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Vitamin D pp 57–84Cite as

Metabolism and Catabolism of Vitamin D, Its Metabolites, and Clinically Relevant Analogs

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Part of the book series: Nutrition and Health ((NH))

Abstract

The elucidation of the metabolism of vitamin D3 is arguably one of the most important developments in nutritional sciences over the latter half of the 20th century. An appreciation that vitamin D3 represents a precursor to the functionally active form and that two steps of activation are necessary to produce the hormone 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] constitute historical landmarks in modern vitamin research (1). These developments spawned not only detailed studies of the biologic properties of vitamin D metabolites produced and the regulation of cytochrome P450-containing enzymes involved in their production but also provided the stimulus for the chemical synthesis of a plethora of vitamin D analogs (approx 300 at last count). Furthermore, it appears that susceptibility to vitamin D catabolic pathways and other important parameters such as binding to the vitamin D receptor (VDR) functional complex and binding to the vitamin D binding protein (DBP) are probably key elements in dictating the differences in the actions of so-called calcemic and noncalcemic vitamin D analogs. Therefore, from the perspective of its historical significance and relevance, it seems entirely logical to consider the metabolism of vitamin D and its analogs together at this stage of a general text on vitamin D.

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References

  1. Holick MF. Vitamin Dphotobiology, metabolism and clinical applications. In: Endocrinology, 3rd ed., vol. 2. Degroot L, ed. Philadelphia: WB Saunders, 1995; 990–1014.

    Google Scholar 

  2. Bhattacharyya MH, DeLuca HF. The regulation of the rat liver calciferol-25-hydroxylase. J Biol Chem 1973; 248: 2969–2973.

    PubMed  CAS  Google Scholar 

  3. Andersson S, Davis DL, Dahlback H, Jornvall H, Russell DW. Cloning, structure and expression of the mitochondrial cytochrome P450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem 1989; 246: 8222–8229.

    Google Scholar 

  4. Okuda KI, Usui E, Ohyama Y. Recent progress in enzymology and molecular biology of enzymes involved in vitamin D metabolism. J Lipid Res 1995; 36: 1641–1652.

    PubMed  CAS  Google Scholar 

  5. Guo Y-D, Strugnell S, Back DW, Jones G. Transfected human liver cytochrome P-450 hydroxylates vitamin D analogs at different side-chain positions. Proc Natl Acad Sci USA1993; 90: 8668–8672.

    Google Scholar 

  6. Fukushima M, Suzuki Y, Tohira Y, Nishii Y, Suzuki M, Sasaki S, Suda T. 25-Hydroxylation of lahydroxyvitamin D3 in vivo and in the perfused rat liver. FEBS Lett 1976; 65: 211–214.

    Article  PubMed  CAS  Google Scholar 

  7. Baran DT, Milne ML. 1,25-Dihydroxyvitamin D increases heapatocyte cytosolic calcium levels: a potential regulator of vitamin D-25-hydroxylase. J Clin Invest 1986; 77: 1622–1626.

    Article  PubMed  CAS  Google Scholar 

  8. Berginer VM, Shany S, Alkalay D, Berginer J, Dekel S, Salen G, Tint GS, Gazit D. Osteoporosis and increased bone fractures in cerebrotendinous xanthomatosis. Metabolism 1993; 42: 69–74.

    Article  PubMed  CAS  Google Scholar 

  9. Postlind H, Axen E, Bergman T, Wikvall K. Cloning, structure and expression of a cDNA encoding vitamin D3 25-hydroxylase. Biochem Biophys Res Commun 1997; 241: 491–497.

    Article  PubMed  CAS  Google Scholar 

  10. Tucker G, Gagnon RE, Haussier MR. Vitamin D3–25-hydroxylase: tissue occurrence and lack of regulation. Arch Biochem Biophys 1973; 155: 47–57.

    Article  PubMed  CAS  Google Scholar 

  11. Axen E, Postlind H, Wikvall K. Effects of CYP27 mRNA expression in rat kidney and liver by l a,25dihydroxyvitamin D3, a suppressor of renal 25-hydroxyvitamin D3–1a-hydroxylase activity. Biochem Biophys Res Commun 1995; 215: 136–141.

    Article  PubMed  CAS  Google Scholar 

  12. Ichikawa F, Sato K, Nanjo M, Nishii Y, Shinki T, Takahashi N, Suda T. Mouse primary osteoblasts express vitamin D3 25-hydroxylase mRNA and convert la-hydroxyvitamin D3 into la,25-dihydroxyvitamin D3. Bone 1995; 16: 129–135.

    PubMed  CAS  Google Scholar 

  13. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature 1970; 228: 764–766.

    Article  PubMed  CAS  Google Scholar 

  14. St-Arnaud R., Messerlian S, Moir JM, Omdahl JL, Glorieux FH. The 25-hydroxyvitamin D 1-alphahydroxylase gene maps to the pseudovitamin D-deficiency rickets (PDDR) disease locus. J. Bone Miner Res 1997; 12: 1552–1559.

    Article  PubMed  CAS  Google Scholar 

  15. Takeyama K-I, Kitanaka S, Sato T, Kobori, M, Yanagisawa J, Kato S. 25-Hydroxyvitamin D3 lahydroxylase and vitamin D synthesis. Science 1997; 277: 1827–1830.

