The Metabolism and Functions of Vitamin D

  • Hector F. DeLuca
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 196)


Vitamin D functions by stimulating intestinal calcium and phosphorus absorption, by stimulating bone calcium mobilization, and by increasing renal reabsorption of calcium in the distal tubule. These functions on bone and possibly kidney, but not intestine, require the parathyroid hormone. As a result of these functions, serum calcium and phosphorus concentrations are elevated to supersaturating levels required for the mineralization of bone to prevent rickets, osteomalacia, and hypocalcemic tetany. Recent experiments demonstrate that maintaining serum calcium and phosphorus levels in vitamin D-deficient rats in the normal range results in normal bone growth and mineralization. However, increased calcification results because bone resorption by osteoclasts is a vitamin D-dependent process. Thus, bone resorption, modeling and remodeling must be considered vitamin D-dependent processes.

Vitamin D must be metabolized to 25-hydroxyvitamin D3 by the liver and subsequently by the kidney to 1,25-dihydroxyvitamin D3 before function. 1,25-Dihydroxyvitamin D3 is metabolized to a C-23 carboxylic acid (calcitroic acid) but the pathway is unknown. Although 25-hydroxyvitamin D3 is metabolized to 24R, 25-dihydroxyvitamin D3, 25,26-dihydroxyvitamin D3 and 25-hydroxyvitamin D326,23-lactone, these pathways play no role in the function of vitamin D as shown by appropriate fluoro analogs of 25-hydroxyvitamin D3.

1,25-Dihydroxyvitamin D3 binds to a specific receptor in the intestinal nuclei to elicit a stimulation of calcium transport. 1,25-Dihydroxyvitamin D3 plus the receptor causes transcription of specific genes that code for calcium and phosphorus transport proteins. Only one protein, the calcium binding protein, has been identified as being vitamin D dependent. Two others have been described, but no clear description of the molecular mechanism of action of 1,25-dihydroxyvitamin D3 is yet available.


Parathyroid Hormone Calcium Transport Plasma Calcium Renal Reabsorption Intestinal Calcium Transport 


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  1. 1.
    A. Hess, Rickets, Including Osteomalacia and Tetany. Lea and Febiger, Philadelphia, 22 (1929).Google Scholar
  2. 2.
    H. F. DeLuca, Mechanism of action and metabolic fate of vitamin D. Vitamins and Hormones 25: 315 (1967).PubMedCrossRefGoogle Scholar
  3. 2.
    H. F. DeLuca, Mechanism of action and metabolic fate of vitamin D. Vitamins and Hormones 25: 315 (1967).PubMedCrossRefGoogle Scholar
  4. 2.
    H. F. DeLuca, Mechanism of action and metabolic fate of vitamin D. Vitamins and Hormones 25: 315 (1967).PubMedCrossRefGoogle Scholar
  5. 5.
    H. F. DeLuca, Bone and Mineral Research. Excerpta Medica, Amsterdam, p. 7 (1983).Google Scholar
  6. 6.
    H. F. DeLuca, H. K. Schnoes, Vitamin D: Recent advances. Ann. Rev. Biochem. 52: 411 (1983).PubMedCrossRefGoogle Scholar
  7. 7.
    H. Rasmussen, H. DeLuca, C. Arnaud, C. Hawker, M. von Stedingk, The relationship between vitamin D and parathyroid hormone. J. Clin. Invest. 42: 1940 (1963).PubMedCrossRefGoogle Scholar
  8. 8.
    M. Garabedian, Y. Tanaka, M. F. Holick, H. F. DeLuca, Response of intestinal calcium transport and bone calcium mobilization to 1,25-dihydroxyvitamin D3 in thyroparathyroidectomized rats. Endocrinology 94: 1022 (1974).PubMedCrossRefGoogle Scholar
  9. 9.
    T. H. Steele, J. E. Engle, Y. Tanaka, R. S. Lorenc, K. L. Dugeon, H. F. DeLuca, Phosphatemic action of 1,25-dihydroxyvitamin D3. Am. J. Physiol. 229: 489 (1975).PubMedGoogle Scholar
  10. 10.
