Abstract
The past two decades have witnessed new facets in vitamin D metabolism. Free vitamin D3 till now considered to be limited to animal sources, has been shown to occur in plants. Further, the extrarenal synthesis of active vitamin D3 or calcitriol has been documented in physiological as well as in certain pathological conditions. At the cellular level, calcitriol acts through a dual mechanism. The genomic pathway involves the vitamin D receptor (VDR) which is of ubiquitous distribution and linked with various diseases. Besides, a nongenomic VDR—independent pathway also exists. The biological effects of calcitriol can no longer be dismissed by merely referring to calcium/bone homeostasis. It enhances the perinatal growth and suppresses the abnormal growth, as well. The effects on the endocrine, immune, cardiovascular, reproductive and nervous systems have also been characterized. It is compelling to believe that calcitriol and/or its analogues will find extensive applications at least in the treatment of osteoporosis, perinatal growth retardation, neoplasia, psoriasis, insulin resistance and transplantation.
Similar content being viewed by others
References
Prema, T.P. and Raghuramulu, N. (1996) Vitamin D3 and its metabolites in the tomato plant. Phytochemistry 42, 617–620.
Holick, M.F. (1995) Environmental factors that influence the cutaneous production of vitamin D. Am. J. Clin. Nutr. 61 (Suppl), 638S-645S.
Reichel, H., Koeffler, H.P. and Norman, A.W. (1989) The role of the vitamin D endocrine system in health and disease. N. Engl. J. Med. 320, 980–991.
Singh, K.P. and Dash, R.J. (1997) Vitamin D endocrine system. J. Assoc. Physicians India, 45, 559–568.
Norman, A.W., Nemere, I., Zhou, L.X., Bishop, J.E., Lowe, K.E., Maiyar, A.C., Collins, E.D., Taoka, T., Sergeev, I. and Farach-Carson, M.C. (1992) 1,25 (OH)2-vitamin D3, a steroid hormone that produces biological effects via both genomic and nongenomic pathways. J. Steroid Biochem. Mol. Biol. 41, 231–240.
Gouillon, R., Okamura, W.H. and Norman, A.W. (1995) Structure-function relationships in the vitamin D3 endocrine system. Endocr. Rev. 16, 200–257.
Slatter, S.J., Kelly, M.B., Taddeo, F.J., Larkin, J.D., Yeager, M.D., McLanes, J.A., Ho, C. and Stubbs, C.D. (1995) Direct activation of protein kinase C by 1α, 25-Dihydroxyvitamin D3. J. Biol. Chem. 270, 6639–6643.
Christakos, S., Raval-Pandya, M., Wernyj, R.P. and Yang, W. (1996) Genomic mechanisms involved in the pleiotropic actions of 1,25-dihydroxyvitamin D3. Biochem. J. 316, 361–371.
Anzano, M.A., Smith, J.M., Uskokovic, M.R., Peer, C.W., Mullen, L.T., Letterio, J.J., Welsh, M.C., Shrader, M.W., Logsdon, D.L., Driver, C.L., Brown, C.C., Roberts, A.B. and Sporn, M.B. (1994) 1-α 25-dihydroxy-16-ene-23-yne-26, 27-hexafluorocholecalciferol (Ro24-5531), a new deltanoid (vitamin D analogue) for prevention of breast cancer in the rat. Cancer Res. 54, 1653–1656.
Skowronski, R.J., Peehl, D.M. and Feldman, D. (1995) Actions of vitamin D3 analogs on human prostate cancer cell lines: comparison with 1,25-Dihydroxyvitamin D3. Endocrinology 136, 20–26.
Brown, A.J. (1998) Vitamin D analogues. Am. J. Kidney Dis. 32 (Suppl), S25-S39.
Cohn, D.V., Fasciotto, B.H., Reese, B.K. and Zhang, J.X. (1995) Chromogranin A: a novel regulation of parathyroid gland secretion. J. Nutr. 125 (Suppl), 2015S-2019S.