    Article  PubMed  CAS  Google Scholar 

  16. Monkawa T, Yoshida T, Wakino S, Shinki T, Anazawa H, DeLuca HF, Suda T, Hayashi M, Saruta T. Molecular cloning of cDNA and genomic DNA for human 25-hydroxyvitamin D3 1-alpha hydroxylase. Biochem Biophys Res Commun 1997; 239: 527–533.

    Article  PubMed  CAS  Google Scholar 

  17. Fu GK, Lin D, Zhang MY, Bikle DD, Shackleton CH, Miller WL, Portale AA. Cloning of human 25-hydroxyvitamin D-1-alpha-hydroxylase and mutations causing vitamin D dependent rickets type 1. Mol Endocrionol 1997; 11: 1961–1970.

    Article  CAS  Google Scholar 

  18. Fu GK, Portale AA, Miller WL. Complete structure of the human gene for the vitamin D lahydroxylase, P450c1a. DNA Cell Biol 1997; 16: 1499–1507.

    Article  PubMed  CAS  Google Scholar 

  19. Gray RW, Omdahl JL, Ghazarian JG, DeLuca HF. 25-Hydroxycholecalciferol- 1-hydroxylase: sub-cellular location and properties. J Biol Chem 1972; 247: 7528–7532.

    PubMed  CAS  Google Scholar 

  20. Henry HL. Regulation of the hydroxylation of 25-hydroxyvitamin D3 in vivo and in primary cultures of chick kidney cells. J Biol Chem 1979; 254: 2722–2729.

    PubMed  CAS  Google Scholar 

  21. Kitanaka S, Takeyama K, Murayama A, Sato T, Okumura K, Nogami M, Hasegawa Y, Niimi H, Yanigisawa J, Tanaka T, Sato K. Inactivating mutations in the 25-hydroxyvitamin D3-la-hydroxylase gene in patients with pseudovitamin D deficiency rickets. N Engl J Med 1998; 338: 653–661.

    Article  PubMed  CAS  Google Scholar 

  22. Fraser D, Kooh SW, Kind P, Holick MF, Tanaka Y, DeLuca HF. Pathogenesis of hereditary vitamin D dependency rickets. N Engl J Med 1973; 289: 817–822.

    Article  PubMed  CAS  Google Scholar 

  23. Lester GE, Gray TK, Williams ME. In vitro la-hydroxylation of 3H-25-hydroxyvitamin D3 by isolated cells from rat kidneys and placentae In: Hormonal Control of Calcium Metabolism. Cohn DV, Talmage RV, Matthews JL, eds. Amsterdam: Excerpta Medica, 1981; 376.

    Google Scholar 

  24. Adams JS, Gacad MA. Characterization of la-hydroxylation of vitamin D3 sterols by cultured alveolar macrophages from patients with sarcoidosis. J Exp Med 1985; 161: 755–765.

    Article  PubMed  CAS  Google Scholar 

  25. Holick MF, Schnoes HK, DeLuca HF, Gray RW, Boyle IT, Suda T. Isolation and identification of 24,25-dihydroxycholecalciferol: a metabolite of vitamin D3 made in the kidney. Biochemistry 1972; 11: 4251–4255.

    Article  PubMed  CAS  Google Scholar 

  26. Holick MF, Kleiner-Bossaller A, Schnoes HK, Kasten PM, Boyle IT, DeLuca HF. 1,24,25-Trihydroxyvitamin D3. A metabolite of vitamin D3 effective on intestine. J Biol Chem 1973; 248: 6691–6696.

    PubMed  CAS  Google Scholar 

  27. Ornoy A, Goodwin D, Noff D, Edelstein S. 24,25-Dihydroxyvitamin D is a metabolite of vitamin D essential for bone formation. Nature 1978; 276: 517–519.

    Article  PubMed  CAS  Google Scholar 

  28. Rasmussen H, Bordier P. Vitamin D and bone. Metab Bone Dis Rel Res 1978; 1: 7–13.

    Article  CAS  Google Scholar 

  29. Henry HL, Norman AW. Vitamin D: two dihydroxylated metabolites are required for normal chicken egg hatchability. Science 1978; 201: 835–837.

    Article  PubMed  CAS  Google Scholar 

  30. Jones G, Vriezen D, Lohnes D, Palda V, Edwards NS. Side chain hydroxylation of vitamin D3 and its physiological implications. Steroids 1987; 49: 29–55.

    Article  PubMed  CAS  Google Scholar 

  31. Makin G, Lohnes D, Byford V, Ray R, Jones G. Target cell metabolism of 1,25-dihydroxyvitamin D3 to calcitroic acid. Evidence for a pathway in kidney and bone involving 24-oxidation. Biochem J 1989; 262: 173–180.

    PubMed  CAS  Google Scholar 

  32. Reddy GS, Tserng K-Y. Calcitroic acid, end product of renal metabolism of 1,25-dihydroxyvitamin D3 through C-24 oxidation pathway. Biochemistry 1989; 28: 1763–1769.

    Article  PubMed  CAS  Google Scholar 

  33. Esvelt RP, Schnoes HK, DeLuca HF. Isolation and characterization of la-hydroxy-23-carboxytetranorvitamin D: a major metabolite of 1,25-dihydroxyvitamin D3. Biochemistry 1979; 18: 3977–3983.

