Vitamin D Production, Metabolism, and Health Effects

LabdoorScience
Vitamin D

Vitamin D refers to a group of 5 similarly structured compounds known as vitamers, the most important of which (for human health) are plant-produced Vitamin D2 and endogenously synthesized vitamin D3. It is commonly referred to as the ‘sunshine vitamin’, and for good reason: it is only synthesized upon contact with sunlight. Mushrooms, for example, are particularly rich in D2, with the highest concentrations typically found in the more highly sun-exposed fungi. Other natural sources of vitamin D include eggs and fatty fish, but the typical American diet is generally considered to be deficient in natural sources of vitamin D. To rememdy this, common foods, such as cereal and milk, are often fortified with vitamin D. But the amounts in these products (50-100 IU/8 oz. glass of milk, according to a Harvard Public Health Review) are only a small percentage of the recommended dietary allowance (600 IU). Vitamin D is also commonly found on store shelves as a supplement for those who do not follow a balanced diet or, for example, are exposed to limited sunlight.

But why is vitamin D so popular? Vitamin D has a variety of vital biological roles, including suggested ones in immunity and cognition. The most prominent and well studied, however, is its ability to promote calcium and phosphorus absorption, a process essential for maintaining skeletal integrity.

A Dive Into the Chemistry

Vitamin D is known as a secosterol, a molecule similar in structure to a steroid. Vitamin D3 is, in fact, synthesized in the skin from a derivative of cholesterol, which serves as the precursor to all endogenously produced steroids (including the sex hormones estrogen and testosterone). It is also the basis of medicinal anti-inflammatory drugs (such as dexamethasone) and a variety of recreational drugs.

Because Vitamin D’s chemistry resembles that of a steroid, it makes sense that it would inherit the behavior typical of a steroidal hormone (a compound known to have effects on sites different from its origin). A major advantage of the steroidal structure, and one of vitamin D’s most prominent physical characteristics, is its lipophilicity, or ability to solubilize in fat. In the body, fat acts as storage; for example, when vitamin D production or intake is high, any excess vitamin (not currently needed for physiological function) is tucked away in the body’s fat stores, and released again when vitamin D levels are low (during colder weather). For this reason, vitamin D deficiency during sunny weather is rare, but may occur for any number of reasons, including any factor affecting an individuals exposure to sunlight (seasonal climate, cloud cover, clothing, presence of sunscreen), race (darker skin colors, due to the presence of larger amounts of melanin, have shown reduced capacity to synthesize the vitamin D precursor), or any condition leading to fat malabsorption (typically a gastrointestinal disease such as inflammatory bowel disease).

Related: How Vitamin D Levels Change With the Seasons and Vitamin D and Race

Deficiency is fairly common, with an estimated 1 billion people having inadequate vitamin D levels, according to the Harvard School of Public Health. This is especially true in geographical areas further away from the equator or during times of little sunlight. A second advantage is its ability to easily cross the cell’s semipermeable membrane; lipophilic substances are more effective at accessing DNA, directly affecting physical health outcomes.

Metabolism: The Difference between D2 and D3

Which vitamer, D2 or D3, is more relevant to human health? The answer lies in molecular structure, which, in turn, dictates how the vitamin will be metabolized. In the case of vitamin D, only the final metabolic product–one that has undergone several modifications–will have biological activity.

Both pre-vitamin D2 and D3 are biologically inert upon initial synthesis in the skin, and must undergo two chemical modifications – one in the liver, and the second in the kidneys – to become biologically active. Both undergo the same chemical modification in the liver, and emerge as separate compounds blanketed as calcidiol (also known as 25-hydroxyvitamin D2 or D3). Calcidiol is used as a marker for vitamin D deficiency, and is known as the immediate precursor to the biologically active form of vitamin D. In the kidney, calcidiol is modified one last time into a compound known as calcitriol (1,25-dihydroxyvitamin D2 or D3), the steroidal hormone that is then released into circulation.

Because both D2 and D3 undergo the same process to produce calcitriol, it had been long thought that there were no physiological differences between the two vitamers. Recent findings, however, suggest that the provitamins differ in their ability to raise levels of calcidiol, the established marker for vitamin D status. According to the research, vitamin D3 “…is more efficacious at raising serum 25(OH)D [calcidiol] concentrations than is D2” due to subtle differences in their metabolic pathways, which are beyond the scope of this review. Additionally, vitamin D3 is considered by experts to be more potent and less toxic at higher doses than is D2. Even more practical considerations, such as similar price and D3’s longer shelf life, seem to favor D3 over D2. A growing body of evidence now suggests that D3 should be the preferred form of vitamin D supplementation and, coincidentally, that D2 should be phased out.

Clinical Efficacy

Now that we have a solid understanding of vitamin D basics, we can delve into the nutrients biological role(s). Vitamin D is involved in a number of biological functions, the most prominent of which is its ability to promote calcium absorption in the gut and maintain adequate calcium levels in the body. Why is this important?

Bone Health: Calcium is responsible for the mineralization of teeth and bone, improving bone density and decreasing the risk of developing thin, brittle and easily fractured bones. In fact, vitamin D sufficiently prevents a condition resulting in the softening of bones (rickets in children and osteomalacia in adults). It is also used, together with calcium, to prevent osteoporosis in older adults.

Central Nervous System Health: Calcium functions as a part of a highly sensitive system involved in nerve signal transduction. Calcium, which lives as a positively charged ion in the extracellular fluid, ensures that depolarization (the process by which signals are transmitted along the long bodies of nerve cells) occurs in a timely fashion by regulating the activity of sodium-specific transporters along the nerve cell body. Second, calcium is essential in neurotransmitter release, the process by which one nerve cell communicates with another after the first cells has fully depolarized. Aside from its role alongside calcium, vitamin D itself is considered a neuro-regulatory hormone, with receptors (that, when bound to, produces physiological effect) found through the nervous system, including the brain and spinal cord.

In fact, nerve pain is considered an early warning sign of vitamin D deficiency. Clinical studies have also shown that vitamin D-deficient patients are more likely to suffer from seizures and neurological disease (including Alzheimer’s disease) than non-vitamin D deficient individuals. The conclusion to be drawn from this research, however, is not that a vitamin D deficiency will cause neurological disease and that, logically, vitamin D supplementation will prevent neurological decline. While this is a possibility, it may also be that the development of these diseases may lead to vitamin D deficiency. Further research is required before any conclusions can be drawn.

Immune Health: Vitamin D’s role in immunity is two-fold: it acts to activate the innate immune system (the first line of defense against a pathogen), which protects in a non-specific maner, and reduces the efficacy of the adaptive immune system, recognized as the specific immune response (due to its ability to create immunological memory in response to specific pathogens). The process of creating immunological memory is the basis of any vaccination, including that of the flu during winter months.

Why is the flu is so prevalent during the winter? Several studies have suggested that vitamin D deficiency during the winter months may play a major role. There is strong evidence supporting the theory that our adaptive immune system becomes compromised during the winter due to decreased levels of vitamin D (lack of sunlight), reducing our ability to mount a specific immune response and sustain the immunological memory necessary for combating viral infections.

Other: Some sources also claim that vitamin D plays an important role in the prevention of cancer and autoimmune disease, such as type-1 diabetes. While there is some promising evidence for these effects, confirmation warrants further research.