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Studies on Calciferol Metabolism

V. THE OCCURRENCE AND BIOLOGICAL ACTIVITY OF 1,25-DIHYDROXY-VITAMIN D₃ IN BONE

From the ¹ From the Department of Biochemistry, University of California, Riverside, California 92502

The administration of cholecalciferol (vitamin D₃) (CC) to rachitic chicks results in the production of two major polar metabolites, 25-hydroxycholecalciferol (25-OH-CC) and 1,25-dihydroxycholecalciferol (1,25-diOH-CC), and a number of other minor metabolites. Eighteen hours after a physiological dose (0.65 nmoles) of radioactive cholecalciferol, 80% of the radioactivity in the target intestine is present as 1,25-diOH-CC and 19% as 25-OH-CC. In the other major target organ, the skeletal system, 25% of the radioactivity is present in a form chromatographically identical to 1,25-diOH-CC, 50% as 25-OH-CC and 20% as unaltered CC. 1,25-diOH-CC has been shown previously to be the probable metabolically active form of vitamin D₃ which initiates increased intestinal calcium transport.

1,25-diOH-CC stimulated increased bone calcium mobilization, as measured by serum calcium elevation, in both vitamin D deficient chicks and rats. 1,25-diOH-CC initiates maximal bone calcium mobilization more rapidly than either CC or 25-OH-CC; maximal activity occurs at 8 to 10 hours for 1,25-diOH-CC and at 20 to 24 hours for the other steroids. When the maximal biological activity of 1,25-diOH-CC observed at 9 hours is compared to the maximal activity obtained by the other steroids at 24 hours, it was determined that 1,25-diOH-CC is 5.5 times more active than CC and 3.6 times more active than 25-OH-CC in stimulating bone calcium mobilization. Following administration of 1,25-diOH-[³H]CC, maximal localization of radioactivity in the bone tissue occurred after only 1 to 2 hours. This radioactivity was found by chromatographic analysis to be unaltered 1,25-diOH-CC.

There is an obligatory requirement for the kidney mediated hydroxylation of 25-OH-CC to occur prior to the development of a biological response. Administration of 3.25 nmoles of CC, 3.25 nmoles of 25-OH-CC, 3.25 nmoles of dihydrotachysterol₃, and 0.26 nmoles of 1,25-diOH-CC all produced bone calcium mobilization in vitamin D deficient rats with kidneys present. However, in bilaterally nephrectomized rats (kidneys absent), only 1,25-diOH-CC was capable of initiating bone calcium mobilization. These results indicate that 1,25-diOH-CC, which is believed to be the active form of cholecalciferol in the intestine, may also be the form of this steroid responsible for bone calcium mobilization.

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				A. Norman, M. Mitra, W. Okamura, and R. Wing Vitamin D: 3-deoxy-lalpha-hydroxyvitamin D3, biologically active analog of lalpha-dihydroxyvitamin D3 Science, June 6, 1975; 188(4192): 1013 - 1015. [Abstract] [PDF]