Abstract
Calcitriol (1α,25(OH)2D3), the hormonally active form of vitamin D3(D3) is produced by a cascade of reactions, including photochemical D3synthesis in the skin and subsequent hydroxylation at the C-25 atom in the liver and finally at C-1α position in the kidney. However, there is substantial evidence for additional extrarenal sites of calcitriol synthesis. In vitro, many nonrenal cells,including bone, placenta, prostata, keratinocytes, macrophages, T-lymphocytes and several cancer cells (e.g., from lung, prostata and skin) can enzymatically convert calcidiol (25OHD3) to 1a,25(OH)2D3. We have demonstrated that keratinocytes of the skin have unique properties in the D3pathway; they are not only capable of producing D3from 7-dehydrocholesterol (7-DHC), but also generate 1α,25(OH)2D3from the substrates 25OHD3, 1a-hydroxyvitamin D3(1α-OHD3) and even D3. It is evident that keratinocytes possess at least 1α- OH-, 25OH- and 24OHase activity, which is necessary for enzymatic conversion of D3to 1α,25(OH)2D3, and the 24OHase activity for initiation of catabolism of 1α,25(OH)2D3to more polar metabolites. Thus, the skin is apparently the only extrarenal tissue where the complete UVB-induced pathway from 7-DHC to 1α,25(OH)2D3takes place under physiological circumstances.
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References
Adams JS (1997) Extrarenal production and action of active vitamin D metabolites in human lymphoproliferative diseases. In: Feldman D, Glorieux FH, Pike JW (eds) Vitamin D. Academic Press, San Diego, pp 903–921
Andersson S, Davis D, Dahlb_ck H, Jõrnvall H, Russell DW (1989) Cloning, structure, and expression of the mitochondrial cytochrome P450 sterol 26-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem 264:8222–8229
Barbour GL, Coburn JW, Slatopolsky, Norman AW, Horst RL (1981) Hypercalcemia in an anephric patient with sarcoidosis: evidence for extrarenal generation of 1,25-dihydroxyvitamin D3. N Engl J Med 305:440–443
Bell NH (1998) Renal and non-renal 25-hydroxyvitamin D-1a-hydroxylases and their clinical expression. J Bone Miner Res 13:350–353
Bikle DD (1997) Vitamin D and skin. In: Feldman D, Glorieux FH, Pike JW (eds) Vitamin D. Academic Press, San Diego, pp 379–394
Bikle DD, Nemanic MK, Whitney JO, Elias PW (1986) Neonatal human foreskin keratinocytes produce 1,25-dihydrxyvitamin D3. Biochemistry 8:1545–1548
Brenza HL, Kimmel-Jehan C, Jehan F, Shinki T, Wakino S, Anazawa H, Suda T, Deluca HF (1998) Parathyroid hormone activation of the 25-hydroxyvitamin D3–1a-hydroxylase gene promotor. Proc Natl Acad Sci U S A 95:1387–1391
Cadranel J, Garabedian M, Milleron B, Guillozo H, Akoun G, Hance AJ (1990) 1,25(OH)2D3Production by T-lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis. J Clin Invest 85:1588–1593
Delvin EE, Arabian A, Glorieux FH, Mamer OA (1985) In vitro metabolism of 25-hydroxycholecalciferol by isolated cells from deciduas. J Clin Endocrinol Metab 60:880–885
Dusso AS, Finch J, Brown A, Ritter C, Delmez J, Schreiner G, Slatopolsky E (1991) Extrarenal production of calcitriol in normal and uremic humans. J Clin Endocrinol Metab 72:157–164
Fu GK, Lin D, Zhang MY, Bikle DD, Schackleton CH, Miller WL, Portale AA (1997) Cloning of human 25-hydroxyvitamin D-1a-hydroxylase and mutations causing vitamin D-dependent rickets type 1. Mol Endocrinol 11:1961–1970
Extrarenal Sites of Calcitriol Synthesis: The Particular Role of the Skin 143 Henry HL (1997) The 25-hydroxyvitamin D31a-hydroxylase. In: Feldman D, Glorieux FH, Pike JW (eds) Vitamin D. Academic Press, San Diego, pp 57–68
Hewison M, O_Riordan (1997) Immunomodulatory and cell differentiation effects of vitamin D. In: Feldman D, Glorieux FH, Pike JW (eds) Vitamin D. Academic Press, San Diego,pp 447–462
Hewison M, Zehnder D, Bland R, Stewart PM (2000) 1a-Hydroxylase and the action of vitamin D. J Mol Endocrinol 25:141–148
Holick MF, Schnoes HK, DeLuca HF (1971) Identification of 1,25-dihydroxycholecalciferol, a form of vitamin D3metabolically active in the intestine. Proc Natl Acad Sci U S A 68:803–804
Holick MF, Schnoes HK, DeLuca HF, Gray RW, Boyle IT, Suda T (1972) Isolation and identification of 24,25-dihydroxycholecalciferol, a metabolite of vitamin D made in the kidney.Biochemistry 11:4251–4255
Horsting M, DeLuca HF (1969) In vitro production of 25-hydroxycholecalciferol. Biochem Biophys Res Comm 36:251–256
Ichikawa F, Sato K, Nanjo M, Nishii Y, Shinki T, Takahashi N, Suda T (1995) Mouse primary osteoblasts express vitamin D325-hydroxylase mRNA and convert 1a-hydroxyvitamin D3into 1a,25-dihydroxyvitamin D3. Bone 16:129–135
