Metabolism and Action of 25-Hydroxy-19-nor-Vitamin D3 in Human Prostate Cells

Eiji Munetsuna, Atsushi Kittaka, Tai C. Chen, Toshiyuki Sakaki

研究成果: Conference contribution

1 引用 (Scopus)

抜粋

Since the discovery of 1α,25(OH)2D3 in the early 1970s, it has been widely accepted that this metabolite is responsible for the biological actions of vitamin D. Likewise, we have assumed that 25(OH)-19-nor-D3-dependent growth inhibition of human prostate PZ-HPV-7 cells was the result of its subsequent conversion to 1α,25(OH)2-19-nor-D3, catalyzed by CYP27B1 within the prostate cells. However, further in vitro studies in a reconstituted system using recombinant CYP27B1 revealed that 25(OH)-19-nor-D3 was hardly converted to 1α,25(OH)2-19-nor-D3 by the enzyme. The kinetic analysis of 1α-hydroxylation of 25(OH)D3 and 25(OH)-19-nor-D3 demonstrated that the kcat/Km for 25(OH)-19-nor-D3 is less than 0.1% of that for 25(OH)D3. When 25(OH)-19-nor-D3 was added to cultured PZ-HPV-7 cells, eight metabolites were detected, while no 1α,25(OH)2-19-nor-D3 was found. In addition, the time course of VDR translocation into the nucleus induced by 100 nM 25(OH)-19-nor-D3, and the subsequent transactivation of CYP24A1 gene were almost identical to those induced by 1 nM 1α,25(OH)2-19-nor-D3. These results strongly suggest that 25(OH)-19-nor-D3 binds directly to VDR as a ligand to transport VDR into the nucleus to induce CYP24A1 gene transactivation. Furthermore, knockdown of CYP27B1 gene did not affect the antiproliferative activity of 25(OH)-19-nor-D3, whereas VDR knockdown attenuated the effect, suggesting that the antiproliferative activity of 25(OH)-19-nor-D3 is VDR dependent but CYP27B1 independent. Finally, our recent studies using the same cell line demonstrate that 25(OH)D3 can act as a VDR agonist to induce gene transactivation. These findings suggest that vitamin D analogs without 1α-hydroxyl group could be developed as drugs for osteoporosis or cancer treatment.

元の言語English
ホスト出版物のタイトルVitamin D Hormone, 2016
編集者Gerald Litwack
出版者Academic Press Inc.
ページ357-377
ページ数21
ISBN(印刷物)9780128048245
DOI
出版物ステータスPublished - 01-01-2016

出版物シリーズ

名前Vitamins and Hormones
100
ISSN(印刷物)0083-6729

    フィンガープリント

All Science Journal Classification (ASJC) codes

  • Physiology
  • Endocrinology

これを引用

Munetsuna, E., Kittaka, A., Chen, T. C., & Sakaki, T. (2016). Metabolism and Action of 25-Hydroxy-19-nor-Vitamin D3 in Human Prostate Cells. : G. Litwack (版), Vitamin D Hormone, 2016 (pp. 357-377). (Vitamins and Hormones; 巻数 100). Academic Press Inc.. https://doi.org/10.1016/bs.vh.2015.10.009