    J. P. Bonjour, C. Preston, H. Fleisch, Effect of 1,25-dihydroxyvitamin D3 on renal handling of Pi in thyroparathyroidectomized rats. J. Clin. Invest. 60: 1419 (1977).PubMedCrossRefGoogle Scholar
  11. 11.
    R. A. L. Sutton, J. H. Dirks, Renal handling of calcium. Fed. Proc. 37: 2117 (1978).Google Scholar
  12. 12.
    C. R. Kleeman, D. Bernstein, R. Rockney, J. T. Dowling, M. H. Maxwell, The Parathyroids, Charles C. Thomas, Springfield, p. 353 (1961).Google Scholar
  13. 13.
    G. L. Mechanic, S. U. Toverud, W. K. Ramp, W. A. Gonnerman, The effect of vitamin D on the structural crosslinks and maturation of chick bone collagen. Biochim. Biophys. Acta 383: 419 (1975).Google Scholar
  14. 14.
    J. E. Russel, L. V. Avioli, 25-Hydroxycholecalciferol-enhanced bone maturation in the parathyroprivic state. J. Clin. Invest. 56: 792 (1975).CrossRefGoogle Scholar
  15. 15.
    M. Garabedian, M. T. Corvol, M. Bailly du Bois, M. Leiberherr, S. Balsan, The biological activity of 24,25-dihydroxycholecalciferol on cultured chondrocytes and its in vitro production in cartilage and calvarium. Proc. Sixth Parathyroid Conf., Vancouver, B.C. p. 160 (1977).Google Scholar
  16. 16.
    M. Lieberrherr, M. Garabedian, H. Guillozo, M. du Boi Bailly, S. Balsan, Interaction of 24,25-dihydroxyvitamin D3 and parathyroid hormone on bone enzymes in vitro. Calf Tissue Int. 27: 47 (1979).CrossRefGoogle Scholar
  17. 17.
    J. B. Eastwood, E. Harris, T. C. B. Stamp, H. E. DeWardener, Vitamin D deficiency in the osteomalacia of chronic renal failure. Lancet 2: 1209 (1976).PubMedCrossRefGoogle Scholar
  18. 18.
    G. A. Howard, D. J. Baylink, Matrix formation and osteoid maturation in vitamin D-deficient rats made normocalcemic by dietary means. Min. Electrol. Metab. 3: 44 (1980).Google Scholar
  19. 19.
    M. F. Holtrop, K. A. Cox, M. B. Clark, M. F. Holick, C. S. Anast, 1,25-Dihydroxycholecalciferol stimulates osteoclasts in rat bones in the absence of parathyroid hormone. Endocrinology 108: 2293 (1981).PubMedCrossRefGoogle Scholar
  20. 20.
    L. G. Raisz, C. L. Trummel, M. F. Holick, H. F. DeLuca, 1,25Dihydroxycholecalciferol: A potent stimulator of bone resorption in tissue culture. Science 175: 768 (1972).PubMedCrossRefGoogle Scholar
  21. 21.
    J. J. Reynolds, M. F. Holick, H. F. DeLuca, The role of vitamin D metabolites in bone resorption. Calc. Tiss. Res. 12: 295 (1973).CrossRefGoogle Scholar
  22. 22.
    P. H. Stern, C. L. Trummel, H. K. Schnoes, H. F. DeLuca, Bone resorbing activity of vitamin D metabolites and congeners in vitro: Influence of hydroxyl substituents in the A ring. Endocrinology 97: 1552 (1975).PubMedCrossRefGoogle Scholar
  23. 23.
    H. M. Frost, Bone dynamics in osteoporosis and osteomalacia. Henry Ford Hospital Surgical Monograph Series, Charles A. Thomas Co, Springfield (1966).Google Scholar
  24. 24.
    W. E. Stumpf, M. Sar, F. A. Reid, Y. Tanaka, H. F. DeLuca, Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary and parathyroid. Science 206: 1188 (1979).PubMedCrossRefGoogle Scholar
  25. 25.
    W. E. Stumpf, M. Sar, H. F. DeLuca, Hormonal Control of Calcium Metabolism. Excerpta Medica, Amsterdam p. 222 (1981).Google Scholar
  26. 26.
