Increased biological potency of hexafluorinated analogs of 1,25-dihydroxyvitamin D3 on bovine parathyroid cells |
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Authors: | Imanishi Y Inaba M Seki H Koyama H Nishizawa Y Morii H Otani S |
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Affiliation: | a Department of Biochemistry, Osaka City University Medical School, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545, Japan b Second Department of Internal Medicine, Osaka City University Medical School, 1-4-3, Asahi-Machi, Abeno-ku, Osaka, 545, Japan c Sumitomo Pharmaceuticals Research Center, Sumitomo Pharmaceuticals Co., Ltd, Osaka, 554, Japan |
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Abstract: | 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) is known to be involved in regulating the proliferation of parathyroid cells and PTH synthesis through reactions involving its nuclear receptor. We evaluated the effects of 1,25-(OH)2D3 and its hexafluorinated analog, 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 (26,27-F6-1,25-(OH)2D3), on parathyroid cells. The 1,25-(OH)2D3 and 26,27-F6-1,25-(OH)2D3 each inhibited [3H]thymidine incorporation and ornithine decarboxylase (ODC) activity, which is important in cell proliferation, in primary cultured bovine parathyroid cells. The inhibitory effect of 26,27-F6-1,25-(OH)2D3 on PTH secretion from parathyroid cells was significantly more potent than that of 1,25-(OH)2D 3 between 10−11 M and 10−8 M. Study of 26,27-F6-1,25-(OH)2D3 metabolism in parathyroid cells in vitro elucidated its slower degradation than that of 1,25-(OH)2D3. After 48 h of incubation with [1β-3H]26,27-F6-1,25-(OH)2D3, two HPLC peaks, one for [1β-3H]26,27-F6-1,25-(OH)2D3, and a second larger peak for [1β-3H]26,27-F6-1,23(S),25-(OH)3D3, were detected. No metabolites were detected after the same period of incubation with 1,25-(OH)2[26,27-3H]D3. We observed that 26,27-F6-1,23(S),25-(OH)3D3 was as potent as 1,25-(OH)2D3 in inhibiting the proliferation of parathyroid cells. Data suggest that the greater biological activity of 26,27-F6-1,25-(OH)2D3 is explained by its slower metabolisms and by the retention of the biological potency of 26,27-F6-1,25-(OH)2D3 even after 23(S)-hydroxylation. |
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