Vitamin D

What Is It?

Vitamin D${_3}$ is classified as a nutrient, hormone, and compound that enhances the immune system${^1}$. It can be sourced by the skin from sunlight, a process also referred to as cutaneous synthesis. However, if an individual is not getting enough ultraviolet light B (UV-B), vitamin D is naturally occurring in many foods${^2}$, and can be consumed as a nutrient in the diet${^3}$. Vitamin D${_3}$ is a form of vitamin D that works to enhance intestinal absorption of calcium and phosphorus${^4}$. Vitamin D${_3}$ is essential in conserving a proper calcium concentration in blood serum in order to maintain normal musculoskeletal function${^5}$.  Calcium and phosphorus are minerals that play a crucial role in bone growth, and they also are involved in reabsorption of calcium from the distal tubule of the kidney$^{6,7}$.  

What Are Its Other Names?

Vitamin D${_3}$ is also referred to as cholecalciferol, calcitriol, calcifediol, calciol, (1),25-hydroxyvitamin D, or 25(OH)D. Its molecular formular is C$_{27}$H$_{44}$O, and its IUPAC ID is (3β,5Z,7E)-9,10-secocholesta- 5,7,10(19)-trien-3-ol)$^{8}$. Vitamin D${_2}$, the structurally identical compound excluding the side chain$^{9}$, is referred to as ergocalciferol$^{10}$. 

Vitamin D3 Chemistry

Vitamin D${_3}$ is a secosterol$^{2}$, which means that it is a steroid with a broken bond in its ring$^{9}$. The C9-C10 bond of ring B in vitamin D is broken$^{9}$. Structurally, vitamin D$_{3}$ and vitamin D${_2}$ differ in the side chains$^{9}$. Two chemical reactions take place in human skin in order to produce vitamin D. The first is between 7-dehydrocholesterol and ergosterol, a process which requires sunlight or UV-B. The second is heat isomerization$^{9}$. 

What Are The Sources of Vitamin D3?

Sunlight Absorption of sunlight by the skin is the most prominent source of vitamin D${_3}$. However, this can decrease with certain varying characteristics of individuals such as age, skin type, and lifestyle choices such as sunscreen application or clothing. Melanin absorbs UV radiation, thus individuals with more melanin (darker skin tones) in their skin use the sun less efficiently for the production of vitamin D${_3}$. More melanin increases amount of sun exposure required for vitamin D${_3}$$^{11}$. Vitamin D${_3}$ synthesis can also be restricted based on weather, timing, and location, all of which may alter one’s exposure to the sun. An example of these factors is the lower levels of Vitamin D${_3}$ that Black or Hispanic individuals residing in temperate latitudes have. Therefore, it might be essential to add certain foods into daily diets in order to optimize vitamin D${_3}$ retention. Exposure to UV radiation can be equal to 1000 international units of vitamin D${_3}$. In the ideal circumstance or environment, 15 minutes of full-body exposure to sunlight can mean 10,000 international units of vitamin D${_3}$$^{12}$. 

What Foods Have It?

Foods containing vitamin D${_3}$ are not always obvious or regular dietary choices, and thus extra consideration might need to be applied when deficiency is suspected$^{12}$. 

Fortified Foods

The fortification of foods is when the concentration of a micronutrient is increased in a food that is more commonly consumed. This is done to either improve the nutrient content of that food or to restore nutrients that are lost during food processing$^{13}$. 

What Are Its Main Benefits?