Naveh-Many, T. and Silver, J. (1988) Regulation of calcitonin gene transcription by vitamin D metabolites in vivo in the rat. J. Clin. Invest. 81, 270–273.
Kurose, H., Yamaoka, K., Okada, S., Nakajima, S. and Seino, Y. (1990) 1,25-Dihydroxyvitamin D3 [1,25-(OH)2 D3] increases insulin-like growth factor (IGF-1) receptors in clonal osteoblastic cells. Study on interaction of IGF-1 and 1,25-(OH)2 D3. Endocrinology 126, 2088–2094.
Mundy, G.R. and Guise, T.A. (1999) Hormonal control of calcium homeostasis. Clin. Chem. 45, 1347–1352.
Krane, S.M. and Holick, M.F. (1998) Metabolic bone disease. In: Harrison's Principles of Internal Medicine, Eds. Fauci, A.S., Braunwald, E., Isselbacker, K.J., Wilson, J.D., Martin, J.B., Kasper, D.L., Hauser, S.L. and Longo, D.L.. McGraw-Hill, New York, 14th edn. vol 2, p. 2247–2259.
Malloy, P.J. and Feldman, D. (1999) Vitamin D resistance. Am. J. Med. 106, 355–370.
Carling, T., Kindmark, A., Hellman, P., Holmberg, L., Akerstrom, G. and Rastad, J. (1997) Vitamin D receptor alleles b, a, and T: risk factors for sporadic primary hyperparathyroidism (HPT) but not HPT of uremia or MEN 1. Biochem. Biophys. Res. Commun. 231, 329–332.
Walters, M.R. (1992) Newly identified actions of the vitamin D endocrine system. Endocr. Rev. 13, 719–764.
Clairmont, A., Tessmann, D., Stock, A., Nicolai, S., Stahl, W. and Sies, H. (1996) Induction of gap junctional intercellular communication by vitamin D in human skin fibroblasts is dependent on the nuclear vitamin D receptor. Carcinogenesis 17, 1389–1391.
Vu, D., Ong, J.M., Clemens, T.L. and Kern, P.A. (1996) 1,25-Dihydroxyvitamin D induces lipoprotein lipase expression in 3T3-L1 cells in association with adipocyte differentiation. Endocrinology 137, 1540–1544.
Lal, H., Marya, R.K. and Saini, A.S. (1986) Effect of vitamin D on hepatic cellular growth in the rat. Nutr. Res. 6, 809–813.
Marya, R.K., Lal, H., Chugh, K. and Saini, A.S. (1989). Effect of vitamin D administration during pregnancy on neonatal growth in the rat. Ann. Nutr. Metab. 33, 261–265.
Marya, R.K., Rathee, S., Dua, V. and Sangwan, K. (1988) Effect of vitamin D supplementation during pregnancy on foetal growth. Indian. J. Med. Res. 88, 488–492.
Marya, R.K., Saini, A.S., Lal, H. and Chugh, K. (1991) Effect of vitamin D supplementation in lactating rats on the neonatal growth. Indian J. Physiol. Pharmacol. 35, 170–174.
Marya, R.K., Saini, A.S., Lal, H. and Chugh, K. (1991) Role of vitamin D in perinatal growth in the rat. Nutr. Res. 11, 765–770.
Kaur, J., Marya, R.K., Rathee, S., Lal, H. and Singh, G.P. (1991) Effect of pharmacological doses of vitamin D during pregnancy on placental protein status and birth weight. Nutr. Res. 11, 1077–1081.
Lal, H. and Chugh, K. (1995) Metabolic and regulatory effects of branched chain amino acid supplementation. Nutr. Res. 15, 1717–1733.
Shabahang, M., Buras, R.R., Davoodi, F., Schumaker, L.M., Nauta, R.J. and Evans, S.R.T. (1993) 1,25-Dihydroxyvitamin D3 receptor as a marker of human colon carcinoma cell line differentiation and growth inhibition. Cancer Res. 53, 3712–3718.