    W. E. Stumpf, M. Sar, R. Narbaitz, F. A. Reid, H. F. DeLuca, Y. Tanaka, Cellular and subcellular localization of 1,25-(OH) - vitamin D in rat kidney: Comparison with localization of parathyroid hormone and estradiol. Proc. Natl. Acad. Sci. USA 77: 1149 (1980).PubMedCrossRefGoogle Scholar
  27. 27.
    D. Fraser, S. W. Kooh, H. P. Kind, M. F. Holick, Y. Tanaka, H. F. DeLuca, Pathogenesis of hereditary vitamin D dependent rickets: An inborn error of vitamin D metabolism involving defective conversion of 25-hydroxyvitamin D to la, 25-dihydroxyvitamin D. New England J. Med. 289: 817 (1973).CrossRefGoogle Scholar
  28. 28.
    C. R. Scriver, T. M. Reade, H. F. DeLuca, A. J. Hamstra, Serum 1,25-(OH)2D levels in normal subjects and in patients with hereditary rickets or bone disease. New England J. Med. 299: 976 (1978).CrossRefGoogle Scholar
  29. 29.
    R. P. Esvelt, H. K. Schnoes, H. F. DeLuca, isolation and characterization of la-hydroxy-tetranorvitamin D-23-carboxylic acid: A major metabolite of 1,25-dihydroxyvitamin D3. Biochemistry 18: 3977 (1979).PubMedCrossRefGoogle Scholar
  30. 30.
    B. L. Onisko, R.P. Esvelt, H.K. Schnoes, H. F. DeLuca, Metabolites of 1a,25-dihydroxyvitamin D3 in rat bile. Biochemistry 19: 4124 (1980).PubMedCrossRefGoogle Scholar
  31. 31.
    E. Mayer, J. E. Bishop, R. A. S. Chantraratna, W. H. Okamura, J. R. Kruse, G. Popjak, N. Ohnuma, A. W. Norman, Isolation and identification of 1,25-dihydroxy-24-oxo-vitamin D3 and 1,23,25-trihydroxy-24-oxo-vitamin D3. New metabolites of vitamin D3 produced by a C-24 oxidation pathway of metabolism for 1,25-dihydroxyvitamin D3 present in intestine and kidney. J. Biol. Chem. 258: 13458.Google Scholar
  32. 32.
    R. Kumar, D. Harnden, H. F. DeLuca, Metabolism of 1,25dihydroxyvitamin D3: Evidence for side-chain oxidation. Biochemistry 15: 2420 (1976).PubMedCrossRefGoogle Scholar
  33. 33.
    H. L. Henry, A. W. Norman, Vitamin D: Two dihydroxylated metabolites are required for normal chicken egg hatchability. Science 201: 835 (1978).PubMedCrossRefGoogle Scholar
  34. 34.
    A. Ornoy, D. Goodwin, D. Noff, S. Edelstein, 24,25-Dihydroxyvitamin D is a metabolite of vitamin D essential for bone formation. Nature 276: 517 (1978).PubMedCrossRefGoogle Scholar
  35. 35.
    H. Rasmussen, P. Bordier, Vitamin D and bone. Metab. Bone Dis. Rel. Res. 1: 7 (1978).CrossRefGoogle Scholar
  36. 36.
    H. L. Henry, A. N. Taylor, A. W. Norman, Response of chick parathyroid glands to the vitamin D metabolies 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3. J. Nutr. 107: 1918 (1977).PubMedGoogle Scholar
  37. 37.
    J. K. Wichmann, H. F. DeLuca, H. K. Schnoes, R. L. Horst, R. M. Shepard, N. A. Jorgensen, 25-Hydroxyvitamin D3 26,23-lactone: A new in vivo metabolite of vitamin D. Biochemistry 18: 4775 (1979).PubMedCrossRefGoogle Scholar
  38. 38.
    Y. Tanaka, H. F. DeLuca, H. K. Schnoes, N. Ikekawa, T. Eguchi, 23,25-Dihydroxyvitamin D3: A natural precursor in the biosynthesis of 25-hydroxyvitamin D3–26,23-lactone. Proc. Natl. Acad. Sci. USA 78: 4805 (1981).PubMedCrossRefGoogle Scholar
  39. 39.
