Vitamin D3 (Cholecalciferol)

1. Introduction

Vitamin D3, or Cholecalciferol, is a fat-soluble secosteroid that is essential for human health. It is one of the two major forms of Vitamin D, the other being Vitamin D2 (Ergocalciferol). Cholecalciferol is naturally synthesized in the skin upon exposure to ultraviolet B (UVB) radiation from sunlight, and it is also available through dietary sources and supplements [1].

Chemical/Botanical Basics

Cholecalciferol is chemically a prohormone, meaning it is biologically inactive until it is metabolized in the body. It is structurally similar to cholesterol. In the body, Vitamin D3 is first converted in the liver to 25-hydroxyvitamin D3 (25(OH)D3), also known as calcidiol. This is the main circulating form of Vitamin D and the one measured to determine Vitamin D status [2].

Mechanism of Action

The biologically active form of Vitamin D is 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), or calcitriol, which is produced primarily in the kidneys from calcidiol. Calcitriol functions as a steroid hormone, binding to the Vitamin D Receptor (VDR), which is present in nearly all tissues and cells in the body [1].

The primary and most well-established mechanism of action is the regulation of calcium and phosphate homeostasis. Calcitriol promotes the absorption of calcium in the gut and maintains adequate serum calcium and phosphate concentrations, which is crucial for normal bone mineralization and to prevent conditions like hypocalcemic tetany [1]. Beyond bone health, the VDR is found in numerous tissues, suggesting calcitriol’s pleiotropic effects, including modulation of cell growth, neuromuscular and immune function, and reduction of inflammation [1].

2. Chemical Composition/Key Bioactive Roles

The key bioactive compound is Cholecalciferol, which is metabolized into its active forms.

Compound	Chemical Name	Role in the Body
Cholecalciferol (Vitamin D3)	(5Z,7E)-9,10-Secocholesta-5,7,10(19)-trien-3ß-ol	Prohormone, precursor to active Vitamin D forms.
25-hydroxyvitamin D3 (Calcidiol)	25(OH)D3	Main circulating and storage form; biomarker for Vitamin D status.
1,25-dihydroxyvitamin D3 (Calcitriol)	1,25(OH)2D3	Biologically active form; acts as a steroid hormone to regulate gene expression, calcium, and phosphate metabolism.

3. Health Benefits

Vitamin D3 supplementation is primarily indicated for maintaining bone and overall health, with emerging evidence supporting roles in immune function and other chronic diseases [1, 3].

Bone Health and Osteoporosis

Vitamin D is essential for intestinal calcium absorption and bone mineralization. Clinical trials have shown that Vitamin D and calcium supplements can increase bone mineral density in postmenopausal women and older men, thereby reducing the risk of fractures [1].

Immune System Modulation

Low levels of serum 25(OH)D have been associated with an increased risk of developing several immune-related diseases and disorders [4]. Vitamin D is known to modulate both the innate and adaptive immune responses. It can enhance the function of immune cells like macrophages and T cells, and its anti-inflammatory properties are being studied for their potential role in autoimmune conditions and infectious diseases [4].

Cancer Mortality

Some evidence suggests that higher serum 25(OH)D levels might reduce cancer mortality rates, although clinical trials have generally failed to show that Vitamin D supplementation prevents the incidence of cancer [1]. Further research is needed to confirm the effects of Vitamin D supplementation in people with cancer [1].

Multiple Sclerosis (MS)

Epidemiological studies have found an association between low 25(OH)D levels and an increased risk of contracting multiple sclerosis. Observational data suggests that adequate Vitamin D concentrations might reduce the risk of contracting MS, slow the disease’s progression, and decrease the risk of relapse [1].

4. Dosage and Usage

The recommended dietary allowance (RDA) for Vitamin D is based on age and is expressed in both micrograms (mcg) and International Units (IU), where 1 mcg = 40 IU [2].

Age Group	RDA (mcg)	RDA (IU)
Infants (0–12 months)	10 mcg	400 IU
Children & Adults (1–70 years)	15 mcg	600 IU
Adults (>70 years)	20 mcg	800 IU

Note on Deficiency: For individuals with confirmed Vitamin D deficiency (serum 25(OH)D levels < 30 nmol/L or 12 ng/mL), higher doses, often in the range of 1,000–4,000 IU (25–100 mcg) per day, may be recommended by a healthcare provider to restore adequate levels [2].

Food Sources

Few foods naturally contain Vitamin D. Fatty fish (such as salmon, tuna, and mackerel) and fish liver oils are among the best sources. Small amounts are found in beef liver, egg yolks, and cheese. Many foods, such as milk, breakfast cereals, and orange juice, are fortified with Vitamin D [2].

5. Safety and Precautions

Side Effects and Warnings

Serious Safety Warning: Excessive Vitamin D intake can lead to Vitamin D toxicity, which causes hypercalcemia (abnormally high calcium levels in the blood) [2]. Hypercalcemia can result in nausea, vomiting, weakness, frequent urination, and in severe cases, can lead to renal failure, calcification of soft tissues (including the heart and kidneys), and death [2].

The Tolerable Upper Intake Level (UL) for Vitamin D, which is the maximum daily intake unlikely to cause adverse health effects, is 100 mcg (4,000 IU) for children aged 9 and older and adults [2].

Contraindications

Vitamin D supplementation is generally contraindicated in individuals with:

• Hypercalcemia or hypercalciuria (excessive calcium in urine).
• Certain medical conditions such as sarcoidosis, which can increase the risk of hypercalcemia.

Drug Interactions

Vitamin D supplements may interact with several medications [2]:

• Orlistat (Xenical, Alli): This weight-loss drug can reduce the absorption of fat-soluble vitamins, including Vitamin D, leading to lower 25(OH)D levels.
• Statins: These cholesterol-lowering drugs may reduce endogenous Vitamin D synthesis, although the evidence is mixed.
• Corticosteroids (e.g., Prednisone): These medications can reduce calcium absorption and impair Vitamin D metabolism.
• Thiazide Diuretics (e.g., Hydrochlorothiazide): The combination of these diuretics with Vitamin D supplements can increase intestinal calcium absorption, which might lead to hypercalcemia, especially in older adults or those with compromised renal function.

6. References

[1] Al-Hashimi N, Abraham S. Cholecalciferol. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Available from: https://www.ncbi.nlm.nih.gov/books/NBK549768/

[2] Office of Dietary Supplements (ODS). Vitamin D – Health Professional Fact Sheet. National Institutes of Health (NIH). U.S. Department of Health and Human Services. Available from: https://ods.od.nih.gov/factsheets/VitaminD-HealthProfessional/

[3] Bikle DD. Vitamin D Metabolism, Mechanism of Action, and Clinical Applications. Chem Biol. 2014 Mar 20;21(3):319-29. Available from: https://www.sciencedirect.com/science/article/pii/S1074552114000246

[4] Charoenngam N, Holick MF. Immunologic Effects of Vitamin D on Human Health and Disease. Nutrients. 2020 Jul 15;12(7):2097. Available from: https://pubmed.ncbi.nlm.nih.gov/32679784/