Page not availableHowever, worldwide reports have highlighted a variety of vitamin D insufficiency and deficiency diseases. Despite many publications and scientific meetings reporting advances in vitamin D science, a prohormone trenbolone realization is growing that the newer scientific and clinical knowledge is not being translated vitamin d secosteroid better human health. Over the past several decades, the biological sphere of influence of vitamin D 3as defined by the tissue distribution of the VDR, has broadened at least 9-fold from the target organs required for calcium homeostasis intestine, bone, kidney, and parathyroid. As a consequence, the nutritional guidelines for vitamin D 3 vitamin d secosteroid defined by serum hydroxyvitamin D 3 concentrations should be vitamin d secosteroid, taking into account the contributions to good health that all 36 VDR target organs can provide. Vitamin D 3 is essential for life in higher animals.
Vitamin D: the secosteroid hormone and human reproduction. - PubMed - NCBI
However, worldwide reports have highlighted a variety of vitamin D insufficiency and deficiency diseases. Despite many publications and scientific meetings reporting advances in vitamin D science, a disturbing realization is growing that the newer scientific and clinical knowledge is not being translated into better human health.
Over the past several decades, the biological sphere of influence of vitamin D 3 , as defined by the tissue distribution of the VDR, has broadened at least 9-fold from the target organs required for calcium homeostasis intestine, bone, kidney, and parathyroid. As a consequence, the nutritional guidelines for vitamin D 3 intake defined by serum hydroxyvitamin D 3 concentrations should be reevaluated, taking into account the contributions to good health that all 36 VDR target organs can provide.
Vitamin D 3 is essential for life in higher animals. Research has shown, for example, that vitamin D 3 is one of the primary biological regulators of calcium homeostasis. Vitamin D is not technically a vitamin, ie, it is not an essential dietary factor; rather, it is a prohormone produced photochemically in the skin from 7-dehydrocholesterol.
The molecular structure of vitamin D is closely allied to that of classic steroid hormones eg, estradiol, cortisol, and aldosterone in that they have the same root cyclopentanoperhydrophenanthrene ring structure. Technically, vitamin D is a secosteroid because one of the rings of its cyclopentanoperhydrophenanthrene structure has a broken carbon-carbon bond; in vitamin D, this occurs in the 9,10 carbon-carbon bond of ring B Figure 1.
Given that fact as a starting point, the reader must have access to some of the details of the sunlight-mediated photochemical conversion of 7-dehydrocholesterol into vitamin D 3 ; this information is provided in Figure 1. Chemistry and irradiation pathway for the production of vitamin D 3. The main portion of the figure also illustrates the 2 principal conformations of the molecule that result from rotation about the 6,7 carbon single bond of the seco B ring: The interconversion of the 2 conformers occurs millions of times per second.
For all vitamin D molecules, this results in a multitude of different shapes in solution and in biological systems 8. The skin produces vitamin D 3 photochemically from the provitamin D, 7-dehydrocholesterol, which is present in the epidermis or skin of higher animals, by the action of sunlight in most geographical locations or of artificial UV light. The conjugated double-bond system in ring B see Figure 1 allows the absorption of light quanta at certain wavelengths in the UV range, initiating a complex series of transformations of the provitamin partially summarized in Figure 1 that ultimately result in the generation of vitamin D 3.
Thus, vitamin D 3 can be endogenously produced. As long as the animal or human has access to adequate sunlight on a regular basis, the animal or human might not need to obtain this vitamin from the diet.
However, dermatologists are concerned that individuals with extensive UV radiation exposure could have an increased risk of skin cancer or melanoma 3. A discussion of the parameters affecting the balance between sun exposure and dietary vitamin D to meet bodily requirements is available elsewhere 4. Because vitamin D 3 is also a vitamin, animals and humans can meet some or all of their vitamin D 3 needs through the diet. For the past 6 decades, the literature has claimed that vitamin D 3 and vitamin D 2 see Figure 2 for their structures have equivalent biological effects in humans.
However, with the realization that the serum 25 OH D clinical assay provides the best assessment of vitamin D nutritional status 5 , researchers needed to determine whether vitamin D 2 is as effective in elevating serum 25 OH D concentrations in humans as is vitamin D 3.
Heaney and others recently confirmed earlier data suggesting that vitamin D 3 is substantially more effective than vitamin D 2 6 , 7. In a study of 20 healthy human volunteers, these investigators found that vitamin D 2 's potency was less than one-third of vitamin D 3 'spotency on the basis of ability to elevate serum 25 OH D concentrations. Structural and biological similarities and differences between vitamin D 3 and vitamin D 2. Vitamin D 3 does not have any known intrinsic biological activity.