    S. Yamada, M. Ohmori, H. Takayama, Y. Takasaki, T. Suda, Isolation and identification of la- and 23-hydroxylated metabolites of 25-hydroxy-24-oxovitamin D3 from in vitro incubates of chick kidney homogenates. J. Biol. Chem. 258: 457 (1983).PubMedGoogle Scholar
  40. 40.
    N. Ikekawa, N. Koizumi, E. Ohshima, S. Ishizuka, T. Takeshita, Y. Tanaka, H. F. DeLuca, Natural 25,26-dihydroxyvitamin D3 is an epimeric mixture. Proc. Natl. Acad. Sci. USA 80: 5286 (1983).CrossRefGoogle Scholar
  41. 40.
    N. Ikekawa, N. Koizumi, E. Ohshima, S. Ishizuka, T. Takeshita, Y. Tanaka, H. F. DeLuca, Natural 25,26-dihydroxyvitamin D3 is an epimeric mixture. Proc. Natl. Acad. Sci. USA 80: 5286 (1983).CrossRefGoogle Scholar
  42. 42.
    Y. Kabayashi, T. Taguchi, T. Terada, J. Oshida, M. Morisaka, N. Ikekawa, Studies on organic fluorine compounds. Part 37. Studies on steroids. Part 78. Synthesis of 24,24-difluoroand 24-fluoro-25-hydroxyvitamin D3. JCS Perkin I: 85 (1982).CrossRefGoogle Scholar
  43. 43.
    S. Yamada, M. Ohmori, H. Takayama, Synthesis of 24,24-difluoro25-hydoxyvitamin D3. Tetrahedron Lett. 21: 1859 (1979).CrossRefGoogle Scholar
  44. 44.
    Y. Tanaka, J. K. Wichmann, H. F. DeLuca, Y. Kobayashi, N. Ikekawa, Metabolism and binding properties of 24, 24-difluoro25-hydroxyvitamin D3. Arch. Biochem. Biophys. 225: 649 (1983).PubMedCrossRefGoogle Scholar
  45. 45.
    Y. Tanaka, H. F. DeLuca, H. K. Schnoes, N. Ikekawa, Y. Kobayashi, 24,24-Difluoro-1,25-dihydroxyvitamin D3: in vitro production, isolation, and biological activity. Arch. Biochem. Biophys. 199: 473 (1980).PubMedCrossRefGoogle Scholar
  46. 46.
    Y. Tanaka, H. F. DeLuca, Y. Kobayashi, T. Taguchi, N. Ikekawa, M. Morisaki, Biological activity of 24,24-difluoro-25-hydroxyvitamin D3. Effect of blocking of 24-hydroxylation on the functions of vitamin D. J. Biol. Chem. 254: 7163 (1979).PubMedGoogle Scholar
  47. 47.
    S. Okamoto, C. Smith, H. F. DeLuca, S. Yamada, H. Takayama, Biological activity of 24,24-difluoro-25-hydroxycholecalciferol in chicks. J. Nutr. 113: 1607, 1983.PubMedGoogle Scholar
  48. 48.
    S. Ameenuddin, M. Sunde, H. F. DeLuca, N. Ikekawa, Y. Kobayashi, 24-Hydroxylation of 25-hydroxyvitamin D3: Is it required for embryonic development in chicks. Science 217: 451 (1982).PubMedCrossRefGoogle Scholar
  49. 49.
    K. Jarnagain, R. Brommage, H. F. DeLuca, S. Yamada, H. Takayama, 1- But not 24-hydroxylation of vitamin D is required for growth and reproduction in rats. Am. J. Physiol. 244: E290 (1983).Google Scholar
  50. 50.
    R. Brommage, K. Jarnagain, H. F. DeLuca, S. Yamada, H. Takayama 1- But not 24-hydroxylation of vitamin D is required for skeletal mineralization in rats. Am. J. Physiol. 244: E298 (1983).PubMedGoogle Scholar
  51. 51.
