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Selective Biological Response by Target Organs (Intestine, Kidney, and Bone) to 1,25-Dihydroxyvitamin D₃ and Two Analogues¹

Division of Biomedical Sciences [A. W. N.], Department of Biochemistry [A. W. N., I. N. S., J. E. B.], and Department of Chemistry [W. H. O.], University of California, Riverside, California 92521

The hormonally active form of vitamin D, 1,25-dihydroxyvitamin D₃ [1,25(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 1,25(OH)₂D₃ interaction with a nuclear receptor protein. Structural analogues of 1,25(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 1,25(OH)₂D₃ receptor in vitamin D-deficient chicks after a single dose of 1,25(OH)₂D₃, 1,25-dihydroxyvitamin-16-ene-23-yne-D₃ (analogue V), or 22-[m-(dimethylhydroxymethyl)phenyl]-23,24,25,26,27-pentanor-1-hydroxy-vitamin D₃ (analogue EV).

The interaction of these compounds with chick intestinal nuclear 1,25-(OH)₂D₃ receptor and chick plasma vitamin D-binding protein was determined in vitro; analogues V and EV bound 68% and 62% [1,25(OH)₂D₃ receptor] and 8% and 13% (vitamin D-binding protein), respectively, as well as 1,25(OH)₂D₃ (100%). 1,25(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 1,25(OH)₂D₃ receptor in the intestine and kidney was determined in vivo after doses of 1,25(OH)₂D₃, analogue V, or analogue EV. Doses (0.25–6.0 nmol) of 1,25(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.

¹ Supported in part by USPHS Grants CA43277 and DK09012 to A. W. N. and Grant DK16595 to W. H. O. Abstracts of this work were presented at the Eighth Workshop on Vitamin D (Paris, France, 1991).

² To whom requests for reprints should be addressed, at Department of Biochemistry, University of California, Riverside, CA 92521.

Received 1/12/93. Accepted 6/24/93.

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