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Selective biological response by target organs (intestine, kidney, and bone) to 1,25-dihydroxyvitamin D3 and two analogues.
Cancer Res 1993; 53(17):3935-42CR

Abstract

The hormonally active form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] stimulates biological responses related to calcium homeostasis, cell differentiation, and immunomodulation in many target cells, including leukemic cells. Most of these responses are dependent upon 1 alpha,25(OH)2D3 interaction with a nuclear receptor protein. Structural analogues of 1 alpha,25(OH)2D3 might allow for separation of biological function, avoiding adverse calcemic effects. This report quantitates intestinal calcium absorption, bone calcium resorption, induction of intestinal and renal calcium-binding protein (CaBP), and occupancy of the intestinal and renal nuclear 1 alpha,25(OH)2D3 receptor in vitamin D-deficient chicks after a single dose of 1 alpha,25(OH)2D3, 1 alpha,25-dihydroxyvitamin-16-ene-23-yne-D3 (analogue V), or 22-[m-(dimethylhydroxymethyl)phenyl]-23,24,25,26,27- pentanor-1 alpha-hydroxy-vitamin D3 (analogue EV). The interaction of these compounds with chick intestinal nuclear 1 alpha,25(OH)2D3 receptor and chick plasma vitamin D-binding protein was determined in vitro; analogues V and EV bound 68% and 62% [1 alpha,25(OH)2D3 receptor] and 8% and 13% (vitamin D-binding protein), respectively, as well as 1 alpha,25(OH)2D3 (100%). 1 alpha,25(OH)2D3 doses (0.075-1.2 nmol) generated responses in intestinal calcium absorption, bone calcium resorption, intestinal CaBP, and renal CaBP. When analogue V (1.2-300 nmol) was administered, increases in bone calcium resorption and renal CaBP were noted. However, a significant response in intestinal calcium absorption and intestinal CaBP appeared only after a 300-nmol dose. Unoccupied nuclear 1 alpha,25(OH)2D3 receptor in the intestine and kidney was determined in vivo after doses of 1 alpha,25(OH)2D3, analogue V, or analogue EV. Doses (0.25-6.0 nmol) of 1 alpha,25(OH)2D3 and analogue EV reduced unoccupied receptor to 24% and 59% (intestine) and to 13% and 41% (kidney), respectively. Analogue V (6.0-600 nmol) decreased unoccupied receptor in the kidney. In the intestine analogue V (300-600 nmol) reduced unoccupied receptor only to 75%. These results confirm that some vitamin D analogues can generate selective biological responses and different levels of target organ receptor occupancy.

Authors+Show Affiliations

Division of Biomedical Sciences, University of California, Riverside 92521.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

8395333

Citation

Norman, A W., et al. "Selective Biological Response By Target Organs (intestine, Kidney, and Bone) to 1,25-dihydroxyvitamin D3 and Two Analogues." Cancer Research, vol. 53, no. 17, 1993, pp. 3935-42.
Norman AW, Sergeev IN, Bishop JE, et al. Selective biological response by target organs (intestine, kidney, and bone) to 1,25-dihydroxyvitamin D3 and two analogues. Cancer Res. 1993;53(17):3935-42.
Norman, A. W., Sergeev, I. N., Bishop, J. E., & Okamura, W. H. (1993). Selective biological response by target organs (intestine, kidney, and bone) to 1,25-dihydroxyvitamin D3 and two analogues. Cancer Research, 53(17), pp. 3935-42.
Norman AW, et al. Selective Biological Response By Target Organs (intestine, Kidney, and Bone) to 1,25-dihydroxyvitamin D3 and Two Analogues. Cancer Res. 1993 Sep 1;53(17):3935-42. PubMed PMID: 8395333.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective biological response by target organs (intestine, kidney, and bone) to 1,25-dihydroxyvitamin D3 and two analogues. AU - Norman,A W, AU - Sergeev,I N, AU - Bishop,J E, AU - Okamura,W H, PY - 1993/9/1/pubmed PY - 1993/9/1/medline PY - 1993/9/1/entrez SP - 3935 EP - 42 JF - Cancer research JO - Cancer Res. VL - 53 IS - 17 N2 - The hormonally active form of vitamin D, 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3] stimulates biological responses related to calcium homeostasis, cell differentiation, and immunomodulation in many target cells, including leukemic cells. Most of these responses are dependent upon 1 alpha,25(OH)2D3 interaction with a nuclear receptor protein. Structural analogues of 1 alpha,25(OH)2D3 might allow for separation of biological function, avoiding adverse calcemic effects. This report quantitates intestinal calcium absorption, bone calcium resorption, induction of intestinal and renal calcium-binding protein (CaBP), and occupancy of the intestinal and renal nuclear 1 alpha,25(OH)2D3 receptor in vitamin D-deficient chicks after a single dose of 1 alpha,25(OH)2D3, 1 alpha,25-dihydroxyvitamin-16-ene-23-yne-D3 (analogue V), or 22-[m-(dimethylhydroxymethyl)phenyl]-23,24,25,26,27- pentanor-1 alpha-hydroxy-vitamin D3 (analogue EV). The interaction of these compounds with chick intestinal nuclear 1 alpha,25(OH)2D3 receptor and chick plasma vitamin D-binding protein was determined in vitro; analogues V and EV bound 68% and 62% [1 alpha,25(OH)2D3 receptor] and 8% and 13% (vitamin D-binding protein), respectively, as well as 1 alpha,25(OH)2D3 (100%). 1 alpha,25(OH)2D3 doses (0.075-1.2 nmol) generated responses in intestinal calcium absorption, bone calcium resorption, intestinal CaBP, and renal CaBP. When analogue V (1.2-300 nmol) was administered, increases in bone calcium resorption and renal CaBP were noted. However, a significant response in intestinal calcium absorption and intestinal CaBP appeared only after a 300-nmol dose. Unoccupied nuclear 1 alpha,25(OH)2D3 receptor in the intestine and kidney was determined in vivo after doses of 1 alpha,25(OH)2D3, analogue V, or analogue EV. Doses (0.25-6.0 nmol) of 1 alpha,25(OH)2D3 and analogue EV reduced unoccupied receptor to 24% and 59% (intestine) and to 13% and 41% (kidney), respectively. Analogue V (6.0-600 nmol) decreased unoccupied receptor in the kidney. In the intestine analogue V (300-600 nmol) reduced unoccupied receptor only to 75%. These results confirm that some vitamin D analogues can generate selective biological responses and different levels of target organ receptor occupancy. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/8395333/Selective_biological_response_by_target_organs__intestine_kidney_and_bone__to_125_dihydroxyvitamin_D3_and_two_analogues_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=8395333 DB - PRIME DP - Unbound Medicine ER -