    Article  PubMed  CAS  Google Scholar 

  34. Knutson JC, DeLuca HF. 25-Hydroxyvitamin D3–24-hydroxylase. Subcellular location and properties. Biochemistry 1974; 13: 1543–1548.

    Article  PubMed  CAS  Google Scholar 

  35. Ohyama Y, Noshiro M, Okuda K. Cloning and expression of cDNA encoding 25-hydroxyvitamin D3 24-hydroxylase. FEBS Lett 1991; 278: 195–198.

    Article  PubMed  CAS  Google Scholar 

  36. Ohyama Y, Okuda K. Isolation and characterization of a cytochrome P450 from rat kidney mitochondria that catalyzes the 24-hydroxylation of 25-hydroxyvitamin D3. J Biol Chem 1991; 266: 8690–8695.

    PubMed  CAS  Google Scholar 

  37. Tomon M, Tenenhouse HS, Jones G. Expression of 25-hydroxyvitamin D3–24-hydroxylase activity in CaCo-2 cells. An in vitro model of intestinal vitamin D catabolism. Endocrinology 1990; 126: 2868–2875.

    Article  PubMed  CAS  Google Scholar 

  38. Bouillon R, Okamura WH, Norman AW. Structure-function relationships in the vitamin D endocrine system. Endocr Rev 1995; 16: 200–257.

    PubMed  CAS  Google Scholar 

  39. Suda T, DeLuca HF, Schnoes HK, Tanaka Y, Holick MF. 25,26-dihydroxyvitamin D3, a metabolite of vitamin D3 with intestinal transport activity. Biochemistry 1970; 9: 4776–4780.

    Article  PubMed  Google Scholar 

  40. Horst RL. 25-OH-D3-26,23-Lactone: a metabolite of vitamin D3 that is 5 times more potent than 25OH-D3 in the rat plasma competitive protein binding radioassay. Biochem Biophys Res Commun 1979; 89:286–293.

    Google Scholar 

  41. Yamada S, Nakayama K, Takayama H, Shinki T, Takasaki Y, Suda T. Isolation, identification and metabolism of (23S,25R)-25-hydroxyvitamin D3–26,23-lactol: a biosynthetic precursor of (23S,25R)-25-hydroxyvitamin D3–26,23-lactone. J Biol Chem 1984; 259: 884–889.

    PubMed  CAS  Google Scholar 

  42. Akiyoshi-Shibata M, Sakaki T, Ohyama Y, Noshiro M, Okuda K, Yabusaki Y. Further oxidation of hydroxycalcidiol by calcidiol 24-hydroxylase-a study with the mature enzyme expressed in Escherichia coli. Eur J Biochem 1994; 224: 335–343.

    Article  PubMed  CAS  Google Scholar 

  43. Beckman M, Tadikonda P, Werner E, Prahl JM, Yamada S, DeLuca HF. Human 25-hydroxyvitamin D3–24-hydroxylase, a multicatalytic enzyme. Biochemistry 1996; 35: 8465–8472.

    Article  PubMed  CAS  Google Scholar 

  44. Ishizuka S, Ishimoto S, Norman AW. Isolation and identification of 1a,25-dihydroxy-24-oxovitamin D3, 1a,25-dihydroxyvitamin D3–26,23-lactone, la,24(S),25-trihydroxyvitamin D3: in vivo metabolites of 1a,25-dihydroxyvitamin D3. Biochemistry 1984; 23: 1473–1478.

    CAS  Google Scholar 

  45. Shinki T, Jin CH, Nishimura A, Nagai Y, Ohyama Y, Noshiro M, Okuda K, Suda T. Parathyroid hormone inhibits 25-hydroxyvitamin D3–24-hydroxylase mRNA expression stimulated by 1a,25dihydroxyvitamin D3 in rat kidney but not in intestine. J Biol Chem 1992; 267:13, 757–13, 762.

    Google Scholar 

  46. Lohnes D, Jones G. Further metabolism of 1a,25-dihydroxyvitamin D3 in target cells. J Nutr Sci Vitam Special Issue. 1992; 75–78.

    Google Scholar 

  47. St-Arnaud R, Arabian A, Travers R, Glorieux FH. Abnormal intramembranous ossification in mice deficient for the vitamin D 24-hydroxylase gene. In: Vitamin D. Chemistry, Biology and Clinical Applications of the Steroid Hormone. Norman AW, Bouillon, R, Thomasset M, eds. Vitamin D Workshop, Inc., University of California Press, Riverside, CA. 1997; 635–639.

    Google Scholar 

  48. St-Arnaud R, Arabian A, Travers R, Glorieux FH. Partial rescue of abnormal bone formation in 24hydroxylase knock-out mice supports a role for 24,25(OH)2D3 in intramembranous ossification. J Bone Miner Res 1997; 12: 33 (abstract 5111).

    Article  Google Scholar 

  49. Esvelt RP, DeLuca HF. Calcitroic acid: biological activity and tissue distribution studies. Arch Biochem Biophys 1980; 206: 404–413.

    Google Scholar 

  50. Suda T, DeLuca HF, Schnoes HK, Blunt JW. Isolation and identification of 25-hydroxyergocalciferol. Biochemistry 1969; 8: 3515–3520.

