Increased biological potency of hexafluorinated analogs of 1,25-dihydroxyvitamin D3 on bovine parathyroid cells

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 70; no. 4-6; pp. 243 - 248
• Main Authors: IMANISHI, Y, INABA, M, SEKI, H, KOYAMA, H, NISHIZAWA, Y, MORII, H, OTANI, S
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 01.09.1999
• Subjects: Animals; Biological and medical sciences; Biotransformation; Calcitriol - analogs & derivatives; Calcitriol - pharmacokinetics; Calcitriol - pharmacology; Cattle; Cell Division - drug effects; Cells, Cultured; Chromatography, High Pressure Liquid; DNA - biosynthesis; General and cellular metabolism. Vitamins; Kinetics; Medical sciences; Ornithine Decarboxylase - metabolism; Parathyroid Glands - cytology; Parathyroid Glands - drug effects; Parathyroid Glands - physiology; Parathyroid Hormone - metabolism; Pharmacology. Drug treatments; Thymidine - metabolism; Steroid hormone; Cholecalciferol(1,25-dihydroxy); Ox; Metabolism; In vitro; Biological activity; Vertebrata; Mammalia; Vitamin D; Analog; Animal; Parathyroid glands; Artiodactyla; Ungulata
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/s0960-0760(99)00112-0

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)2D3 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 [1beta-3H]26,27-F6-1,25-(OH)2D3, two HPLC peaks, one for [1beta-3H]26,27-F6-1,25-(OH)2D3, and a second larger peak for [1beta-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.