 11839. https://doi.org/10.3390/ijms222111839

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