    Article  PubMed  CAS  Google Scholar 

  51. Jones G, Schnoes HK, DeLuca, HF. Isolation and identification of 1,25-dihydroxyvitamin D2. Biochemistry 1975; 14: 1250–1256.

    Article  PubMed  CAS  Google Scholar 

  52. Jones G, Rosenthal A, Segev D, Mazur Y, Frolow F, Halfon Y, Rabinovich D, Shakked Z. Isolation and identification of 24,25-dihydroxyvitamin D2 using the perfused rat kidney. Biochemistry 1979; 18: 1094–1101.

    Article  PubMed  CAS  Google Scholar 

  53. Jones G, Schnoes HK, Levan L, DeLuca HF. Isolation and identification of 24-hydroxyvitamin D2 and 24,25-dihydroxyvitamin D2. Arch Biochem Biophys 1980; 202: 450–457.

    Article  PubMed  CAS  Google Scholar 

  54. Horst RL, Koszewski NJ, Reinhardt TA. 1 a-Hydroxylation of 24-hydroxyvitamin D2 represents a minor physiological pathway for the activation of vitamin D2 in mammals. Biochemistry 1990; 29: 578–582.

    Article  PubMed  CAS  Google Scholar 

  55. Koszewski NJ, Reinhardt TA, Napoli JL, Beitz DC, Horst RL. 24,26-Dihydroxyvitamin D2: a unique physiological metabolite of vitamin D2. Biochemistry 1988; 27: 5785–5790.

    Article  PubMed  CAS  Google Scholar 

  56. Reddy GS, Tserng K-Y. Isolation and identification of 1,24,25-trihydroxyvitamin D2, 1,24,25,28tetrahydroxyvitamin D2, 1,24,25,26-tetrahydroxyvitamin D2: new metabolites of 1,25-dihydroxyvitamin D2 produced in the rat kidney. Biochemistry 1986; 25: 5328–5336.

    CAS  Google Scholar 

  57. Horst RL, Koszewski NJ, Reinhardt TA. Species variation of vitamin D metabolism and action: lessons to be learned from farm animals. In: Vitamin D. Molecular, Cellular and Clinical Endocrinology. Norman AW, Schaefer K, Grigoleit H-G, von Herrath D, eds. Berlin: de Gruyter, 1988; 93–101.

    Google Scholar 

  58. Clark JW, Reddy GS, Santos-Moore A, Wankadiya KF, Reddy GP, Lasky S, Tserng K-Y, Uskokovic MR. Metabolism and biological activity of 1,25-dihydroxyvitamin D2 and its metabolites in a chronic myelogenous leukemia cell line, RWLEU-4. Bioorg Med Lett 1993; 3: 1873–1878.

    Article  CAS  Google Scholar 

  59. Jones G, Byford V, Kremer R, Makin HLJ, Rice RH, deGraffenreid LA, Knutson JC, Bishop CA. Anti-proliferative activity and target cell catabolism of the vitamin D analog, 1a,24(S)-dihydroxyvitamin D2 in normal and immortalized human epidermal cells. Biochem Pharmacol 1996; 52: 133–140.

    Article  PubMed  CAS  Google Scholar 

  60. Suda T, Hallick RB, DeLuca HF, Schnoes HK. 25-hydroxydihydrotachysterol3 Synthesis and biological activity. Biochemistry 1970; 9: 1651–1657.

    Article  PubMed  CAS  Google Scholar 

  61. Bosch R, Versluis C, Terlouw JK, Thijssen JHH, Duursma SA. Isolation and identification of 25hydroxydihydrotachysterol2, 1a,25-dihydroxydihydrotachysterol2 and 1ß,25-dihydroxydihydrotachysterol2. J Steroid Biochem 1985; 23: 223–229.

    Article  PubMed  CAS  Google Scholar 

  62. Jones G, Edwards N, Vriezen D, Porteous C, Trafford DJH, Cunningham J, Makin HLJ. Isolation and identification of seven metabolites of 25-hydroxy-dihydrotachysterol3 formed in the isolated perfused rat kidney: a model for the study of side-chain metabolism of vitamin D. Biochemistry 1988; 27: 7070–7079.

    Article  PubMed  CAS  Google Scholar 

  63. Qaw F, Calverley MJ, Schroeder NJ, Trafford DJH, Makin HLJ, Jones G. In vivo metabolism of the vitamin D analog, dihydrotachysterol. Evidence for formation of la,25- and 10,25-dihydroxydihydrotachysterol metabolites and studies of their biological activity. J Biol Chem 1993; 268: 282–292.

    PubMed  CAS  Google Scholar 

  64. Bhattacharyya MH, DeLuca HF. Comparative studies on the 25-hydroxylation of vitamin D3 and dihydrotachysterol3. J Biol Chem 1973; 248: 2974–2977.

    PubMed  CAS  Google Scholar 

  65. Wing RM, Okamura WH, Pirio MP, Sine SM, Norman AW. Vitamin D in solution: conformations of vitamin D3, 1,25-dihydroxyvitamin D3 and dihydrotachysterol3. Science 1974; 186: 939–941.