Researchers have isolated and chemically characterized some 37 vitamin D 3 metabolites 8. The steps in the vitamin D endocrine system 8 include the following Figure 3: An additional key component in the operation of the vitamin D endocrine system is the plasma vitamin D binding protein, which carries vitamin D 3 and its metabolites to their metabolism and target organs The vitamin D endocrine system.
Thirty-six tissues definitively possess the VDR, which means that the cells in these tissues have the potential to produce biological responses, depending on the availability of appropriate amounts of vitamin D 3. For reference citations on the distribution of the vitamin D receptor, see reference 8. The consequences that the new knowledge of the vitamin D endocrine system and the various vitamin D metabolites has had on the rate of publication of peer-reviewed articles on vitamin D is illustrated in Figure 4.
Thus, an enormous body of scientific literature currently exists for vitamin D. This total includes articles that combine the use of vitamin D with one of the following terms: Figure 2 emphasizes the structural differences between vitamins D 3 and D 2 and provides a clear description and comparison of the biological properties of these 2 key molecules. This figure shows that 1 vitamin D 3 is the only naturally occurring form of vitamin D in humans and other animals and 2 vitamin D 2 has only one-third the biological activity of vitamin D 3 in humans 7.
VDR, vitamin D receptor. As is true for all nuclear receptors for the steroid hormones involved, the primary amino acid sequence of the VDR nuc consists of 6 functional domains: A detailed discussion of the VDR nuc and its participation in the regulation of gene transcription is available elsewhere The many possible outcomes include opening the voltage-gated calcium or chloride channels or generating the indicated second messengers.
Formation of the ligand-receptor complex, which results in conformational changes in the receptor protein, then allows the ligand-receptor complex to specifically interact with the many proteins that collectively constitute the transcriptional machinery. Fundamentals of the vitamin D endocrine system that contribute to the daily maintenance of a vitamin D nutritional status that is essential for achieving good health. Researchers have shown more recently that this membrane receptor is the classic VDR previously found primarily in the nucleus and cytosol associated with caveolae present in the plasma membrane of a variety of cells Caveolae are flask-shaped membrane invaginations enriched in sphingolipids and cholesterol that are commonly found in a wide variety of cells Careful research using a variety of structural analogues of 1,25 OH 2 D 3 has shown that the genomic and nongenomic responses to this conformationally flexible steroid hormone have different requirements for ligand structure For example, a key consideration is the position of rotation about the 6,7 single carbon-carbon bond that can be either the 6-s- cis or 6-s- trans orientation see Figure 1.
In contrast, structure-function studies of rapid nongenomic actions of 1,25 OH 2 D 3 and its analogues show that the VDR mem preferentially binds a ligand with a 6-s- cis shape Surprisingly, despite extensive efforts, no routine clinical assay is available for determining the serum concentration of either vitamin D 3 or vitamin D 2.
Furthermore, researchers are unlikely to develop a routine serum vitamin D clinical assay in the future. However, the US Institute of Medicine has endorsed the view that the circulating concentration of 25 OH D 3 is an acceptable functional measure of vitamin D nutritional status 5 , Information on obtaining insight into vitamin D nutritional status by determining the serum concentrations of several vitamin D metabolites is presented in Tables 3 and 4.
Table 3 4 presents a tabulation of the circulating serum concentrations of the 3 major vitamin D metabolites: The molar ratio of the total not free steroid serum concentrations of these metabolites is Investigators primarily measure circulating concentrations of 24,25 OH D 3 for experimental animal studies or selected clinical studies; such measurements are not available through commercial laboratories.
Serum circulating concentrations of key vitamin D metabolites 1. A US Institute of Medicine report has endorsed the view that the circulating concentration of 25 OH D is a functional measure of vitamin D nutritional status 5 ; see also reference The classification of 25 OH D concentrations into sufficiency, insufficiency, deficiency, and severe deficiency represents the author's interpretation of definitions in the publications listed.
Researchers have suggested 2 distinct minimum serum concentrations of 25 OH D for vitamin D sufficiency: However, mass spectrometry provides discrete values for each form of 25 OH D.
Most researchers agree that the range of the serum concentration of 25 OH D 3 in a population of healthy subjects is the best indicator for assessing the vitamin D status in patients with a vitamin D—related disease. The factors supporting this include: Hollis et al 41 argued that the relation between vitamin D 3 and 25 OH D 3 is not linear, but rather saturable and controlled.
