Review
Vitamin D: newly discovered actions require reconsideration of physiologic requirements

https://doi.org/10.1016/j.tem.2010.01.003Get rights and content

Vitamin D is not just for preventing rickets and osteomalacia. Recent findings in animal experiments, epidemiologic studies and clinical trials indicate that adequate vitamin D levels are important for cancer prevention, controlling hormone levels and regulating the immune response. Although 25 hydroxyvitamin D (25OHD) levels >10 ng/ml can prevent rickets and osteomalacia, these levels are not sufficient to provide these more recently discovered clinical benefits. Rather, levels of 25OHD >30 ng/ml are generally recommended. Determining optimal levels of 25OHD and the amount of vitamin D supplementation required to achieve those levels for the numerous actions of vitamin D will only be established with additional trials. In this review, these newer applications are summarized and therapeutic considerations are provided.

Section snippets

Vitamin D production

Two forms of vitamin D exist: vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol) (Figure 1). The former is produced in the skin under the influence of ultraviolet B radiation (UVR), whereas the latter, also produced by UVR, is produced in a variety of plant materials and yeast. Differences exist in their binding to the major transport protein in blood, vitamin D binding protein (DBP) and in their metabolism because of the different structures of their side chains. In humans, 25OHD2 is

Vitamin D metabolism

To be biologically active, vitamin D must first be converted to 25OHD (Figure 1). Several enzymes, both mitochondrial and microsomal, are capable of this function [7]. These enzymes are found in many tissues and their activity is limited primarily by substrate (i.e. vitamin D) availability [8]. As such, serum 25OHD is a reliable indicator of vitamin D status [9]. To be fully active, 25OHD must be further converted to 1,25(OH)2D via CYP27B1. Although the proximal renal tubule is the major source

Regulation of hormone secretion

1,25(OH)2D regulates the production and secretion of several hormones (Figure 3), which in some cases feedback on renal production of 1,25(OH)2D3. Vitamin D deficiency has been linked to a variety of diseases resulting from either over or under secretion of such hormones, providing a physiologic basis for the importance of this regulation. The following are examples.

Regulation of immune function

The potential role for vitamin D and its active metabolite 1,25(OH)2D to modulate the immune response rests on the observations that VDRs are found in activated dendritic cells, macrophages and lymphocytes 46, 47, that these cells produce 1,25(OH)2D (i.e. express CYP27B1) [46], and that 1,25(OH)2D regulates their proliferation and function [48]. Two forms of immunity exist – adaptive and innate – and each are regulated by 1,25(OH)2D (Figure 4).

Regulation of proliferation and differentiation

The proliferation and differentiation of many cell types is controlled, at least to some degree, by vitamin D and its metabolites. As such, the role of vitamin D in the prevention and/or treatment of conditions where such regulation goes awry has been the focus of considerable attention. Much interest has focused on cancer prevention and treatment. 1,25(OH)2D has been evaluated for its potential anticancer activity in animal and cell studies. The list of malignant cells that express VDR is now

Defining vitamin D sufficiency

Serum 25OHD levels, collectively constituted by 25OHD2 from nutritional sources and 25OHD3 from both cutaneous sources and nutritional sources, provide a useful surrogate for assessing vitamin D status. 1,25(OH)2D levels, unlike 25OHD levels, are well maintained until the extremes of vitamin D deficiency because of secondary hyperparathyroidism, and thus do not provide a useful index for assessing vitamin D deficiency at least at the initial stages. Historically, vitamin D sufficiency was

Summary and concluding remarks

Vitamin D regulates numerous physiologic processes in addition to maintaining calcium homeostasis through its actions on bone, intestine and kidney. These non-classical actions include regulating the production and secretion of several hormones, controlling cellular proliferation and differentiation, and modulating both the adaptive and innate immune response. These pleiotropic actions reflect the ubiquitous distribution of VDR and the enzyme, CYP27B1, that produces the preferred ligand for

Glossary

CYP27B1
25OHD 1α hydroxylase [the enzyme that produces 1,25(OH)2D].
CYP24
25OHD 24 hydroxylase [the enzyme that degrades 1,25(OH)2D and 25OHD].
1,25(OH)2D
1,25 dihydroxyvitamin D, the preferred ligand for the vitamin D receptor.
7-DHC
7 dehydrocholesterol, the precursor in skin for vitamin D production.
DBP
vitamin D binding protein, the major carrier of vitamin D metabolites in the circulation.
DM
diabetes mellitus.
FGF23
fibroblast growth factor 23, a major regulator of phosphate reabsorption and 1,25(OH)2

References (84)

  • L. Adorini

    Intervention in autoimmunity: the potential of vitamin D receptor agonists

    Cell. Immunol.

    (2005)
  • L. Adorini

    Prevention of chronic allograft rejection by vitamin D receptor agonists

    Immunol. Lett.

    (2005)
  • K. Kragballe

    Double-blind, right/left comparison of calcipotriol and betamethasone valerate in treatment of psoriasis vulgaris

    Lancet

    (1991)
  • A.A. Litonjua et al.

