Molecular Pharmacology, Vol 17, 362-366, Copyright © 1980 by the American Society for Pharmacology and Experimental Therapeutics

Intestinal Calcium-Binding Protein (CaBP) and Bone Calcium Mobilization in Response to 1,24(R),25-(OH)₃D₃

Comparative Effects of 1,25-(OH)₂D₃ and 24(R),25-(OH)₂D₃ in Rats

¹ Laboratoire de Recherches sur le Métabolisme Hydro-Minéral, INSERM U.120, 44 Chemin de Ronde, 78110 Le Vésinet, France
² Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin, Madison, Wisconsin 53706

The response of intestinal calcium-binding protein (CaBP) synthesis and the rise in the serum calcium level to vitamin D metabolites were measured in vitamin D-deficient rats fed a low-calcium diet. Our results showed a linear relationship between the amount of intestinal CaBP and the logarithm of the dose for all the compounds. 1,24(R),25-(OH)₃D₃ was approximately four times less effective than 1,25-(OH)₂D₃ in increasing the CaBP level and about eight times more effective than 24(R),25-(OH)₂D₃. The bone calcium mobilization response expressed as the rise in serum calcium was also dose related. The relative potencies of the metabolites in increasing the serum calcium level were approximately the same as those elevating CaBP synthesis. Time course studies showed that 1,24(R),25-(OH)₃D₃ was as rapidly active as 1,25-(OH)₂D₃ in inducing intestinal CaBP synthesis and increasing serum calcium. The duration of its calcemic response was shorter and the magnitude less than that of 1,25-(OH)₂D₃. A longer time lag was necessary to obtain intestinal and calcemic responses after 24(R),25-(OH)₂D₃ injection. 1,24(R),25-(OH)₃D₃ and 1,25-(OH)₂D₃ were still active in promoting intestinal CaBP synthesis in nephrectomized rats, whereas a large dose of 24(R),25-(OH)₂D₃ was inactive. Thus C-1 hydroxylation is essential for the stimulation of both the intestinal CaBP production and the rise in the serum calcium level, whereas C-24 hydroxylation diminishes the magnitude of the intestinal and calcemic responses. These results strongly suggest that 1,24(R),25-(OH)₃D₃ represents an inactivation rather than an activation of the hormonal form of vitamin D₃.

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ACKNOWLEDGMENTS We are grateful to N. Gouhier and A. Subrenat for expert and devoted technical assistance and to M. Courat and P. Schuman for the preparation of the manuscript. We wish to thank Dr. P. Marche for supplying CaBP-specific antiserum and Dr. M. Moukhtar (INSERM U. 113, Paris) for providing us with laboratory facilities to prepare ¹²⁵I-CaBP). We are grateful to Dr. Uskokovic (Hoffmann-La Roche, Nutley, New Jersey) for supplying the synthetic compounds.