Vitamin D

What Are Its Other Names?

Vitamin D₃ is also referred to as cholecalciferol, calcitriol, calcifediol, calciol, 1,25-hydroxyvitamin D, or 25(OH)D. Its molecular formular is C₂₇H₄₄O, and its IUPAC ID is (3β,5Z,7E)-9,10-secocholesta- 5,7,10(19)-trien-3-ol)⁸. Vitamin D₂, the structurally identical compound excluding the side chain⁹, is referred to as ergocalciferol¹⁰. 

Vitamin D3 Chemistry

Vitamin D₃ is a secosterol², which means that it is a steroid with a broken bond in its ring⁹. The C9-C10 bond of ring B in vitamin D is broken⁹. Structurally, vitamin D₃ and vitamin D₂ differ in the side chains⁹. 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 isomerization⁹. 

What Are The Sources of Vitamin D3?

Sunlight

Absorption of sunlight by the skin is the most prominent source of vitamin D₃. 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 D₃. More melanin increases amount of sun exposure required for vitamin D₃¹¹. Vitamin D₃ 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 D₃ 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 D₃ retention. Exposure to UV radiation can be equal to 1000 international units of vitamin D₃. In the ideal circumstance or environment, 15 minutes of full-body exposure to sunlight can mean 10,000 international units of vitamin D₃¹². 

What Foods Have It?

Foods containing vitamin D₃ are not always obvious or regular dietary choices, and thus extra consideration might need to be applied when deficiency is suspected¹². 

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 processing¹³. 

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 nutrient¹¹. 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 D₂ or D₃¹¹. 

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/mL¹². Vitamin D deficiency can cause rickets and osteomalacia, diseases indicating weak or soft bones in children and adults, respectfully¹³. If vitamin D₃ 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 intestine¹². 

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 D₃, 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 States¹⁶. 

In addition to being linked with a lower risk of colorectal cancer, serum levels of 25-hydroxyvitamin D₃ (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 D₃ 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 D₃, for individuals in North America  could lead to a 25% reduction in incidence of breast cancer and a 27% reduction in incidence of colorectal cancer¹⁷. Although these numbers are estimates and are likely aggressive, they demonstrate the potential benefits of vitamin D₃ supplementation.

Skin cancer is a disease with complexity regarding vitamin D₃ and cancer prevention. This is because vitamin D₃ 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 D₃ 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 Lymphoma¹⁹.

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 D₃ and then the inability to isomerize this into vitamin D₃²⁰. 

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 cardiomyopathy²¹. 

Immune System

Vitamin D₃ plays a role in ensuring the healthy functioning of the immune system, specifically with regards to suppressor T cells, cytokine formation, and programmed cell death¹².  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 cancer²². 

What Are Its Main Drawbacks?

Since one of the main ways to acquire Vitamin D₃ 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 safe¹².

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 kidney¹⁹. 

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 genes¹⁸. While vitamin D₃ 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 transcriptase¹⁸. 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 cancer²³.  
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 instability²⁴. Through binding to the vitamin D Receptor, 1,25-(OH)₂D₃ and other ligands of the receptor can induce genes responsible for the process¹⁸.   
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 D₃ 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 localization¹⁸.   

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 D₃ and D₂: 

Vitamin D₃ is derived primarily from UVB in cutaneous synthesis in comparison to from the diet. Vitamin D₂ is derived from plants and the exposure of yeast to radiation¹¹. Vitamin D₃ is more potent and wears off slower than Vitamin D₂²⁷. 

Vitamin D₃ and Calcium 

Research has shown that combining vitamin D₃ and calcium can have a positive effect on cancer prevention²⁸. 29 of the studies included in the summary tables created from reviewing randomized control trials involved the co-administration of vitamin D₃ 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 calcium²⁹. 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 setting³⁰.

Vitamin D₃ and Omega-3  

Out of the studies used to create the summary tables, 5 included co-administration of vitamin D₃ 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 vessels³¹. One proposed mechanism of cancer suppression through cell death is ferroptosis, which is the intracellular destruction of cells with iron³², and it has been proposed that Omega-3 supresses cancer in this manner³¹. 

Summary of Data

Summary of clinical trials administering vitamin D₃ on its own for prevention 

Summary of clinical trials administering vitamin D₃ as an adjunct to therapy + surgery (adjunct to treatments) for preventing recurrence

Summary of clinical trials administering vitamin D₃ + Calcium for prevention 

Summary of clinical trials administering vitamin D₃ + Calcium as an adjunct to therapy + surgery (adjunct to treatments).

Summary of clinical trials administering vitamin D₃ + Omega for prevention. 

Summary of clinical trials administering vitamin D₃ + Omega as an adjunct to therapy + surgery (adjunct to treatments)

Summary of clinical trials administering vitamin D₃ 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

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