Vitamin D (calciferol) is a fat-soluble pro-hormone presenting two major forms -vitamin D 2 (ergocalciferol) and vitamin D 3 (cholecalciferol). Vitamin D 2 is obtained via ultraviolet B (UVB) irradiation of ergosterol, a fungi sterol, and vitamin D 3 is synthesized in the human/animal skin, after exposure of 7-dehydrocholesterol to UVB radiation. Both forms are produced commercially and found in supplements and in fortified foods. Either from the cutaneous synthesis (D 3 ), or from the diet (D

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... and D 3 ), both vitamins need to be activated, which requires two hydroxylation reactions, one mediated by the 25-hydroxylase and other mediated by the 1α-hydroxylase. Thus, either vitamin D 2 or D 3 originate the calcitriol. This active metabolite is responsible for biological actions, characterized as genomic, mediated via the vitamin D receptor (VDR) transcriptional effects in the nuclei of target cells, and non-genomic, mediated via the rapid VDR-induced signal transduction pathways on the cell membrane and/or cytoplasm. Besides the endocrine actions of calcitriol (regulation of calcium and phosphorus, with interactions in the kidneys, bones, parathyroid glands, and small intestine), the ubiquitous presence of VDR in the organism contributes to the autocrine and paracrine actions of calcitriol, such as the inhibition of cell proliferation, promotion of cell differentiation (including differentiation of keratinocytes), apoptosis and immune regulation. Also, calcitriol is involved in the preventive and therapeutic action in cancer, auto-immune conditions (including type 1 diabetes), cardiovascular diseases, and infections. KEYWORDS Calcitriol, Vitamin D, Vitamin D receptor RESUMO A vitamina D (calciferol) é uma pró-hormona lipossolúvel que apresenta duas formas principais -vitamina D 2 (ergocalciferol) e vitamina D 3 (colecalciferol). A vitamina D 2 é obtida via irradiação ultravioleta B (UVB) do ergosterol, um esterol dos fungos, e a vitamina D 3 é sintetizada na pele humana/animal, após exposição do 7-desidrocolesterol à radiação UVB. Ambas as formas são produzidas comercialmente e encontradas em suplementos e alimentos fortificados. Quer provenham da síntese cutânea (D 3 ), quer da dieta (D 2 e D 3 ), ambas as vitaminas precisam de ser ativadas, o que requer duas reações de hidroxilação, uma mediada pela 25-hidroxilase e outra mediada pela 1α-hidroxilase. Assim, quer a vitamina D 2 quer a D 3 originam o calcitriol. Este metabolito ativo é responsável por ações biológicas caracterizadas como genómicas, mediadas pelos efeitos transcricionais do recetor de vitamina D (VDR) nos núcleos das células-alvo, e não genómicas, mediadas pelas vias rápidas de transdução de sinal induzidas pelo VDR na membrana celular e/ou citoplasma. Além das ações endócrinas do calcitriol (regulação de cálcio e fósforo, com interações ao nível dos rins, ossos, glândulas paratiroides, e jejuno), a presença ubíqua de VDR no organismo contribui para as ações autócrinas e parácrinas do calcitriol, tal como a inibição da proliferação celular, promoção da diferenciação celular (incluindo a diferenciação de queratinócitos), apoptose e regulação da resposta imune. Além disso, o calcitriol está envolvido na ação preventiva e terapêutica do cancro, nas doenças autoimunes (como a diabetes tipo 1), doenças cardiovasculares e infeções. Vitamin D, the fourth known vitamin -now recognized as a pro-hormone (1) -, was discovered in the early 20 th century (2, 3). At that time, there was a high prevalence of rickets with more than 90% of affected children in northern Europe (4). In 1921, the exposure to sunlight was reported as an effective treatment for rickets (5). In fact, the exposure to ultraviolet B radiation promotes the cutaneous synthesis of vitamin D 3 , which is essential to the bone metabolism, regulating calcium and phosphorus levels in the organism (6). Thus, the rickets epidemic contributed to understand the association between sunlight and vitamin D for the promotion of bone health (7). Nowadays, it is well known that the effects of vitamin D go beyond the skeletal health (8, 9) . Introducing Vitamins D 2 and D 3 Vitamin D (calciferol) encompasses fat-soluble seco-sterols also includes the control of the 1) renin-angiotensin system, 2) insulin secretion, 3) muscle function, and 4) nervous system (6). Sources and Recommendations Vitamin D can be obtained through the endogenous cutaneous synthesis by the exposure to the UVB radiation, and by the intake of foods containing naturally present vitamin D (e.g., fatty fish, egg yolk), foods fortified with vitamin D (e.g., milk, cereals), and medical supplements (e.g., cholecalciferol, calcifediol, calcitriol, alfacalcidol, paricalcitol) (1, 4). Cutaneous Synthesis During exposure to UVB radiation, 7-DHC (present in all the layers of human skin) is converted into pre-vitamin D 3 (8, 22). Holick suggested that more than 90% of the vitamin D requirement for most people is attained from casual exposure to sunlight (24). However, the report of the International Agency for Research on Cancer (IARC) on vitamin D and cancer did not support this statement and reinforced the importance of exogenous sources of vitamin D (25). Season and latitude are determinants of the cutaneous synthesis of vitamin D 3 (1). An increase in the maximum angle of the sun during winter and early morning and late afternoon results in a longer path VITAMIN D -FROM THE PRO-HORMONE TO THE BIOLOGICAL ACTIONS ACTA PORTUGUESA DE NUTRIÇÃO 19 (2019) 50-54 | LICENÇA: cc-by-nc | http://dx.doi.org/10.21011/apn.2019.1909 ASSOCIAÇÃO PORTUGUESA DE NUTRIÇÃO ® | WWW.ACTAPORTUGUESADENUTRICAO.PT | ACTAPORTUGUESADENUTRICAO@APN.ORG.PT 16. Chanakul A, Zhang MY, Louw A, Armbrecht HJ, Miller WL, Portale AA, et al. FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues. PLoS One. 2013;8(9):e72816. 17. Haussler MR, Jurutka PW, Mizwicki M, Norman AW. Vitamin D receptor (VDR)mediated actions of 1α,25(OH)2 vitamin D3: genomic and non-genomic mechanisms. Best Pract Res Clin Endocrinol Metab. 2011;25(4):543-59. 18. Trochoutsou AI, Kloukina V, Samitas K, Xanthou G. Vitamin-D in the immune system: genomic and non-genomic actions. Mini Rev Med Chem. 2015;15(11):953-63. 19. Vanchinathan V, Lim HW. A dermatologist's perspective on vitamin D. Mayo Clin Proc. 2012;87(4):372-80. 20. Marquina C, Mousa A, Scragg R, de Courten B. Vitamin D and cardiometabolic disorders: a review of current evidence, genetic determinants and pathomechanisms. Obes Rev. 2019;20(2):262-77.