Garland, C.F., Comstock, G.W., Garland, F.C., Helsing, K.J., Shaw, E.K. and Gorham, E.D. (1989) Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet ii, 1176–1178.
Boutron, M.C., Faivre, J., Marteau, P., Couillault, C., Senesse, P. and Quipourt, V. (1996) Calcium, phosphorus, vitamin D, dairy product and colorectal carcinogenesis: a French case-control study. Br. J. Cancer 74, 145–151.
Thomas, M.G., Nugent, K.P., Forbes, A. and Williamson, R.C.N. (1994) Calcipotriol inhibits rectal epithelial cell proliferation in ulcerative proctocolitis. Gut 35, 1718–1720.
Wali, R.K., Bissonnette, M., Khare, S., Aquino, B., Niedriela, S., Siutrin, M. and Brasitus, T.A. (1996) Protein kinase isoforms in the chemopreventive effects of a novel vitamin D analogue in rat colonic tumorigenesis. Gastroenterology 111, 118–126.
Nagakura, K., Abe, E., Suda, T., Hayakawa, M., Nakamura, H. and Tazakitt, H. (1986) Inhibitory effect of 1,α 25-dihydroxyvitamin D3 on the growth of the renal carcinoma cell line. Kidney Int. 29, 834–840.
Rocker, D., Ravid, A., Liberman, V.A., Garach-Jehoshua, O. and Koren, R. (1994) 1,25-Dihydroxyvitamin D3 potentiates the cytotoxic effect of TNF on human breast cancer cells. Mol. Cell. Endocrinol. 106, 157–162.
Yacobi, R., Koren, R., Liberman, U.A., Rotem, C., Wasserman, L. and Ravid, A. (1996) 1,25-dihydroxyvitamin D3 increases the sensitivity of human renal carcinoma cells to tumor necrosis factor α but not to interferon α or lymphokine-activated killer cells. J. Endocrinol. 149, 327–333.
Berger U., Wilson, P., McClelland, R.A., Colston, K., Haussler, M.R., Pike, J.W. and Coombes, R.C. (1987) Immunocytochemical detection of 1,25 dihydroxyvitamin D3 receptor in breast cancer. Cancer Res. 47, 6793–6799.
Colston, K.W., Berger, U. and Coombes, R.C. (1989) Possible role for vitamin D in controlling breast cancer cell proliferation. Lancet i, 188–191.
Escaleira, M.T.F., Sonhara, S. and Brentani, M.M. (1993) Sex steroids induced up-regulation of 1,25-(OH)2 vitamin D3 receptors in T47D breast cancer cells. J. Steroid Biochem. Mol. Biol 45, 257–263.
Koya, M., Eisman, J.A. and Suterhland, R.L. (1988) Regulation of epidermal growth factor receptor levels by 1,25-Dihydroxyvitamin D3 in human breast cancer cells. Cancer Res. 48, 2734–2739.
Sergeev, I.N. and Rhoten, W.B. (1998) Regulation of intracellular calcium in human breast cancer cells. Endocrine 9, 321–327.
Love-Schimenti, C.D., Gibson, D.F., Ratnam, A.V. and Bikle, D.D. (1996) Antiestrogen potentiation of antiproliferative effects of vitamin D3 analogues in breast cancer cells. Cancer Res. 56, 2789–2794.
Satani, H., Yamakawa, K., Kawamura, J., Mori, O., Saito, K., Kato, H., Tochigi, H., Sakurai, M. and Kato, T. (1997) Bone metabolism and phosphorus metabolism in patients with prostate cancer: paracrine and endocrine effects produced by prostate neoplasm. Hinyokika Kiyo 43, 849–854.