Jones G, Ramshaw H, Zhang A, Cook R, Byford V, White J, Petkovitch M (1999) Expression and activity of vitamin D-metabolizing Cytochrome P450s (CYP1a and CYP24) in human nonsmall cell lung carcinomas. Endocrinology 140:3303–3310
Lambert PW, Stern PH, Avioli RC, Brackett NC, Turner RT, Green A, Fu IY, Bell NH (1982) Evidence for extrarenal production of 1a,25-dihydroxyvitamin D in man. J Clin Invest 69:722–725
Lehmann B, Pietzsch J, K_mpf A, Meurer M (1998) Human keratinocyte line HaCaT metabolizes 1a-hydroxyvitamin D3and vitamin D3to 1a,25-dihydroxyvitamin D3(calcitriol). J Dermatol Sci 18:118–127
Lehmann B, Tiebel O, Meurer M (1999) Expression of vitamin D325-hydroxylase (CYP27) mRNA after induction by vitamin D3or UVB irradiation of human skin equivalents – a preliminary study. Arch Dermatol Res 291:507–510
Lehmann B, Knuschke P, Meurer M (2000a) UVB-induced conversion of 7-dehydrocholesterol to 1a,25-dihydroxyvitamin D3(calcitriol) in the human keratinocyte line HaCaT. Photochem Photobiol 72:803–809
Lehmann B, Rudolph T, Pietzsch J, Meurer M (2000b) Conversion of vitamin D3to 1a,25-dihydroxyvitamin D3in human skin equivalents. Exp Dermatol 9:97–103
Lehmann B, Genehr T, Knuschke P, Pietzsch J, Meurer M (2001) UVB-induced conversion of 7-dehydrocholesterol to 1a,25-dihydroxyvitamin D3in an in vitro human skin equivalent model. J Invest Dermatol 117:1179–1185
Littledike ET, Horst RL (1982) Metabolism of vitamin D3in nephrectomized pigs given pharmacological amounts of vitamin D3. Endocrinology 111:2008–2013
Mawer EB, Hayes ME, Heys SE, Davies M, White A, Stewart MF, Smith GN (1994) Constitutive synthesis of 1,25-dihydroxyvitamin D3by a human small cell lung cancer cell line. J Clin Endocrinol Metab 79:554–560
Pillai S, Bikle DD, Elias PM (1988) 1,25-dihydroxyvitamin D production and receptor binding in human keratinocytes varies with differentiation. J Biol Chem 263:5390–5395
Ponchon G, Kennan A, DeLuca HF (1969) Activation of vitamin D by the liver. J Clin Invest 48:2032–2037
Puzas JE, Turner RT, Howard GA, Brand JS, Baylink DJ (1987) Synthesis of 1,25-dihydroxycholecalciferol and 24,25-dihydroxycholecalciferol by calvarial cells. Characterization of the enzyme systems. Biochem J 245:333–338
Reichel H, Koeffler HP, Norman AW (1989) The role of the vitamin D endocrine system in health and disease. N Engl J Med 320:980–991
Schuessler M, Astecker N, Herzig G, Vorisek G, Schuster I (2001) Skin is an autonomous organ in synthesis, two-step activation and degradation of vitamin D3: CYP27 in epidermis completes the set of essential vitamin D3-hydroxylases. Steroids 66:399–408 144 Bodo Lehmann, Michael Meurer
Schuster I, Egger H, Herzig G, Reddy GS, Schuessler M, Vorisek G (2000) Constitutive activity of 1a-hydroxylase in primary human keratinocytes, revealed by selective inhibition of CYP24. In: Norman AW. Bouillon R, Thomasset M (eds) Vitamin D endocrine system structural. Biological and clinical aspects. Proceedings of the 11th workshop on vitamin D, Nashville, Tennesse, USA, May 27–June 1, 2000., Printing and Reprographics, University of California, Riverside, pp 182–185
Schwartz GG, Whitlatch LM, Chen TC, Lokeshwar BL, Holick MF (1998) Human prostate cells synthesize 1,25-dihydroxyvitamin D3from 25-hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev 7:391–395
St-Arnaud R, Glorieux FH (1998) 24,25-Dihydroxyvitamin D - active metabolite or inactive catabolite. Endocrinology 139:3371–3374
Takeyama K, Kitanaka S, Sato T, Kobori M, Yanagisawa J, Kato S (1997) 25-Hydroxyvitamin D31a-hydroxylase and vitamin D synthesis. Science 277:1827–1830
Van Leeuwen JPTM, Pols HAP, van den Bemd GCM, Kempenaar J, Thio HB, Birkenh_ger JC, Ponec M (1994) Role of extracellular calcium in the regulation of 1,25-dihydroxyvitamin D3formation in cultured keratinocytes. Biochim Biophys Acta 1221:167–170
Zehnder D, Bland R, Stewart PM, Hewison M (2000) Analysis of the tissue distribution of 1ahydroxylase identifies novel extra-renal sites for the synthesis of 1,25-dihydroxyvitamin D3. J Endocrinol 164:P1
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Lehmann, B., Meurer, M. (2003). Extrarenal Sites of Calcitriol Synthesis:The Particular Role of the Skin. In: Reichrath, J., Tilgen, W., Friedrich, M. (eds) Vitamin D Analogs in Cancer Prevention and Therapy. Recent Results in Cancer Research, vol 164. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-55580-0_9
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DOI: https://doi.org/10.1007/978-3-642-55580-0_9
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