BIOLOGIC ACTIVITY OF DIHYDROXYLATED 19-NOR-(PRE)VITAMIN-D(3)

Vitamin D3 and its hydroxylated metabolites are normally in thermal eq uilibrium with their previtamin D isomers. To evaluate the biologic ac tivity of 1alpha,25-dihydroxyprevitamin D3, we synthesized 19-nor anal ogs of 1alpha,25-dihydroxy(pre)vitamin D3 because the absence of a C19 methylene group prevents the isomerization of these analogs. The affi nity of 1alpha,25-(OH)2D3-19-nor-D3 for the intestinal vitamin D recep tor and plasma vitamin D binding protein was mildly decreased [30 and 20% of the affinity of 1alpha,25-(OH)2D3, respectively], but the affin ity of 1alpha,25-(OH)2-19-nor-previtamin D3 was only 1 and 6% of that of 1alpha,25-(OH)2D3 for the receptor and DBP, respectively. The in vi tro effects on human promyeloid leukemia (HL-60 cell) differentiation and osteocalcin secretion by human osteosarcoma (MG-63) cells by 1alph a,25-(OH)2-19-nor-D3 were nearly identical to those of 1alpha-25-(OH)2 D3, whereas 19-nor-previtamin D3 showed poor activity (2%). The in viv o calcemic effects of both analogs, studied in vitamin D-deficient chi cks treated for 10 consecutive days with the analogs, showed no activi ty of the previtamin D3 analog and reduced calcemic effects (less-than -or-equal-to 10%) of 1alpha,25-(OH)2-19-nor-D3. We conclude that the p revitamin D form of 1alpha,25-(OH)2D3 has lost most of its biologic ac tivity in vitro and in vivo.