    CAS  Google Scholar 

  66. Shany S, Ren S-Y, Arbelle JE, Clemens TL, Adams JS. Subcellular localization and partial purification of the 25-hydroxyvitamin D-1-hydroxylation reaction in the avian myelomonocytic cell line HD-11. J Bone Miner 1993; 8: 269–276.

    Article  CAS  Google Scholar 

  67. Qaw F, Schroeder NJ, Calverley MJ, Maestro M, Mourino A, Trafford DJH, Makin, HLJ, Jones G. In vitro synthesis of 1,25-dihydroxydihydrotachysterol in the myelomonocytic cell line, HD-11. J Bone Miner Res 1992; 7: 5161 (abstract 274).

    Google Scholar 

  68. Qaw FS, Makin HLJ, Jones G. Metabolism of 25-hydroxy-dihydrotachysterol3 in bone cells in vitro. Steroids 1992; 57: 236–243.

    Article  PubMed  CAS  Google Scholar 

  69. Schroeder NJ, Qaw F, Calverley MJ, Trafford DJH, Jones G, Makin HLJ. Polar metabolites of dihydrotachysterol3 in the rat: comparison with in vitro metabolites of la,25-dihydroxydihydrotachysterol3. Biochem Pharm 1992; 43: 1893–1905.

    Article  PubMed  CAS  Google Scholar 

  70. Holick MF, Semmler E, Schnoes HK, DeLuca HF. la-Hydroxy derivative of vitamin D3: a highly potent analog of la,25-dihydroxyvitamin D3. Science 1973; 180: 190, 191.

    Google Scholar 

  71. Barton DH, Hesse RH, Pechet MM, Rizzardo E. A convenient synthesis of la-hydroxy-vitamin D3. J Am Chem Soc 1973; 95: 2748–2749.

    Article  PubMed  CAS  Google Scholar 

  72. Gallagher JC, Goldgar D. Treatment of postmenopausal osteoporosis with high doses of synthetic calcitriol. A randomized control study. Ann Intern Med 1990; 113: 649–655.

    PubMed  CAS  Google Scholar 

  73. Strugnell S, Byford V, Makin HLJ, Moriarty RM, Gilardi R, LeVan LW, Knutson JC, Bishop CW, Jones G. 1a,24(S)-dihydroxyvitamin D2: a biologically active product of la-hydroxyvitamin D2 made in the human hepatoma, Hep3B. Biochem J 1995; 310: 233–241.

    PubMed  CAS  Google Scholar 

  74. Sjoden G, Smith C, Lindgren V, DeLuca HF. 1-Alpha-hydroxyvitamin D2 is less toxic than 1-alphahydroxyvitamin D3 in the rat. Proc Soc Exp Biol Med 1985; 178: 432–436.

    PubMed  CAS  Google Scholar 

  75. Frazao JM, Chesney RW, Coburn JW, the la-OH-D2 Study Group. Intermittent oral la-hydroxyvitamin D2 is effective and safe for the suppression of secondary hyperparathyroidism in haemedialysis patients. Nephrol Dial Transplant 1998; 13 (Suppl 3): 68–72.

    Article  PubMed  CAS  Google Scholar 

  76. Calverley MJ. Synthesis of MC-903, a biologically active vitamin D metabolite analog. Tetrahedron 1987; 43: 4609–4619.

    Article  CAS  Google Scholar 

  77. Kragballe K, Gjertsen BT, De Hoop D, Karlsmark T, van de Kerkhof PC, Larko O, Nieboer C, Roed-Petersen J, Strand A, Tikjob G. Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris. Lancet 1991; 337: 193–196.

    Article  PubMed  CAS  Google Scholar 

  78. Jones G, Calverley MJ. A dialogue on analogues: newer vitamin-D drugs for use in bone disease, psoriasis, and cancer. Trends Endocrinol Metab 1993; 4: 297–303.

    Article  PubMed  CAS  Google Scholar 

  79. Binderup L. MC903-A novel vitamin D analogue with potent effects on cell proliferation and cell differentiation. In: Vitamin D. Molecular, Cellular and Clinical Endocrinology. Norman AW, Schaefer K, Grigoleit H-G, von Herrath D, eds. Berlin: de Gruyter, 1988; 300–309.

    Google Scholar 

  80. Sorensen H, Binderup L, Calverley MJ, Hoffmeyer L, Rastrup Anderson N. In vitro metabolism of calcipotriol (MC 903), a vitamin D analogue. Biochem Pharmacol 1990; 39: 391–393.

    Article  PubMed  CAS  Google Scholar 

  81. Masuda S, Strugnell S, Calverley MJ, Makin HLJ, Kremer R, Jones, G. In vitro metabolism of the anti-psoriatic vitamin D analog, calcipotriol, in two cultured human keratinocyte models. J Biol Chem 1994; 269: 4794–4803.

    PubMed  CAS  Google Scholar 

  82. Murayama E, Miyamoto K, Kubodera N, Mori T, Matsunaga I. Synthetic studies of vitamin D analogues. VIII. Synthesis of 22-oxavitamin D3 analogues. Chem Pharm Bull (Tokyo) 1986; 34: 4410–4413.