Half of the people in the world have vitamin D insufficiency. Moreover, 1 billion people worldwide are deficient in the nutrient$^{11}$. There are essential benefits to having sufficient vitamin D, such as bone strength, muscle strength, cancer prevention, cardiovascular health, and support of the immune system. Treatment can be done with either D${_2}$ or D${_3}$$^{11}$.  Bone Strength Vitamin D increases absorption of calcium by 15-25% and phosphorus by 20%. The concentration of minerals within the bone is maximized when blood levels of 25-hydroxyvitamin D exceed 40 ng/mL, but are decreased when the level is less than 30 ng/mL$^{12}$. Vitamin D deficiency can cause rickets and osteomalacia, diseases indicating weak or soft bones in children and adults, respectfully$^{13}$. If vitamin D${_3}$ deficiencies occur during fetal development or during childhood, bones will lack calcium. If the deficiency persists, parathyroid glands will be overactivated which can lead to secondary hyperparathyroidism$^{14,15}$. If an individual has a malabsorption disease; inflammatory bowel disease, pancreatic insufficiency, celiac disease, cystic fibrosis, cholestatic liver disease, or short bowel disease, they are likely to be deficient in vitamin D due to its fat-soluble nature and absorption facilitated by bile salts in the intestine$^{12}$.  Cancer Prevention Participant-level data from 5706 patients with colorectal cancer and 7107 control participants in 2018 demonstrated that higher blood levels of the circulating form of Vitamin D${_3}$, 25-hydroxyvitamin D (25(OH)D), are associated with a reduced risk of colorectal cancer in women and men, but these reductions were only statistically significant in women. The recommended 25(OH)D concentration from this study was 75-100 nmol/L. This is more than the recommendation provided by the Institute of Medicine in the United States$^{16}$.  In addition to being linked with a lower risk of colorectal cancer, serum levels of 25-hydroxyvitamin D${_3}$ (25(OH)D) are also known to lower cases of 12 other cancers including breast, ovarian, prostate, pancreatic, and renal$^{17,18}$.   One review projected that raising the recommended Vitamin D${_3}$ intake could prevent over fifty-thousand new breast cancer cases, and almost fifty-thousand new colorectal cancer cases. This review also estimates that a recommended intake of 2,000 IU/day of vitamin D${_3}$, for individuals in North America  could lead to a 25% reduction in incidence of breast cancer and a 27% reduction in incidence of colorectal cancer$^{17}$. Although these numbers are estimates and are likely aggressive, they demonstrate the potential benefits of vitamin D${_3}$ supplementation. Skin cancer is a disease with complexity regarding vitamin D${_3}$ and cancer prevention. This is because vitamin D${_3}$ can be synthesized on the skin through absorption of sunlight (cutaneous synthesis).  However, being exposed to an excess amount of sunlight is also a risk factor for nonmelanoma skin cancer. Some forms of moderate exposure to sunlight or vitamin D${_3}$ intake can help reduce the risk of developing melanoma skin cancer, which is the most fatal type of skin cancer. It can also reduce the number of cases of non-Hodgkin’s Lymphoma$^{19}$. It is recommended to be exposed to the sun without sunscreen for 5 to 30 minutes a day multiple times in a week. This is because SPF that is less than or equal to 8 can block the absorption of UVB rays from the 7-dehydrocholesterol in the skin. The downstream effects of this would be the inability to convert sun exposure to pre-vitamin D${_3}$ and then the inability to isomerize this into vitamin D${_3}$$^{20}$.  Cardiovascular Health Metabolites of vitamin D influence pathways that result in decreased atherosclerosis (a process wherein arterial walls thicken due to plaque buildup), decreased high blood pressure, decreased aneurysm-related phenotype, decreased blood clotting, decreased calcium build-up (which could lead to a hardening of tissues), and decreased hypertrophic cardiomyopathy$^{21}$.  Immune System Vitamin D${_3}$ plays a role in ensuring the healthy functioning of the immune system, specifically with regards to suppressor T cells, cytokine formation, and programmed cell death$^{12}$.  This is also related to colorectal cancer prevention as vitamin D bound to its receptor can help control inflammatory bowel diseases such as Crohn’s disease and Irritable Bowel Syndrome that may increase the risk of colorectal cancer$^{22}$. 

What Are Its Main Drawbacks?

Since one of the main ways to acquire Vitamin D${_3}$ is through exposure to sun and absorption by the skin, it is a drawback that there is no agreement on how much exposure to sunlight is actually safe$^{12}$. Toxicity Vitamin D toxicity is a rare illness that occurs when vitamin D is consumed in excess, which would be around 100 000 international units every day for at least 6 months. Vitamin D toxicity can cause abnormally high levels of calcium or phosphorus in the blood, which can lead to calcium in the coronary arteries and in the kidney$^{19}$. 

What Are Its Mechanisms of Action?

1. Inhibition of Tumor Cell Growth and Increased Apoptosis : In various types of cancer, calcitriol contributes to arresting the cell cycle in the G0/G1 phase. This inhibits the tumor from growing out of control. It does so by upregulating and downregulating respective genes$^{18}$. While vitamin D${_3}$ is not directly responsible for programmed cell death, it can upregulate proteins that are pro-apoptotic such as BAX or G0S2, while downregulating anti-apoptotic proteins such as thymidylate synthase or BCL-2 $^{18,22}$. This is specific for colon, breast, and prostate cancers in the epithelial tissues. In ovarian epithelial tissue cancer, it activates caspase 9, which is essential to the apoptotic pathway, and inactivates telomerase reverse transcriptase$^{18}$. Telomerase reverse transcriptase is responsible for the stability of chromosome and thus is crucial to the survival of cells which can lead to the development and progression of cancer$^{23}$.  
2. Vitamin D Receptor Pathway: Autophagy is a cellular process by which energy is conserved through the self-degradation of unnecessary or damaged cellular elements. It is involved in the prevention of cancer through stimulating cellular senescence and the presentation of cell surface antigens as well as the prevention of necrosis and genomic instability$^{24}$. Through binding to the vitamin D Receptor, 1,25-(OH)${_2}$D${_3}$ and other ligands of the receptor can induce genes responsible for the process$^{18}$.   
3. Wnt/β-Catenin Pathway : If a mutation occurs in the Wnt/β-Catenin pathway, either by overexpression of the pathway’s factors and receptors or the repression of the pathway's inhibitors, there is the potential for the transformation of healthy cells into cancer cells. In colorectal cancer, 94% of the tumors or metastases are positive for a mutation in this pathway. However, the pathway mutations are also found in a variety of other cancers including blood cell, liver, or lung cancers. Vitamin D${_3}$ may decrease nuclear concentrations of β-Catenin, a protein which forms complexes with T-cell factor to promote cell endurance or proliferation of cancer cells. There are two mechanisms by which this occurs, either through the vitamin D/vitamin D receptor complex binding to nuclear β-Catenin to inhibit complex formation, or the plasma membrane localization of β-Catenin following its synthesis to prevent nuclear localization$^{18}$.   