Peehl, D.M., Skowronski, R.J., Leung, G.K., Wong, S.T., Stamey, T.A. and Feldman, D. (1994) Antiproliferative effects of 1,25-dihydroxyvitamin D3 on primary cultures of human prostatic cells. Cancer Res. 54, 805–810.
Hedlund, T.E., Moffat, K.A. and Miller, G.J. (1996) Stable expression of the nuclear vitamin D receptor in the human prostatic carcinoma cell line JCA-1: Evidence that the antiproliferative effects of 1 α, 25-Dihydroxyvitamin D3 are mediated exclusively through the genomic signaling pathway. Endocrinology 137, 1554–1561.
Brown, T.R., Stonehouse, T.J., Branch, J.S., Brickell, P.M. and Katz, D.R. (1997) Stable transfection of U937 cells with sense or antisense RXR-alpha cDNA suggests a role for RXR-alpha in the control of monoblastic differentiation induced by retinoic acid and vitamin D. Exp. Cell Res. 236, 94–102.
Albert, D.M., Marcus, D.M., Gallo, J.P. and O'Brien, J.M. (1992) The antineoplastic effect of vitamin D in transgenic mice with retinoblastoma. Invest. Ophthalmol. Vis. Sci. 33, 2354–2364.
Solomon, C., White, J.H. and Kremer, R. (1999) Mitogen-activated protein kinase inhibits 1, 25-dihydroxyvitamin D3-dependent signal transduction by phosphorylating human retinoid X receptor α. J. Clin. Invest. 103, 1729–1735.
Hosoi, J., Abe, E., Suda T. and Kuroki, T. (1985) Regulation of melanin synthesis of B16 mouse melanoma cells by 1 α, 25-Dihydroxyvitamin D3 and retinoic acid. Cancer Res. 45, 1474–1478.
Fukuoka, M., Ohta, T. and Kiyoki, M. (1997) Novel pharmacological activity of a vitamin (novel pharmacological action of vitamin D). Nippon Yakurigaku Zasshi 110 (Suppl), 39P-43P.
Morimoto, S., Yoshikawa, K., Kozuka, T., Kitano, Y., Imanaka, S., Fukoo, K., Koh, E. and Kumahara, Y. (1986) An open study of vitamin D3 treatment in psoriasis vulgaris. Br. J. Dermatol. 115, 421–429.
Kragballe, K. (1989) Treatment of psoriasis by the topical application of the novel cholecalciferol analogue calcipotriol (MC903). Arch. Dermatol. 125, 1647–1652.
Schedl, H.P., Christensen, K.K. and Ronnenberg, W.C. (1995) Effects of diabetes on calcium uptake by rat brush border membrane vesicles. Clin. Exp. Pharmacol. Physiol. 22, 272–276.
Ozono, K., Seino, Y., Yano, H., Yamaoka, K. and Seino, Y. (1990) 1,25-Dihydroxyvitamin D3 enhances the effect of refeeding on steady state preproinsulin messenger ribonucleic acid levels in rats. Endocrinology 126, 2041–2045.
Bourlon, P-M., Faure-Dussert, A. and Billaudel, B. (1999) Thedenovo synthesis of numerous proteins is decreased during vitamin D3 deficiency and is gradually restored by 1,25-dihydroxyvitamin D3 repletion in the islet of Langerhans of rats. J. Endocrinol. 162, 101–109.
Bourlon, P.M., Faure-Dussert, A., Billaudel, B., Sutter, B.C.J., Tramu, G. and Thomasset, M. (1996) Relationship between calbindin-D28K levels in the A and B cells of the rat endocrine pancreas and the secretion of insulin and glucagon: influence of vitamin D3 deficiency and 1,25-dihydroxyvitamin D3. J. Endocrinol. 148, 223–232.
Raghunath, M. and Raghuramulu, N. (1992) Diabetes mellitus and vitamin D. In: Nutrition News, National Institute of Nutrition, Hyderabad vol. 13, p. 1–3.
