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SummaryChicks regulated to a lowcalcium diet exhibited the expected facultative process regarding the intestinal absorption of calcium. Augmentation of the facultative process was noted when such low-calcium adapted chicks were given a high-calcium diet. This response was transitory, becoming evident 72 hr after initiation of the high-calcium feeding and declining rapidly thereafter. The potentiative response was actinomycin sensitive and could not be produced by the molar substitution of strontium for calcium. Vitamin D was essential for development of the facultative process in lowcalcium fed chicks and the potentiative effect noted in such animals given a high-calcium diet. It is suggested that the additional calcium could have acted on the intestinal cellular processes to accentuate the facultative response by increasing mitotic activity or by inhibiting ribonuclease. It is also theorized that calcium could have effected the facultative response indirectly by controlling synthesis of an active vitamin...

Inhibition of calcium absorption by dietary strontium is the result of a block in the renal synthesis of 1,25-dihydroxycholecalciferol (1,25-(OH)2CC) from 25-hydroxycholecalciferol (25-OHCC). The administration of 1,25-(OH)2CC but not 25-OHCC restores to normal calcium absorption in strontium-fed chicks. Kidney mitochondria from strontium-fed chicks do not metabolize 25-OHCC to 1,25-(OH)2CC, but rather to a metabolite designated Peak Va. The function of Peak Va is unknown while it is believed that 1,25-(OH)2CC is the metabolically active form of vitamin D in the stimulation of calcium absorption from intestine and mobilization from bone. The changes in the kidney metabolism of 25-OHCC in response to dietary strontium occur over a period of several days and correlate closely with changes in intestinal calcium absorption. Feeding a normal calcium diet can correct the strontium-induced inhibition of intestinal calcium absorption. This restoration of calcium absorption correlates with an increased rate of in vitro 1,25-(OH)2CC synthesis. The exact mechanism whereby strontium alters the renal metabolism of 25-OHCC is unknown. However, indirect evidence suggests that it may operate through humoral agents such as parathyroid hormone, or calcitonin, or both, which are responsible for maintenance of plasma calcium concentration.

The subcellular distribution and properties of an enzyme system responsible for hydroxylation of 25-hydroxycholecalciferol (25-OHD3) to 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) in chicken kidney have been described. The enzyme, which is highly specific for 25-OHD3 since it does not hydroxylate cholecalciferol or dihydrotachysterol, is located in the mitochondria and has a pH optimum of 7.4 and an apparent Km of 2.2 x 10-6 m. At 8.34 x 10-7 m 25-OHD3, 1,25-(OH)2D3 production is linear with mitochondrial protein concentrations of up to 8 mg per ml. Enzyme activity is maximal in Tris-acetate buffer and requires Mg2+, oxygen, and a source of reduced pyridine nucleotide, which in intact mitochondria is provided by malate or succinate. The succinate-supported hydroxylation is dependent upon electron transport and oxidative phosphorylation. The 25-OHD3-1-hydroxylase is inhibited by carbon monoxide, metapyrone, p-chloromercuribenzoate, and diphenyl-p-phenylenediamine. The enzyme is also inhibited by its product, 1,25-(OH)2D3. It is, however, much more strongly inhibited competitively by 25-hydroxydihydrotachysterol, a close analog of 1,25-(OH)2D3.

24,25-Dihydroxyvitamin D3 (24,25-(OH)2D3) gives a marked increase in intestinal calcium transport and serum calcium concentration of vitamin D-deficient rats fed a diet containing adequate calcium and phosphorus. These responses occur after a considerable time lag following administration of the metabolite. The 24,25-(OH)2D3 on a long term basis and at low doses has striking activity in the stimulation of intestinal calcium transport but not bone calcium mobilization. Radioactive 24,25-(OH)2D3 is metabolized to a more polar compound which increases in concentration in serum, intestinal mucosa, and bone over a 48-hour period. Nephrectomy or the feeding of a high calcium diet abolishes the stimulation of intestinal calcium transport by 24,25-(OH)2D3 and the in vivo genesis of the more polar compound from tritiated 24,25-(OH)2D3. It is concluded that 24,25-(OH)2D3, the usual dihydroxy metabolite of vitamin D3 in normal rats, has potential physiological importance through its conversion to a more polar metabolite. This metabolite possibly acts to facilitate intestinal calcium absorption without stimulating bone calcium mobilization.

Summary1,25-Dihydroxycholecaliferol (1,25-DHCC) is a metabolite of vitamin D produced in the kidney from the major circulating biologically active form of the vitamin, 25-hydroxycholecalciferol (25-HCC) and has been demonstrated to be the derivative of cholecalciferol (CC) primarily responsible for the initiation of calcium transport from the gut contents. Because previous studies have shown that both CC and 25-HCC act acutely to enhance phosphate, sodium and calcium reabsorption in the kidney, the effect of 1,25-DHCC was evaluated in clearance studies performed in mildly expanded thyroparathyroidectomized dogs. In a dose of 25 U (0.625 μg), 1,25-DHCC induced an invariable fall in both fractional and absolute phosphate excretion (mean declines of 40 and 36%, respectively, p < .05 and < .01). Fractional sodium and calcium excretion also deccreased by mean values of 26 and 36%, respectively (p < .02). Renal hemodynamic changes and alterations in serum ultrafilterable calcium and phosphate concentrations did...

IT is now recognized that hydroxylated metabolites of vitamin D (that is, cholecalciferol) function as effectors of the physiological actions originally attributed to the unaltered vitamin1. The activation of vitamin D by specific hydroxylation reactions and sequestration of the resultant metabolites by target tissues represents a hormonal control loop which is feed-back sensitive. 25-Hydroxycholecalciferol (25-HCC) and 1,25-dihydroxycholecalciferol (1,25-DHCC) have been shown to be participants in the control loop, vitamin D being first metabolized in the liver to 25-HCC2 which in turn is hydroxylated in the C-1 position to 1,25-DHCC in the kidney3,4. The metabolically active form in the intestine appears to be 1,25-DHCC5,6.

This chapter discusses the experimental study made in both vitamin D-deficient and vitamin D-supplemented rats of the effect of varying the dietary calcium content on the in vivo production of 1,25-DHCC from 25-hydroxycholecalciferol (25-HCC). The profiles of radioactive metabolites separated on Sephadex LH-20 from serum extracts were obtained from rats fed the various diets with and without vitamin D. The small dose of vitamin D 3 is chosen to minimize dilution of radioactive metabolites and to provide a small amount of 25-HCC to induce the factor(s) necessary for 1-hydroxylation in the kidney. A consideration of the serum calcium values and rat illustrates a growth effect of the vitamin even at the low level although vitamin D deficiency persisted. In vitamin D-deficient rats fed diets with 0–02% Ca through 2–0% Ca, 14 to 18% of the total radioactivity in the serum is recovered consistently as 1,25-DHCC. No correlation is found between the serum inorganic phosphorus levels and production of the metabolites.