    Y. Tanaka, D. N. Pahuja, J. K. Wichmann, H. F. DeLuca, Y. Kobayashi, T. Taguchi, N. Ikekawa, 25-Hydroxy-26,26,26,27, 27,27-hexofluorovitamin D3: Biological activity in the rat. Arch. Biochem. Biophys. 218: 134 (1982).PubMedCrossRefGoogle Scholar
  52. 52.
    J. L. Napoli, M. A. Fivizzani, H. K. Schnoes, H. F. DeLuca, 1-Fluorovitamin D3: A vitamin D3 analog more active on bone-calcium mobilization than intestinal-calcium transport. Biochemistry 18: 1641 (1979).PubMedCrossRefGoogle Scholar
  53. 53.
    B. L. Onisko, H. K. Schnoes, H. F. DeLuca, R. S. Glover, Metabolism and biological activity of 25-fluorocholecalciferol, 24-dehydrocholecalciferol and 25-dehydroxycholecalciferol in the rat. Biochem. J. 182: 1 (1979).PubMedGoogle Scholar
  54. 54.
    Y. Tanaka, H. F. DeLuca, Y. Kobayashi, N. Ikekawa, 26,26,26,27, 27,27-Hexofluoro-1,25-dihydroxyvitamin D3: A highly potent, long-lasting analog of 1,25-dihydroxyvitamin D3. Arch. Biochem. Biophys. 229: 348 (1984).PubMedCrossRefGoogle Scholar
  55. 55.
    S. Okamoto, Y. Tanaka, H. F. DeLuca, Y. Kobayashi, N. Ikekawa, Biological activity of 24,24-difluoro-1,25-dihydroxyvitamin D3. Am. J. Physiol. 7: E159 (1983).Google Scholar
  56. 56.
    J. L. Napoli, W. S. Mellon, M. A. Fivizzani, H. K. Schnoes, H. F. DeLuca, Direct chemical synthesis of la,25-dihydroxy[26, 27–3H]-vitamin D3 with high specific activity: Its use in receptor studies. Biochemistry 19: 2515 (1980).PubMedCrossRefGoogle Scholar
  57. 57.
    B. E. Kream, R. D. Reynolds, J. C. Knutson, J. A. Eisman, H. F. DeLuca, Intestinal cytosol binders of 1,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3. Arch. Biochem. Biophys. 176: 779 (1976).PubMedCrossRefGoogle Scholar
  58. 58.
    P. F. Brumbaugh, M. R. Haussier, Nuclear and cytoplasmic binding components for vitamin D metabolites. Life Sci. 16: 353 (1975).PubMedCrossRefGoogle Scholar
  59. 59.
    N. H. Bell, A. J. Hamstra, H. F. DeLuca, Vitamin D-dependent rickets Type II: Resistance of target organs to 1,25-dihydroxyvitamin D. New England J. Med. 298: 996 (1978).CrossRefGoogle Scholar
  60. 60.
    J. F. Rosen, A. R. Fleishman, L. Finberg, A. Hamstra, H. F. DeLuca, Rickets with alopecia: An inborn error of vitamin D metabolism. J. Pediat. 94: 729 (1979).PubMedCrossRefGoogle Scholar
  61. 61.
    C. Eil, U. A. Liberman, J. F. Rosen, S. J. Marx, A cellular defect in hereditary vitamin D-dependent rickets Type II: Defective nuclear uptake of 1,25-dihydroxyvitamin D in cultured skin fibroblasts. New England J. Med. 304: 1588 (1981).CrossRefGoogle Scholar
  62. 62.
    J. W. Pike, S. Dokoh, M. R. Haussier, U. A. Liberman, S. J. Marx and C. Eil, Vitamin D3-resistant fibroblasts have immunoassayable, 1,25-dihydroxyvitamin D3 receptors. Science 224: 879 (1984).PubMedCrossRefGoogle Scholar
  63. 63.
    B. P. Halloran, H. F. DeLuca, Appearance of the intestinal cytosolic receptor for 1,25-dihydroxyvitamin D3 during neonatal development in the rat. J. Biol. Chem. 256: 7338 (1981).PubMedGoogle Scholar
  64. 64.