What Are Typical Doses?

The optimal level of 25(OH)D that maximizes the aforementioned benefits is more than 30 ng/mL. Any level between 20 and 30 ng/mL is considered Vitamin D insufficiency. Any level less than 20 ng/mL is considered vitamin D deficiency$^{25,26}$.  Differences between D${_3}$ and D${_2}$:  Vitamin D${_3}$ is derived primarily from UVB in cutaneous synthesis in comparison to from the diet. Vitamin D${_2}$ is derived from plants and the exposure of yeast to radiation$^{11}$. Vitamin D${_3}$ is more potent and wears off slower than Vitamin D${_2}$$^{27}$.  Vitamin D${_3}$ and Calcium  Research has shown that combining vitamin D${_3}$ and calcium can have a positive effect on cancer prevention$^{28}$. 29 of the studies included in the summary tables created from reviewing randomized control trials involved the co-administration of vitamin D${_3}$ and calcium. This combination was used for both cancer prevention, as well as during treatment or following a cancer diagnosis. The mechanism for the positive effects of combining the two nutrients has been proposed to be due to the vitamin D ultraviolet metabolite, which has beneficial impacts on the metabolism or absorption of calcium$^{29}$. Calcium is linked to decreasing epithelial hyperproliferation in the colon, which is usually initiated by bile and fatty acids. It also decreases ornithine decarboxylase, an enzyme that promotes the formation of tumors. Additionally, there have been studies where calcium has inhibited the development of colon cancer cells in a laboratory setting$^{30}$. Vitamin D${_3}$ and Omega-3   Out of the studies used to create the summary tables, 5 included co-administration of vitamin D${_3}$ and Omega-3. Research has demonstrated that Omega-3 might play a role in preventing the development of cancer by inhibiting inflammation and uncontrollable cell proliferation, and by preventing tumors from growing blood vessels$^{31}$. One proposed mechanism of cancer suppression through cell death is ferroptosis, which is the intracellular destruction of cells with iron$^{32}$, and it has been proposed that Omega-3 supresses cancer in this manner$^{31}$. 

Summary of Data

Summary of clinical trials administering vitamin D${_3}$ on its own for prevention 

Summary of clinical trials administering vitamin D${_3}$ as an adjunct to therapy + surgery (adjunct to treatments) for preventing recurrence

Summary of clinical trials administering vitamin D${_3}$ + Calcium for prevention 

Summary of clinical trials administering vitamin D${_3}$ + Calcium as an adjunct to therapy + surgery (adjunct to treatments).

Summary of clinical trials administering vitamin D${_3}$ + Omega for prevention. 

Summary of clinical trials administering vitamin D${_3}$ + Omega as an adjunct to therapy + surgery (adjunct to treatments)

Summary of clinical trials administering vitamin D${_3}$ in palliative care

Below are links to detailed vitamin D human clinical trial study notes analyzed by Anticancer.ca.

📄 Detailed vitamin D (administered alone for cancer prevention) study notes analyzed by Anticancer.ca

📄 Detailed vitamin D (as adjuvant to therapy + surgery) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin D and calcium (for prevention) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin D and calcium (as adjunct to therapy + surgery) human clinical trial study notes analyzed by Anticancer.ca

📄 Detailed vitamin D and omega-3 (for prevention) study notes analyzed by Anticancer.ca

📄 Detailed vitamin D and omega-3 (as adjunct to therapy + surgery) human clinical trial and association study notes analyzed by Anticancer.ca

📄 Detailed vitamin D (for palliative care) human clinical trial and association study notes analyzed by Anticancer.ca

References

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23. Encyclopedia of Cancer. Accessed September 21, 2023. https://www.sciencedirect.com/topics/neuroscience/telomerase-reverse-transcriptase#:~:text=The%20human%20telomerase%20reverse%2Dtranscriptase%20(TERT)%20gene%20encodes%20a,immortalization%2C%20cancer%20development%20and%20progression.
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• Vitamin D
• What Is It?
• What Are Its Other Names?
• Vitamin D3 Chemistry
• What Are The Sources of Vitamin D3?
• What Foods Have It?
• What Are Its Main Benefits?
• What Are Its Main Drawbacks?
• What Are Its Mechanisms of Action?
• What Are Typical Doses?
• Summary of Data
• References
• About This Article
• Disclaimer