    Article  CAS  Google Scholar 

  83. Hansen K, Calverley MJ, Binderup L. Synthesis and biological activity of 22-oxa vitamin D analogues. In: Vitamin D. Gene Regulation, Structure-Function Analysis and Clinical Application. Norman AW, Bouillon R, Thomasset M, eds. Berlin: de Gruyter, 1991; 161–162.

    Google Scholar 

  84. Brown AJ, Berkoben M, Ritter C, Kubodera N, Nishii Y, Slatopolsky E. Metabolism of 22-oxacalcitriol by a vitamin D-inducible pathway in cultured parathyroid cells. Biochem Biophys Res Commun 1992; 189: 759–764.

    Article  PubMed  CAS  Google Scholar 

  85. Bikle DD, Abe-Hashimoto J, Su MJ, Felt S, Gibson DFC, Pillai S. 22-Oxa-calcitriol is a less potent regulator of keratinocyte proliferation and differentiation due to decreased cellular uptake and enhanced catabolism. J Invest Dermatol 1995; 105: 693–698.

    Article  PubMed  CAS  Google Scholar 

  86. Masuda S, Byford V, Kremer R, Makin HLJ, Kubodera N, Nishii Y, Okazaki A, Okano T, Kobayashi T, Jones G. In vitro metabolism of the vitamin D analog, 22-oxacalcitriol, using cultured osteosarcoma, hepatoma and keratinocyte cell lines. J Biol Chem 1996; 271: 8700–8708.

    Article  PubMed  CAS  Google Scholar 

  87. Kobayashi T, Tsugawa N, Okano T, Masuda S, Takeuchi A, Kubodera N, Nishii Y. The binding properties with blood proteins and tissue distribution of 22-oxa- 1 a,25-dihydroxyvitamin D3, a noncalcemic analogue of 1a,25-dihydroxyvitamin D3 in rats. J Biochem 1994; 115: 373–380.

    PubMed  CAS  Google Scholar 

  88. Dilworth FJ, Calverley MJ, Makin HLJ, Jones G. Increased biological activity of 20-epi-1,25dihydroxyvitamin D3 is due to reduced catabolism and altered protein binding. Biochem Pharmacol 1994; 47: 987–993.

    Article  PubMed  CAS  Google Scholar 

  89. Dilworth FJ, Scott I, Green A, Strugnell S, Guo Y-D, Roberts EA, Kremer R, Calverley MJ, Makin HLJ, Jones G. Different mechanisms of hydroxylation site selection by liver and kidney cytochrome P450 species (CYP27 and CYP24) involved in vitamin D metabolism. J Biol Chem 1995; 270: 16, 766–16, 774.

    Google Scholar 

  90. Kissmeyer A-M, Mathiasen IS, Latini S, Binderup L. Pharmacokinetic studies of vitamin D analogues: relationship to vitamin D binding protein (DBP). Endocrine 1995; 3: 263–266.

    Article  PubMed  CAS  Google Scholar 

  91. Dilworth FJ, Williams GR, Kissmeyer A-M, LOgsted-Nielsen J, Binderup E, Calverley MJ, Makin HLJ, Jones G. The vitamin D analog, KH1060 is rapidly degraded both in vivo and in vitro via several pathways: principal metabolites generated retain significant biological activity. Endocrinology 1997; 138: 5485–5496.

    Article  PubMed  CAS  Google Scholar 

  92. Rastrup-Anderson N, Buchwald FA, Grue-Sorensen G. Identification and synthesis of a metabolite of KH1060, a new potent la,25-dihydroxyvitamin D3 analogue. Bioorg Med Chem Lett 1992; 2: 1713–1716.

    Article  Google Scholar 

  93. Kobayashi Y, Taguchi T, Mitsuhashi S, Eguchi T, Ohshima E, Ikekawa N. Studies on organic fluorine compounds. XXXIX. Studies on steroids. LXXIX. Synthesis of la,25-dihydroxy-26,26, 26,27,27,27-hexaflurovitamin D3. Chem Pharm Bull (Tokyo) 1982; 30: 4297–4303.

    Article  CAS  Google Scholar 

  94. Koeffler HP, Armatruda T, Ikekawa N, Kobayashi Y, DeLuca HF. Induction of macrophage differentiation of human normal and leukemic myeloid stem cells by la,25-dihydroxyvitamin D3 and its fluorinated analogs. Cancer Res 1984; 44: 6524–6528.

    Google Scholar 

  95. Inaba M, Okuno S, Nishizawa Y, Yukioka K, Otani S, Matsui-Yuasa I, Morisawa S, DeLuca HF, Morii H. Biological activity of fluorinated vitamin D analogs at C-26 and C-27 on human promyelocytic leukemia cells, HL-60. Arch Biochem Biophys 1987; 258: 421–425.

    Article  PubMed  CAS  Google Scholar 

  96. Kistler A, Galli B, Horst R, Truitt GA, Uskokovic MR. Effects of vitamin D derivatives on soft tissue calcification in neonatal and calcium mobilization in adult rats. Arch Toxicol 1989; 63: 394–400.

    Article  PubMed  CAS  Google Scholar 

  97. Inaba M, Okuno S, Nishizawa Y, Imanishi Y, Katsumata T, Sugata I, Morii H. Effect of substituting fluorine for hydrogen at C-26 and C-27 on the side chain of la,25-dihydroxyvitamin D3. Biochem Pharmacol 1993; 45: 2331–2336.