    B. P. Halloran, H. F. DeLuca, Calcium transport in the small intestine during early development: The role of vitamin D. Am. J. Physiol. 239: G473 (1980).PubMedGoogle Scholar
  65. 65.
    E. R. Massaro, R. U. Simpson, H. F. DeLuca, Glucocorticoids and appearance of 1,25-dihydroxyvitamin D3 receptor in rat intestine. Am. J. Physiol. 244: E230 (1983).PubMedGoogle Scholar
  66. 66.
    J. W. Pike, S. L. Marion, C. A. Donaldson, M. R. Haussler, Serum and monoclonal antibodies against the chick intestinal receptor for 1,25-dihydroxyvitamin D3. J. Biol. Chem. 258: 1289 (1983).PubMedGoogle Scholar
  67. 67.
    M. R. Walters, W. Hunziker, A. W. Norman, Unoccupied 1,25dihydroxyvitamin D3 receptors. Nuclear/cytosol ratio depends on ionic strength. J. Biol. Chem. 255: 6799 (1980).PubMedGoogle Scholar
  68. 68.
    Y. Tanaka, H. F. DeLuca, J. Omdahl, M. F. Holick, Mechanism of action of 1,25-dihydroxycholecalciferol on intestinal calcium transport. Proc. Natl. Acad. Sci. USA 68: 1286 (1971).PubMedCrossRefGoogle Scholar
  69. 69.
    D. D. Bikle, D. T. Zolock, R. L. Morrissey, R. H. Herman, Independence of 1,25-dihydroxyvitamin D3-mediated calcium transport from de novo RNA and protein synthesis. J. Biol. Chem. 253: 484 (1978).PubMedGoogle Scholar
  70. 70.
    Y. Tanaka, H. F. DeLuca, Bone mineral mobilization activity of 1,25-dihydroxycholecalciferol, a metabolite of vitamin D. Arch. Biochem. Biophys. 146: 574 (1971).PubMedCrossRefGoogle Scholar
  71. 71.
    H. Rasmussen, T. Matsumoto, 0. Fontaine, D. B. P. Goodman, Role of changes in membrane lipid structure in the action of 1,25-dihydroxyvitamin D3. Fed. Proc. 41: 72 (1982).PubMedGoogle Scholar
  72. 72.
    R. A. Corradino, 1,25-Dihydroxycholecalciferol: Inhibition of action in organ-cultured intestine by actinomycin D and a-amanitin. Nature 243: 41 (1973).PubMedCrossRefGoogle Scholar
  73. 73.
    R. T. Franceschi, H. F. DeLuca, The effect of inhibitors of protein and RNA synthesis on 1 a,25-dihydroxyvitamin D3 dependent calcium uptake in cultured embryonic chick duodenum. J. Biol. Chem. 256: 3848 (1981).PubMedGoogle Scholar
  74. 74.
    R. H. Wasserman, J. J. Feher, Calcium Binding Proteins and Calcium Function. Elsevier, New York p. 292 (1977).Google Scholar
  75. 75.
    R. Spencer, M. Charman, P. W. Wilson, D. E. M. Lawson, The relationship between vitamin D-stimulated calcium transport and intestinal calcium-binding protein in the chicken. Biochem. HJ 170: 93 (1978).Google Scholar
  76. 76.
    C. W. Bishop, N. C. Kendrick, H. F. DeLuca, Induction of calcium binding protein before 1,25-dihydroxyvitamin D3 stimulation of duodenal calcium uptake. J. Biol. Chem. 258: 1305 (1982).Google Scholar
  77. 77.
    C. W. Bishop, N. C. Kenrick, H. F. DeLuca, The early time course of calcium-binding protein induction by 1,25-dihydroxyvitamin D3 as determined by computer analysis of two-dimensional electrophoresis gels. J. Biol. Chem. 259: 3355 (1984).PubMedGoogle Scholar

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© Plenum Press, New York 1986

Authors and Affiliations

  • Hector F. DeLuca
    • 1
  1. 1.Department of BiochemistryUniversity of Wisconsin-Madison College of Agricultural and Life SciencesMadisonUSA

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