Structure-function studies of 1,25-dihydroxyvitamin D3 and the vitamin D endocrine system. 1,25-Dihydroxy-pentadeuterio-previtamin D3 (as a 6-s-cis analog) stimulates nongenomic but not genomic biological responses
1993
Norman, A.W. | Okamura, W.H. | Farach-Carson, M.C. | Allewaert, K. | Branisteanu, D. | Nemere, I. | Muralidharan, K.R. | Bouillon, R.
The hormone 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) generates biological responses via both genomic and nongenonic mechanisms. This article addresses activity differences between the 6-s-trans (extended) and the 6-s-cis (steroid-like) conformation of 1,25-(OH)2D3 to initiate these responses. Because of facile interconversion of the 6-s-trans and 6-s-cis conformers of 1,25-(OH)2D3, kinetically competent amounts of both conformers exist to interact with any potential receptors for 1,25-(OH)2D3. We have chemically synthesized 1,25-(OH)2-9,14,19,19, 19-pentadeuterio-pre-D3 (1,25-(OH)2-d5-pre-D3), an analog of the 6-s-cis conformation of 1,25-(OH)2D3. We found that 1,25-(OH)2-d5-pre-D3 and 1,25-(OH)2D3 were equivalently active in two nongenomic systems (transcaltachia as measured in the perfused chick intestine and (45)Ca2+ uptake through voltage-gated Ca2+ channels in ROS 17/2.8 cells). 1,25-(OH)2-d5-pre-D3 was significantly less active both in binding in vitro to the plasma vitamin D-binding (7%) and to the chick (10%) and pig (4%) intestinal nuclear 1,25-(OH)2D3 receptors generating genomic biological responses in vivo (induction of plasma levels of osteocalcin, less than 5%) or in cultured cells (inhibition of HL-60 cell differentiation, less than 5%; inhibition of MG-63 proliferation, less than 2%; and induction of osteocalcin, less than 2%. These results suggest that the genomic and nongenomic responses are mediated by separate receptors. Further, the 6-s-cis form (steroid-like conformation) of the natural hormone, 1,25-(OH)2D3, may be selectively responsible for its nongenomic function(s).
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