    Article  PubMed  CAS  Google Scholar 

  98. Sasaki H, Harada H, Hanada Y, Morino H, Suzawa M, Shimpo E, Katsumata T, Masuhiro Y, Matsuda K, Ebihara K, Ono T, Matsushige S, Kato S. Transcriptional activity of a fluorinated vitamin D analog on VDR-RXR-mediated gene suppression. Biochemistry 1995; 34: 370–377.

    Article  PubMed  CAS  Google Scholar 

  99. Nakatsuka K, Imanishi Y, Morishima Y, Sekiya K, Sasao K, Mild T, Nishizawa Y, Katsumata T, Nagata A, Murakawa S. Biological potency of a fluorinated vitamin D analogue in hypoparathyroidism. Bone Miner 1992; 16: 73–81.

    Article  PubMed  CAS  Google Scholar 

  100. Nishizawa Y, Morii H, Ogura Y, DeLuca HF. Clinical trial of 26,26,26,27,27,27-hexaflurola,25-dihydroxyvitamin D3 in uremic patients on hemodialysis: preliminary report. Contrib Nephrol 1991; 90: 196–203.

    PubMed  CAS  Google Scholar 

  101. Zhou J-Y, Norman AW, Chen D-L, Sun G, Uskokovic M, Koeffler HP. 1,25-Dihydroxy-16ene-23-yne-vitamin D3 prolongs survival time of leukemic mice. Proc Natl Acad Sci USA 1990; 87: 3929–3932.

    Article  PubMed  CAS  Google Scholar 

  102. Binderup E, Calverley MJ, Binderup L. Synthesis and biological activity of la-hydroxylated vitamin D analogues with poly-unsaturated side chains. In: Vitamin D: Gene Regulation, Structure-Function Analysis and Clinical Application. Norman AW, Bouillon R, Thomasset M, eds. Berlin: de Gruyter, 1991; 192, 193.

    Google Scholar 

  103. Colston KW, Mackay AG, James SY, Binderup L, Chandler S, Coombes RC. EB 1089: a new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro. Biochem Pharmacol 1992; 44: 2273–2280.

    Article  PubMed  CAS  Google Scholar 

  104. James SY, Mackay AG, Binderup L, Colston KW. Effects of a new synthetic analogue, EB 1089, on the oestrogen-responsive growth of human breast cancer cells. J Endocrinol 1994; 141: 555–563.

    Article  PubMed  CAS  Google Scholar 

  105. Reddy GS, Clark JW, Tserng K-Y, Uskokovic MR, McLane JA. Metabolism of 1,25(OH)2–16-ene D3 in kidney: influence of structural modification of D-ring on side chain metabolism. Bioorg Med Lett 1993; 3: 1879–1884.

    Article  CAS  Google Scholar 

  106. Satchell DP, Norman AW. Metabolism of the cell differentiating agent 1,25(OH)2–16-ene-23-yne vitamin D3 by leukemic cells. J Steroid Biochem Mol Biol 1996; 57: 117–124.

    Article  PubMed  CAS  Google Scholar 

  107. Dantuluri PK, Haning C, Uskokovic MR, Tserng K-Y, Reddy GS. Isolation and identification of 1,25,26(OH)3-16-ene-23-yne D3, a metabolite of 1,25(OH)2-16-ene-23-yne D3 produced in the kidney. In: Ninth Workshop on Vitamin D Abstract Book, Orlando, May 28-June 2 1994, abstract #43, p. 32.

    Google Scholar 

  108. Shankar VN, Makin HLJ, Schroeder NJ, Trafford DJH, Kissmeyer A-M, Calverley MJ, Binderup E, Jones G. Metabolism of the antiproliferative vitamin D analogue, EB 1089, in a cultured human keratinocyte model. Bone 1995; 17: 326 (abstract).

    Article  Google Scholar 

  109. Shankar VN, Dilworth FJ, Makin HLJ, Schroeder NJ, Trafford DAJ, Kissmeyer A-M, Calverley MJ, Binderup E, Jones G. Metabolism of the vitamin D analog EB 1089 by cultured human cells: redirection of hydroxylation site to distal carbons of the side chain. Biochem Pharmacol 1997; 53: 783–793.

    Article  PubMed  CAS  Google Scholar 

  110. Kissmeyer A-M, Binderup E, Binderup L, Hansen CM, Andersen NR, Schroeder NJ, Makin HLJ, Shankar VN, Jones G. The metabolism of the vitamin D analog EB 1089: identification of in vivo and in vitro metabolites and their biological activities. Biochem Pharmacol 1977; 53: 1087–1097.

    Article  Google Scholar 

  111. Dilworth FJ, Scott I, Calverley MJ, Makin HLJ, Jones G. Enzymes of side chain oxidation pathway not affected by addition of methyl groups to end of the vitamin D3 side chain. J Bone Miner Res 1995; 10: S388 (abstract M546).

    Google Scholar 

  112. Wandkadiya KF, Uskokovic MR, Clark J, Tserng K-Y, Reddy GS. Novel evidence for the reduction of the double bond in 022–1,25-dihydroxyvitamin D3. J Bone Miner Res 1992; 7: S171 (abstract 315).

