We compared the activation of vitamin D-responsive genes by 24,24-difluorocalcitriol [F2-1 alpha,25(OH)2D3] and 26,26,26,27,27,27-hexafluorocalcitriol [F6-1 alpha,25(OH)2D3] with that by calcitriol [1 alpha,25(OH)2D3] in rat osteoblastic ROB-C26 cells. F2-1 alpha,25(OH)2D3 and F6-1 alpha, 25(OH)2D3 were ten times more potent than 1 alpha,25(OH)2D3 in inducing the expression of 1 alpha, 25(OH)2D3-24-hydroxylase (24-OHase) mRNA 6 h after adding vitamin D compounds. The lower affinity of these two fluorinated analogs compared with that of 1 alpha,25(OH)2D3 for vitamin D binding protein in serum (serum DBP) seemed to be partly involved in their increased ability to activate the 24-OHase gene. A time course study revealed that the expression of the 24-OHase and osteopontin mRNAs in the cells incubated with 1 alpha, 25(OH)2D3 and F2-1 alpha,25(OH)2D3 attained maximal levels at 6 h for 24-OHase mRNA and 18 h for osteopontin mRNA, the both decreased thereafter. On the contrary, F6-1 alpha,25(OH)2D3 increased the expression of 24-OHase and osteopontin exponentially until 72 h. While F2-1 alpha,25(OH)2[1 beta-3H]D3 was catabolized quickly by ROB-C26 cells, F6-1 alpha,25(OH)2[1 beta-3H]D3 was slowly and quantitatively converted into putative 26,26,26,27,27,27-hexafluoro-23S-hydroxy[1 beta-3H]calcitriol (F6-1 alpha,23S,25(OH)3[1 beta-3H]D3). This may explain why the time-course profiles of the accumulation of mRNAs for 24-OHase and osteopontin differed in the cells exposed to the fluorinated analogs. In addition to the longer retention, unknown up-regulating mechanisms appeared to be involved in the exponential activation of the 24-OHase and osteopontin genes induced by F6-1 alpha,25(OH)2D3.
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The vitamin D hormone and its nuclear receptor: molecular actions and disease states.
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