Increased biological potency of hexafluorinated analogs of 1,25-dihydroxyvitamin D3 on bovine parathyroid cells.
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.
Imanishi
Y
Y
Department of Biochemistry, Osaka City University Medical School, Osaka, Japan.
Inaba
M
M
Seki
H
H
Koyama
H
H
Nishizawa
Y
Y
Morii
H
H
Otani
S
S
D000818:Animals; D001711:Biotransformation; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000096:biosynthesis; D007700:Kinetics; D009955:Ornithine Decarboxylase / Q000378:metabolism; D010280:Parathyroid Glands / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010281:Parathyroid Hormone / Q000378:metabolism*; D013936:Thymidine / Q000378:metabolism; D005466:Fluorocarbons
D002117:Calcitriol; D004247:DNA; D009955:Ornithine Decarboxylase; D010281:Parathyroid Hormone; D013936:Thymidine; C040488:26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3; D005466:Fluorocarbons