    Google Scholar 

  113. Jones G, Lohnes D, Strugnell S, Guo Y-D, Masuda S, Byford V, Makin HLJ, Calverley MJ. Target cell metabolism of vitamin D and its analogs. In: Vitamin D. A Pluripotent Steroid Hormone: Structural Studies, Molecular Endocrinology and Clinical Applications. Norman AW, Bouillon R, Thomasset M, eds. Berlin: de Gruyter, 1994; 161–169.

    Google Scholar 

  114. Cheskis B, Lemon BD, Uskokovic MR, Lomedico PT, Freedman LP. Vitamin D3-retinoid X receptor dimerization, DNA binding, and transactivation are differentially affected by analogs of 1,25dihydroxyvitamin D3. Mol Endocrinol 1995; 9: 1814–1824.

    Article  PubMed  CAS  Google Scholar 

  115. Peleg S, Sastry M, Collins ED, Bishop JE, Norman AW. Distinct conformational changes induced by 20-epi analogues of la,25-dihydroxyvitamin D3 are associated with enhanced activation of the vitamin D receptor. J Biol Chem 1995; 270:10, 551–10, 558.

    Google Scholar 

  116. Nayeri S, Danielsson C, Kahlen J, Schrader M, Mathiasen IS, Binderup L, Carlberg C. The anti-proliferative effect of vitamin D3 analogues is not mediated by inhibition of the AP-1 pathway, but may be related to promoter selectivity. Oncogene 1995; 11: 1853–1858.

    PubMed  CAS  Google Scholar 

  117. Bouillon R, Allewaert K, Xiang DZ, Tan BK, Van Baelen H. Vitamin D analogs with low affinity for the vitamin D binding protein: Enhanced in vitro and decreased in vivo activity. J Bone Miner Res 1991; 6: 1051–1057.

    Article  PubMed  CAS  Google Scholar 

  118. Dusso AS, Negrea L, Gunawardhana S, Lopez-Hilker S, Finch J, Mori T, Nishii Y, Slatopolsky E, Brown AJ. On the mechanisms for the selective action of vitamin D analogs. Endocrinology 1991; 128: 1687–1692.

    Article  PubMed  CAS  Google Scholar 

  119. Lohnes D, Mark M, Mendelsohn C, Dolle P, Dierich A, Gorry P, Gansmuller A, Chambon P. Function of the retinoic acid receptors (RARs) during development. (I) Craniofacial and skeletal abnormalities in RAR double mutants. Development 1994; 120: 2723–2748.

    PubMed  CAS  Google Scholar 

  120. Paaren HE, Hamer DE, Schnoes HK, DeLuca HF. Direct C-1 hydroxylation of vitamin D compounds: convenient preparation of la-hydroxyvitamin D3, la,25-dihydroxyvitamin D3 and la-hydroxyvitamin D2. Proc Natl Acad Sci USA 1978; 75: 2080, 2081.

    Google Scholar 

  121. Baggiolini EG, Wovkulich PM, Iacobelli JA, Hennessy BM, Uskokovic MR. Preparation of 1-alpha hydroxylated vitamin D metabolites by total synthesis. In: Vitamin D: Chemical, Biochemical and Clinical Endocrinology of Calcium Metabolism. Norman AW, Schaefer K, von Herrath D, Grigoleit H-G, eds. Berlin: de Gruyter, 1982; 1089–1100.

    Google Scholar 

  122. Perlman KL, Sicinski RR, Schnoes HK, DeLuca HF 1a,25-Dihydroxy-19-nor-vitamin D3, a novel vitamin D-related compound with potential therapeutic activity. Tetrahedron Lett 1990; 31: 1823, 1824.

    Google Scholar 

  123. Baggiolini EG, Partridge JJ, Shiuey S-J, Truitt GA, Uskokovic MR. Cholecalciferol 23-yne derivatives, their pharmaceutical compositions, their use in the treatment of calcium-related diseases, and their antitumor activity, US 4,804,502. Chem Abstr 1989; 111: 58160d (abstract).

    Google Scholar 

  124. Calverley MJ, Binderup E, Binderup L. The 20-epi modification in the vitamin D series: selective enhancement of “non-classical” receptor-mediated effects. In: Vitamin D: Gene Regulation, Structure-Function Analysis and Clinical Application. Norman AW, Bouillon R, Thomasset M, eds. Berlin: de Gruyter, 1991; 163, 164.

    Google Scholar 

  125. Nishii Y, Sato K, Kobayashi T. The development of vitamin D analogues for the treatment of osteoporosis. Osteoporos Int 1993; 1 (Suppl): S190–193.

    Article  Google Scholar 

  126. Morisaki M, Koizumi N, Ikekawa N, Takeshita T, Ishimoto S. Synthesis of active forms of vitamin D. Part IX. Synthesis of la,24-dihydroxycholecalciferol. J Chem Soc Perkin Trans 1975; 1: 1421–1424.

    Article  Google Scholar 

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Jones, G. (1999). Metabolism and Catabolism of Vitamin D, Its Metabolites, and Clinically Relevant Analogs. In: Holick, M.F. (eds) Vitamin D. Nutrition and Health. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-4757-2861-3_4

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  • DOI: https://doi.org/10.1007/978-1-4757-2861-3_4

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