Biomedical subjects
Publications and source records attributed to M F Holick.
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Isotachysterol(3), 25-hydroxyisotachysterol(3), and isovitamin D(3) have been synthesized and tested for biological activity. Like 1,25-dihydroxyvitamin D(3), isotachysterol(3) stimulates intestinal calcium transport and bone calcium mobilization in anephric rats, whereas 25-hydroxyvitamin D(3) does not. Although isovitamin D(3) is biologically active in normal rats it is inactive in anephric rats.
The 1alpha-hydroxy derivative of vitamin D(3) has been chemically synthesized and tested for its biological activity. This analog has comparable biological activity on a weight basis to 1,25-dihydroxyvitamin D(3) in the stimulation of intestinal calcium transport and bone calcium mobilization in normnal and anephric rats. Because the 1alpha-hydroxy derivative is synthesized from cholesterol, it is easier and less expensive to prepare than 1alpha,25-dihydroxy derivative, making it attractive as a drug in the treatment of renal osteodystrophy and hypopara-thyroidism.
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A new compound, 5,6-trans-25-hydroxycholecalciferol, has been synthesized and tested for its biological activity. Like 1,25-dihydroxycholecalciferol, it stimulates intestinal calcium transport in anephric rats, whereas 25-hydroxycholecalciferol does not. But this analog has little if any activity in stimulating mobilization of calcium from the bone of anephric rats.
Nephrectomy prevents completely the bone calcium mobilization response to 25-hydroxycholecalciferol. In contrast it does not prevent this response to 1,25-dihydroxycholecalciferol. Because it is known that the kidney is the site of 1,25-dihydroxycholecalciferol formation, these results provide evidence that 1,25-dihydroxycholecalciferol or a further metabolite thereof and not 25-hydroxycholecalciferol is the metabolically active form of vitamin D(3) responsible for bone calcium mobilization.
1,25-Dihydroxycholecalciferol (DHCC), isolated from kidney homogenates incubated with 25-hydroxycholecalciferol (HCC), stimulated the release of previously incorporated (45)45Ca from fetal rat bones in organ culture, at concentrations of 10(-10) to 10(-8)M. The dose response curves for 1,25-DHCC and 25-HCC, the parent compound, are parallel, but 1,25-DHCC is about 100 times as potent on a weight basis. Brief exposure to maximum doses of either agent leads to prolonged bone resorption.
Thyroparathyroidectomy of rats on a diet low in calcium reduces production of 1,25-dihydroxycholecalciferol from 25-hydroxycholecalciferol to negligible levels within 40 hr, and increases production of another metabolite, called Va. Parathyroid extract, at a dose of 20 units per day, prevents these changes. When 40 units per day of parathyroid extract is given 48 hr after thyroparathyroidectomy, 1,25-dihydroxycholecalciferol production is restored almost to control levels within 36 hr. The change brought about by parathyroid extract cannot be attributed to resulting changes in serum calcium or phosphorus concentration. It appears that the parathyroid hormone serves as a tropin for production of 1,25-dihydroxycholecalciferol, the hormonal form of vitamin D responsible for calcium mobilization from intestinal contents and bone.
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A biologically active vitamin D(3) metabolite ("peak V metabolite") more polar than 25-hydroxycholecalciferol has been isolated from chicken intestines in pure form as a mono(trimethylsilyl)ether derivative. The molecule has been identified as 1,25-dihydroxycholecalciferol by means of mass spectrometry, ultraviolet absorption spectrophotometry, and specific chemical reactions.
The prior administration of actinomycin D prevents the metabolism of [(3)H]25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol, a metabolite of vitamin D(3) that is effective in the stimulation of intestinal calcium transport. In this paper, the question of whether the response of intestinal calcium transport to 1,25-dihydroxycholecalciferol is sensitive to actinomycin D was examined. While the response of intestinal transport to physiological amounts of 25-hydroxycholecalciferol is blocked by actinomycin D, the response of intestinal calcium transport to 1,25-dihydroxycholecalciferol is insensitive to the antibiotic. These results suggest that 1,25-dihydroxycholecalciferol, or a further metabolite thereof, is the metabolically active form of vitamin D in the intestine, that it functions by a process not involving transcription of DNA, and that the step sensitive to actinomycin D in the action of vitamin D on the intestine does not occur in the intestine, but is the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the kidney.
A simple yet powerful new chromatographic procedure for vitamin D(3) and its metabolites is described. Liquid-gel partition chromatography on Sephadex LH-20 using a solvent of various percentages of CHCl(3) in Skellysolve B (petroleum ether, bp 67-69 degrees C) permits excellent resolution of vitamin D(3), 25-hydroxyvitamin D(3), and their more polar metabolites. Of special importance is the resolution of the metabolites of vitamin D(3) more polar than 25-hydroxycholecalciferol. Because of this resolution, a new metabolite of vitamin D(3) has been demonstrated in the plasma of rats and in the intestines of chicks given 100 IU of vitamin D(3)-1,2-(3)H.