The Vitamin D3 Pathway in Human Skin and its Role for Regulation of Biological Processes

The skin is the only tissue yet known in which the complete ultraviolet-B (UV-B)–induced pathway from 7-dehydrocholesterol to hormonally active calcitriol (1a,25-dihydroxyvitamin D3) occurs under physiological conditions. Epidermal synthesis of calcitriol could be of fundamental relevance because calcitriol regulates important cellular functions in keratinocytes and immunocompetent cells. Because of their antiproliferative and prodifferentiating effects, calcitriol and other vitamin D analogs are highly efficient in the treatment of psoriasis vulgaris. The known antipsoriatic effect of UV-B light could, at least in part, be mediated via UV-B–induced synthesis of calcitriol. In addition, mounting evidence indicates that cutaneous vitamin D3 synthesis is of high importance for the prevention of a broad variety of diseases, including various malignancies. New but controversially discussed sun-protection guidelines were established for the prevention of internal cancers. A better understanding of the metabolism of vitamin D in the skin opens new perspectives for therapeutic applications of vitamin D analogs. THE VITAMIN D3 PATHWAY IN HUMAN SKIN A photochemical reaction with maximum spectral effectiveness at about 297 nm results in the generation of previtamin D3 from 7dehydrocholesterol (provitamin D3, or 7-DHC) in basal and suprabasal layers of the skin (1). Dependent on temperature and time, previtamin D3 is then isomerized to vitamin D3. After binding to carrier proteins, in particular vitamin D-binding protein (DBP), vitamin D3 is transported to the liver where it is enzymatically hydroxylated by the cytochrome P450 isoform CYP27A1 at the C25 position, generating 25-hydroxyvitamin D3 (calcidiol, or 25OHD3). More recently, it has been found that in all six cytochrome P450 isoforms (CYP27A1, CYP2R1, CYP2C11, CYP3A4, CYP2D25 and CYP2J3) exhibit vitamin D3 25-hydroxylation activities (2,3). 25-Hydroxyvitamin D3, bound to DBP, is then transported to the kidney, and is finally hydroxylated by CYP27B1 at the C1a position to hormonally active calcitriol (1a,25-dihydroxyvitamin D3, or 1a,25[OH]2D3). Calcitriol acts in the kidney but is also transported by DBP to vitamin D-receptor (VDR) positive target tissues (mainly bone, intestine and parathyroid gland) to act in a genomic or nongenomic manner. There is substantial evidence for additional extrarenal sites of calcitriol synthesis. In vitro, many nonrenal cells, including bone, placenta, prostate, keratinocytes, macrophages, Tlymphocytes and several cancer cells (e.g. from lung, prostate and skin) can enzymatically convert 25OHD3 to 1a,25(OH)2D3. A 5step inactivation pathway from calcitriol to calcitroic acid is attributed to a single multifunctional CYP, CYP24A1, which is transcriptionally induced by the action of calcitriol in a very sensitive manner. The physiological importance of a second catabolic pathway which encloses the conversion of 1a,25(OH)2D3 to 1a,25(OH)2D-3epi-D3 is less clear. Skin cells (keratinocytes, fibroblasts and other cells) express VDR, an absolute prerequisite for regulation of genomic effects of calcitriol and other synthetic vitamin D analogs. Experimental and clinical findings have shown that the serum concentration of calcitriol (10 11 to 10 10 M) is too low to induce VDR-mediated hormonal effects in the skin (4,5). It should be noted that more than 99% of the total circulating 1a,25(OH)2D3 is bound to carriers such as DBP and albumin. In the normal human only 0.4% of the circulating 1a,25(OH)2D3 is free (6). According to the ‘‘free hormone hypothesis’’ (7), it is commonly accepted that only the free, and not total, 1a,25(OH)2D3 regulates genomic processes within keratinocytes. This suggests that free plasma calcitriol approximates around 6 3 10 13 M. It has been shown in several studies that calcitriol, at concentrations higher than 10 8 M (equivalent to a highly unphysiological concentration of approximately 2.5 3 10 6 M total calcitriol in the circulating blood), is * To whom correspondence should be addressed: Dresden University of Technology, Medical School ‘‘Carl Gustav Carus,’’ Department of Dermatology, D-01309 Dresden, Germany. Fax: 0351-458-4338; e-mail: Bodo.Lehmann@mailbox.tu-dresden.de Abbreviations: C, calcitriol; CYP, cytochrome P450; D3, vitamin D3; DBP, vitamin D binding protein; 7-DHC, 7-dehydrocholesterol; 1a,25(OH)2D3, 1a,25-dihydroxyvitamin D3; IgE, immunoglobulin E; IL, interleukin; INF-c, interferon c; IU, international unit; MED, minimal erythemal dose; mVDR, membrane-bound vitamin D receptor; 25OHD3, 25-hydroxyvitamin D3; PCNA, proliferating cell nuclear antigen; pre-D3, previtamin D3; RXR, retinoid X receptor; Th, T-helper cell; UV-B, ultraviolet-B; VDR, vitamin D receptor; VDRE, vitamin D response element. 2005 American Society for Photobiology 0031-8655/05