Selective biological response by target organs (intestine, kidney, and bone) to 1,25-dihydroxyvitamin D3 and two analogues.
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.
Division of Biomedical Sciences, University of California, Riverside 92521.
A W
AW
Norman
I N
IN
Sergeev
J E
JE
Bishop
W H
WH
Okamura
D000818:Animals; D001842:Bone and Bones / Q000378:metabolism*; D064026:Calbindins; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002645:Chickens; D006887:Hydroxycholecalciferols / Q000378:metabolism* / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008297:Male; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000378:metabolism*; D014808:Vitamin D Deficiency / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000378:metabolism
D064026:Calbindins; D006887:Hydroxycholecalciferols; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D064030:S100 Calcium Binding Protein G; D014809:Vitamin D-Binding Protein; C082767:22-(3-(dimethylhydroxymethyl)phenyl)-23,24,25,26,27-pentanor-1-hydroxyvitamin D3; D002117:Calcitriol; C064183:Ro 23-7553; D002118:Calcium