Presented in Table 4 is a classification of circulating levels of 25 OH D in relation to vitamin D nutritional status that was largely obtained from clinical studies relating to calcium homeostasis intestinal calcium absorption, bone mineral density, parathyroid hormone concentrations, etc.
Undoubtedly, it will ultimately be essential to determine the normal 25 OH D range in all ethnic groups and geographical populations of the world at all latitudes to reflect differing UV exposures. The purpose of the Adequate Intake recommendations for vitamin D put forth by the Food and Nutrition Board of the Institute of Medicine 5 in was to provide guidelines of vitamin D 3 intake to achieve normal serum levels of 25 OH D. This was a very difficult goal to achieve, however, given that a quantitative relation of vitamin D's ie, operation of the vitamin D endocrine system contribution to good health was not clearly appreciated by The 2 historical roles of vitamin D, namely stimulation of intestinal calcium absorption and increasing the mineral content and the remodeling of bone, are summarized in Table 5.
For each process intestine or bone , historical reference citations are provided to create the foundation that vitamin D is crucial to bone mineral content and intestinal calcium absorption. Thus, between and , the pioneers Mellanby 54 , McCollum 55 , and Goldblatt 56 made the separate bone-related discoveries, respectively, that 1 the treatment or prevention of rickets could be mediated by cod liver oil; 2 by feeding a new vitamin, termed vitamin D; or 3 by exposure of skin to UV irradiation.
Then in , Nicolayson 49 showed the potent actions of vitamin D 3 on stimulating intestinal calcium absorption in rats. Roles of vitamin D identified in the early 20th century 1. These include prevention and treatment of several cancers breast, colon, and prostate through prodifferentiation, antiproliferation, or induction of apoptosis effects, hypertension infant heart failure , immunomodulation psoriasis, type 1 diabetes, inflammatory bowel disease, periodontal disease, multiple sclerosis, and possibly rheumatoid arthritis , and neuromuscular effects muscle strength and better balance.
The important points made in this presentation are summarized in Figure 7. Researchers must also understand the 5 new physiologic systems that collectively comprise the vitamin D endocrine system. Researchers have also expanded the parent vitamin D 3 's nutritional sphere of influence from a focus on bone health to include 5 additional physiologic systems. The nutritional guidelines for vitamin D 3 intake must be carefully reevaluated to determine the adequate intake balancing sunlight exposure with dietary intake to achieve good health by involving all 36 target organs rather than just the first 4 target organs intestine, kidney, bone, and parathyroid gland that are considered for calcium homeostasis.
More than ever, we need to increase the amount of research on vitamin D ie, increase funding from government agencies and pharmaceutical companies to meet the challenge of maximizing the knowledge of how to use vitamin D in the context of the vitamin D endocrine system to preserve or improve the health of everyone on the planet. I thank Helen Henry for her careful reading of the manuscript and many fruitful discussions and Susan Kim for her secretarial and scientific illustration assistance.
The author had no conflicts of interest. Oxford University Press is a department of the University of Oxford.
It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Close mobile search navigation Article navigation. From vitamin D to hormone D: View large Download slide. Researchers have suggested that in humans, fetal deprivation of vitamin D 3 could be associated with adverse neuropsychiatric outcomes. Dietary reference intakes for calcium, magnesium, phosphorus, vitamin D, and fluoride.
Evidence that vitamin D 3 increases serum hydroxyvitain D more efficiently than does vitamin D 2. Vitamin D 2 is much less effective than vitamin D 3 in humans. Hypercalcemia in an anephric patient with sarcoidosis: Dendritic cells as key targets for immunomodulation by vitamin D receptor ligands. Synthesis of 1,dihydroxyvitamin D 3 by human endothelial cells is regulated by inflammatory cytokines: Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain.
Biological actions of extra-renal hydroxyvitamin D-1alpha-hydroxylase and implications for chemoprevention and treatment. Mechanisms of decreased vitamin D 1alpha-hydroxylase activity in prostate cancer cells. Targeted disruption of the hydroxyvitamin D 3 1alpha-hydroxylase gene in ras -transformed keratinocytes demonstrates that locally produced 1alpha,dihydroxyvitamin D 3 suppresses growth and induces differentiation in an autocrine fashion.
Molecular mechanisms mediating the anti-proliferative effects of vitamin D in prostate cancer.