Kautzky-Willer, A., Pacini, G., Barnas, U., Ludvik, B., Streli, C., Graf, H. and Prager, R. (1995) Intravenous calcitriol normalizes insulin sensitivity in uremic patients. Kidney Int. 47, 200–206.
Druml, W., Schwarzenhofer, M., Apsner, R. and Horl, W.H. (1998) Fat-soluble vitamins in patients with acute renal failure. Miner. Electrolyte Metab. 24, 220–226.
Wark, J.D. and Gurtler, V. (1988) Vitamin D-induction of secretory responses in rat pituitary tumour (GH4C1) cells. J. Endocrinol. 117, 293–298.
Manolagas, S.C., Yu, X.P., Girasole, G. and Bellido, T. (1994) Vitamin D and the hematolymphopoietic tissue: A 1994 update. Semin. Nephrol. 14, 129–143.
Hewison, M. (1992) Vitamin D and the immune system (commentary). J. Endocrinol. 132, 173–175.
Rigby, W.F.C., Denome, S. and Fanger, M.W. (1987) Regulation of lymphokine production and human T lymphocyte activation by 1,25-Dihydroxyvitamin D3. J. Clin. Invest. 79, 1659–1664.
Lemine, J.M., Adams, J.S., Sakai, R. and Jordan, S.C. (1984) 1α, 25-Dihydroxyvitamin D3 suppresses proliferation and immunoglobulin production by normal human peripheral blood mononuclear cells. J. Clin. Invest. 74, 657–661.
Yamamoto N., Naraparaju, V.R. and Asbell, S.O. (1996) Deglycosylation of serum vitamin D3-binding protein leads to immunosuppression in cancer patients. Cancer Res. 56, 2827–2831.
Safadi, F.F., Thornton, P., Magiera, H., Hollis, B.W., Gentile, M., Haddad, J.G., Liebhaber, S.A. and Cooke, N.E. (1999) Osteopathy and resistance to vitamin D toxicity in mice null for vitamin D binding protein. J. Clin. Invest. 103, 239–251.
Bikle, D.D. (1992) Clinical counterpoint: Vitamin D: New actions, new analogs, new therapeutic potential. Endocr. Rev. 13, 756–758.
Johnsson, C., Binderup, L. and Tufveson, G. (1995) The effects of combined treatment with the novel vitamin D analogue MC1288 and cyclosporine A on cardiac allograft survival. Transpl. Immunol. 3, 245–250.
Oshima, T. and Young, E.W. (1995) Systemic and cellular calcium metabolism and hypertension. Semin. Nephrol. 15, 496–503.
Bukoshi, R.D., Ishibashi, K. and Bian, K. (1995) Vascular actions of the calcium-regulating hormones. Semin. Nephrol. 15, 536–549.
Marya, R.K., Rathee, S. and Manrow, M. (1987) Effect of calcium and vitamin D supplementation on toxemia of pregnancy. Gynecol. Obstet. Invest. 24, 38–42.
Halloran, B.P. (1989) Is 1,25-Dihydroxyvitamin D required for reproduction? Proc. Soc. Exp. Biol. Med. 191, 227–232.
Sood, S., Reghunandanan, R., Reghunandanan, V., Marya, R.K. and Singh, P.I. (1995) Effect of vitamin D repletion on testicular function in vitamin D-deficient rats. Ann. Nutr. Metab. 39, 95–98.
Stumpf, W.E. and Privette, T.H. (1991) The steroid hormone of sunlight soltriol (vitamin D) as a seasonal regulator of biological activities and photoperiodic rhythms. J. Steroid Biochem. Mol. Biol. 39, 283–289.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lai, H., Pandey, R. & Aggarwal, S.K. Vitamin D: Actions for the new millennium. Indian J Clin Biochem 15 (Suppl 1), 158–168 (2000). https://doi.org/10.1007/BF02867555
Issue Date:
DOI: https://doi.org/10.1007/BF02867555