Increased biological potency of hexafluorinated analogs of 1,25-dihydroxyvitamin D 3 on bovine parathyroid cells

Abstract

1,25-dihydroxyvitamin D 3 (1,25-(OH) 2D 3) 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) 2D 3 and its hexafluorinated analog, 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D 3 (26,27-F 6-1,25-(OH) 2D 3), on parathyroid cells. The 1,25-(OH) 2D 3 and 26,27-F 6-1,25-(OH) 2D 3 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-F 6-1,25-(OH) 2D 3 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-F 6-1,25-(OH) 2D 3 metabolism in parathyroid cells in vitro elucidated its slower degradation than that of 1,25-(OH) 2D 3. After 48 h of incubation with [1 β- 3H]26,27-F 6-1,25-(OH) 2D 3, two HPLC peaks, one for [1 β- 3H]26,27-F 6-1,25-(OH) 2D 3, and a second larger peak for [1 β- 3H]26,27-F 6-1,23(S),25-(OH) 3D 3, were detected. No metabolites were detected after the same period of incubation with 1,25-(OH) 2[26,27- 3H]D 3. We observed that 26,27-F 6-1,23(S),25-(OH) 3D 3 was as potent as 1,25-(OH) 2D 3 in inhibiting the proliferation of parathyroid cells. Data suggest that the greater biological activity of 26,27-F 6-1,25-(OH) 2D 3 is explained by its slower metabolisms and by the retention of the biological potency of 26,27-F 6-1,25-(OH) 2D 3 even after 23(S)-hydroxylation.