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Volume 272, Number 22, Issue of May 30, 1997 pp. 14115-14119
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

1alpha ,25-Dihydroxyvitamin D3-24-Hydroxylase (CYP24) Hydroxylates the Carbon at the End of the Side Chain (C-26) of the C-24-fluorinated Analog of 1alpha ,25-Dihydroxyvitamin D3

(Received for publication, October 22, 1996, and in revised form, March 17, 1997)

Yoichi Miyamoto Dagger § , Toshimasa Shinki Dagger , Keiko Yamamoto § , Yoshihiko Ohyama par , Hiroshi Iwasaki , Ryuzo Hosotani , Toshio Kasama , Hiroaki Takayama ** , Sachiko Yamada § and Tatsuo Suda Dagger

From the Dagger  Department of Biochemistry, School of Dentistry, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142, the § Division of Molecular Biology, Institute for Medical and Dental Engineering, Tokyo Medical and Dental University, 2-3-10 Surugadai, Kanda, Chiyoda-ku, Tokyo 101, the  Tsukuba Research Laboratory, NOF Corporation, 5-10 Tokodai, Tsukuba-shi, Ibaraki 300-21, the par  Graduate Department of Gene Science, Faculty of Science, Hiroshima University, 1-3-1 Kagamiya, Higashi-Hiroshima, Hiroshima 724, and the ** Faculty of Pharmaceutical Sciences, Teikyo University, Sagamiko, Kanagawa 199-01, Japan

The sequential oxidation and cleavage of the side chain of 1alpha ,25-dihydroxyvitamin D3 (1alpha ,25(OH)2D3) initiated by the hydroxylation at C-24 is considered to be the major pathway of this hormone in the target cell metabolism. In this study, we examined renal metabolism of a synthetic analog of 1alpha ,25(OH)2D3, 24,24-difluoro-1alpha ,25-dihydroxyvitamin D3 (F2-1alpha ,25(OH)2D3), C-24 of which was designed to resist metabolic hydroxylation. When kidney homogenates prepared from 1alpha ,25(OH)2D3-supplemented rats were incubated with F2-1alpha ,25(OH)2D3, it was mainly converted to a more polar metabolite. We isolated and unequivocally identified the metabolite as 24,24-difluoro-1alpha ,25,26-trihydroxyvitamin D3 (F2-1alpha ,25,26(OH)3D3) by ultraviolet absorption spectrometry, frit-fast atom bombardment liquid chromatography/mass spectroscopy analysis, and direct comparison with chemically synthesized F2-1alpha ,25,26(OH)3D3. Metabolism of F2-1alpha ,25(OH)2D3 into F2-1alpha ,25,26(OH)3D3 by kidney homogenates was induced by the prior administration of 1alpha ,25(OH)2D3 into rats. The C-24 oxidation of 1alpha ,25(OH)2D3 in renal homogenates was inhibited by F2-1alpha ,25(OH)2D3 in a concentration-dependent manner. Moreover, F2-1alpha ,25,26(OH)3D3 was formed in ROS17/2.8 cells transfected with a plasmid expressing 1alpha ,25(OH)2D3-24-hydroxylase (CYP24) but not in the cells transfected with that expressing vitamin D3-25-hydroxylase (CYP27) or containing inverted CYP27 cDNA. These results show that CYP24 catalyzes not only hydroxylation at C-24 and C-23 of 1alpha ,25(OH)2D3 but also at C-26 of F2-1alpha ,25(OH)2D3, indicating that this enzyme has a broader substrate specificity of the hydroxylation sites than previously considered.


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