    Is vitamin D deficiency to blame for the asthma epidemic? J

    Allergy Clin. Immunol.

    (2007)
  • P.T. Liu

    Therapeutic implications of the TLR and VDR partnership

    Trends Mol. Med.

    (2007)
  • A. Ustianowski

    Prevalence and associations of vitamin D deficiency in foreign-born persons with tuberculosis in London

    J. Infect.

    (2005)
  • S. Shah

    Trans-repression of beta-catenin activity by nuclear receptors

    J. Biol. Chem.

    (2003)
  • S. Shah

    The molecular basis of vitamin D receptor and beta-catenin crossregulation

    Mol. Cell

    (2006)
  • K.M. Dixon

    Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs

    J. Steroid Biochem. Mol. Biol.

    (2005)
  • R. Gupta

    Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products

    J. Invest. Dermatol.

    (2007)
  • E.D. Gorham

    Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis

    Am. J. Prev. Med.

    (2007)
  • J.M. Lappe

    Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial

    Am. J. Clin. Nutr.

    (2007)
  • R. Vieth

    Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety

    Am. J. Clin. Nutr.

    (1999)
  • R.P. Heaney

    Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol

    Am. J. Clin. Nutr.

    (2003)
  • J.N. Hathcock

    Risk assessment for vitamin D

    Am. J. Clin. Nutr.

    (2007)
  • D. Bikle

    Extra renal synthesis of 1,25 dihydroxyvitamin D and its health implications

    Clin. Rev. Bone Miner. Metab.

    (2009)
  • L.A. Armas

    Vitamin D2 is much less effective than vitamin D3 in humans

    J. Clin. Endocrinol. Metab.

    (2004)
  • M.F. Holick

    Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D

    J. Clin. Endocrinol. Metab.

    (2008)
  • M.F. Holick

    Photosynthesis of previtamin D3 in human skin and the physiologic consequences

    Science

    (1980)
  • M.F. Holick

    Regulation of cutaneous previtamin D3 photosynthesis in man: skin pigment is not an essential regulator

    Science

    (1981)
  • A.R. Webb

    Sunlight regulates the cutaneous production of vitamin D3 by causing its photodegradation

    J. Clin. Endocrinol. Metab.

    (1989)
  • Gascon-Barré, M. (2005) The vitamin D 25-hydroxylase. Elsevier 1,...
  • M.F. Holick

    Vitamin D deficiency

    N. Engl. J. Med.

    (2007)
  • A. Nishimura

    Regulation of messenger ribonucleic acid expression of 1 alpha,25-dihydroxyvitamin D3-24-hydroxylase in rat osteoblasts

    Endocrinology

    (1994)
  • P.T. Liu

    Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response

    Science

    (2006)
  • J. Schauber

    Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism

    J. Clin. Invest.

    (2007)
  • D.D. Bikle

    Regulation of 1,25-dihydroxyvitamin D production in human keratinocytes by interferon-gamma

    Endocrinology

    (1989)
  • S. Christakos

    New insights into the mechanisms of vitamin D action

    J. Cell. Biochem.

    (2003)
  • S.A. Kerner

    Sequence elements in the human osteocalcin gene confer basal activation and inducible response to hormonal vitamin D3

    Proc. Natl. Acad. Sci. U. S. A.

    (1989)
  • A.L. Sutton et al.

    Vitamin D: more than a “bone-a-fide” hormone

    Mol. Endocrinol.

    (2003)
  • N.J. McKenna

    Nuclear receptor coregulators: cellular and molecular biology

    Endocr. Rev.

    (1999)
  • Y. Oda

    Two distinct coactivators, DRIP/mediator and SRC/p160, are differentially involved in vitamin D receptor transactivation during keratinocyte differentiation

    Mol. Endocrinol.

    (2003)
  • Cited by (138)

    • Photobiology of vitamin D

      2023, Feldman and Pike's Vitamin D: Volume One: Biochemistry, Physiology and Diagnostics
    • Chemical synthesis, biological activities and action on nuclear receptors of 20S(OH)D<inf>3</inf>, 20S,25(OH)<inf>2</inf>D<inf>3</inf>, 20S,23S(OH)<inf>2</inf>D<inf>3</inf> and 20S,23R(OH)<inf>2</inf>D<inf>3</inf>

      2022, Bioorganic Chemistry
      Citation Excerpt :

      Vitamin D3 (1, Fig. 1) is formed from 7-dehydrocholesterol (7DHC) by the action of ultraviolet (UVB) radiation [1-4].

    • The Effect of Vitamin D Supplementation in Patients with Acute Traumatic Brain Injury

      2019, World Neurosurgery
      Citation Excerpt :

      Cholecalciferol is converted in the liver to calcifediol (25-hydroxycholecalciferol). The metabolite from this reaction, 25-hydroxyvitamin D3 (25-OH vitamin D3), is measured in the serum to determine an individual's vitamin D status.5,6 Vitamin D regulates the proliferation and function of immune cells, such as dendritic cells, macrophages, and lymphocytes, and has been actively studied in the fields of cardiology and oncology.6-8

    View all citing articles on Scopus
    View full text