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Biochemistry and physiology

The skin represents one of the key tissues of the human body's vitamin D endocrine system, which is of critical importance for a broad variety of independent physiological functions. It is well known that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3; calcitriol], the biologically most active naturally occurring vitamin D metabolite, is essential for mineral homeostasis and bone integrity (1;2). 1,25(OH)2D is generated from sequential hydroxylations of vitamin D, which in turn is obtained from the diet or synthesized in the skin from 7-dehydrocholesterol upon exposure to UV-B radiation (3). The first hydroxylation of vitamin D3 occurs at the C-25 position and is catalyzed by vitamin D-25-hydroxylases (CYP2R1; CYP27A1) in the liver to produce 25-dihydroxyvitamin D3 [25(OH)D3], the major circulating form of vitamin D in mammals (2). 25(OH)D is the substrate for a second hydroxylase, the renal enzyme 25-hydroxyvitamin D-1-hydroxylase (CYP27B1) resulting in the production of 1,25(OH)2D3. While up to 10% of the body's requirements in vitamin D can be obtained by the diet (under most living conditions), approximately 90% of all requisite vitamin D has to be formed within the skin through the action of the sun light (UV-B) (2).


At present, there is an ongoing debate in scientific and public communities on how much solar UV exposure is appropriate to balance between positive and negative effects of sunlight (1). We know today that 1,25(OH)2D is not only essential for mineral homeostasis and bone integrity, but also for a broad variety of other physiological functions including regulation of growth and differentiation in a broad variety of normal and malignant tissues, including cells derived from prostate, breast, and bone (2). It has been estimated that approximately 1 billion people worldwide are vitamin D deficient or –insufficient (2). A large number of studies have provided evidence for associations between vitamin D deficiency and the incidence and/or an unfavorable prognosis of various types of cancer (e.g. colon, prostate, and breast cancer), autoimmune diseases, infectious diseases, and cardiovascular diseases (2-4). Notably, an increasing body of evidence demonstrates convincingly an association between several vitamin D receptor (VDR) polymorphisms and cancer risk and progression (5). During the last decade, substantial progress has been made to better understand the link between vitamin D and malignant disease. Of great importance was the discovery that skin, prostate, colon, breast, and many other tissues express the enzyme CYP27B1 to convert 25(OH)D3 to its biologically active form, 1,25(OH)2D. 1,25(OH)2D is now not only considered as a calciotropic hormone, but also as a locally produced potent regulator of various cellular functions including cell growth and differentiation (2).

References

1.     Reichrath J. The challenge resulting from positive and negative effects of sunlight: how much solar UV exposure is appropriate to balance between risks of vitamin D deficiency and skin cancer? Prog Biophys Mol Biol 2006;92:9-16.
2.     Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81.
3.     Gorham ED, Garland FC, Garland CF. Sunlight and breast cancer incidence in the USSR. Int J Epidemiol 1990;19:820-4.
4.     Garland CF, Comstock GW, Garland FC, Helsing KJ, Shaw EK, Gorham ED. Serum 25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989;2:1176-8.
5.     Kostner K, Denzer N, Muller CS, Klein R, Tilgen W, Reichrath J. The relevance of vitamin D receptor (VDR) gene polymorphisms for cancer: a review of the literature. Anticancer Res 2009;29:3511-36.