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Studies on the mode of action of vitamin D XXXVII 1α-hydroxyvitamin D3: A long-acting 1,25-dihydroxyvitamin D3 analog (1983)

Walters, Marian R. ; Hunziker, Willi ; Bishop, June E. ; [et al.]

Springer

Calcified tissue international 35 (1983), S. 372-375

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ISSN: 1432-0827

Keywords: 1α-Hydroxyvitamin D3 ; Vitamin D3 ; 1,25-Dihydroxyvitamin D3 receptors

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Medicine , Physics

Notes: Summary This study was undertaken to determine whether 1α-hydroxyvitamin D3 [1α(OH)D3] administration to chicks in vivo results in 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] intestinal receptor occupancy and to compare the temporal characteristics of the physiological effects of 1α(OH)D3 and 1,25(OH)2D3 for several days after a single dose of either steroid. Occupied 1,25(OH)2D3 receptors of the chick duodenal mucosa were measured by the recently developed exchange assay procedure [J Biol Chem (1980) 255:9534–9537]. Within 2 h after 1α(OH)D3 injection in rachitic chicks, there was a significant elevation of 1,25(OH)2D3 receptor occupancy in the intestinal mucosa. This observation represents the first direct confirmation that this synthetic analog exerts biological effects through occupancy of 1,25(OH)2D3 receptors. Serum 1,25(OH)2D3 levels reached a 3-fold higher peak after 1,25(OH)2D3 injection (3.25 nmol) than after 1α(OH)D3 injection (6.5 nmol); further, after 1α(OH)D3 injection the peak was delayed by 2–4 h. However, serum 1,25(OH)2D3 levels remained elevated for only 3–6 h after 1,25(OH)2D3, compared to 48 h after 1α(OH)D3 injection. Occupied 1,25(OH)2D3 receptor levels paralleled serum 1,25(OH)2D3 levels at all times after administration of either steroid. At 24 h, duodenal vitamin D-dependent calcium binding protein (CaBP) levels were similarly elevated in both treatment groups, but by 48 and 72 h after 1α(OH)D3 administration CaBP and serum Ca2+, respectively, were more significantly elevated. These data confirm that 1α(OH)D3 induces its major biological effects via intracellular 1,25(OH)2D3 receptors and reinforce the concept that 25-hydroxylation is a prerequisite for these effects. These results also suggest that 1α(OH)D3 may become useful in the therapy for sustained treatment of vitamin D deficiency diseases.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/BF02405061

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The vitamin D endocrine system: Manipulation of structure-function relationships to provide opportunities for development of new cancer chemopreventive and immunosuppressive agents (1995)

Norman, Anthony W.

New York, N.Y. : Wiley-Blackwell

Journal of Cellular Biochemistry 59 (1995), S. 218-225

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ISSN: 0730-2312

Keywords: Breast cancer ; immunosuppressant ; leukemia ; psoriasis ; 1α,25(OH)2D3 ; vitamin D ; Life and Medical Sciences ; Cell & Developmental Biology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Chemistry and Pharmacology , Medicine

Notes: Biological responses mediated by vitamin D occur as a consequence of the integrated actions of the vitamin D endocrine system. The vitamin D endocrine system is characterized by the sequential two-step metabolism of vitamin D to 1α,25(OH)2D3 by the liver and kidney, and by the ability to generate biological responses in over 30 target tissues through nuclear receptor (nVDR) regulation of gene transcription and nongenomic pathways. It is now clear that the vitamin D endocrine system embraces many more target tissues than simply the intestine, bone and kidney. Notable additions to this list of tissues containing the nVDR include pancreatic B cells, pituitary gland, breast tissue, placenta, lymphocytes, keratinocytes, colon, and prostate, as well as many cancer cell lines. In addition to the classical actions of 1α,25(OH)2D3 on mediating calcium homeostasis, this seco steroid has been identified as a potent stimulator of cell differentiation as well as an inhibitor of proliferation.Over the past decade at least 400 analogs of 1α,25(OH)2D3 have been chemically synthesized and their biological properties systematically explored in a variety of assays which quantified both their calcemic effects and cell differentiating potential. The objective has been to identify new analogs devoid of the classical calcemic consequences of high does of 1α,25(OH)2D3, namely hypercalcemia, soft tissue calcification and nephrocalcinosis. As a consequence, several analogs of 1α,25(OH)2D3 have recently been identified and are discussed in this paper for consideration as possible chemotherapeutic agents for acute promyelocytic leukemia, breast, colon, and prostate cancer, or as immunosuppressive agents with possible beneficial structure-activity profiles for use in cardiac allografts, autommune graft rejection, lupus erthematosus and psoriasis.

Additional Material: 6 Ill.