Dear Carole,

Dr. Sunil Wimalawansa has been researching vitamin D for over four decades. He is considered one of the world’s leading experts on micronutrients, especially vitamin D. His extensive background includes working with vitamin D in a laboratory setting, applying his vitamin D knowledge working with patients as a medical doctor, and directing clinical trials involving pharmaceuticals and vitamin D.

Today, we present Part 3 of this question-and-answer interview series with Dr. Wimalawansa, in which he shares his answers to questions regarding vitamin D3, 25(OH)D, and 1,25(OH)2D. We introduced Dr. Wimalawansa in Part 1 of this interview series, Vitamin D: Everything You Need to Know… and More, followed by Part 2, Defining Optimal Levels and Doses of Vitamin D for Every Individual.

We hope you have been enjoying this interview series and would like to extend a very big Thank You to Dr. Wimalawansa for sharing his knowledge and time with us! Stay tuned for Part 4, coming soon.

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The terminologies pro-hormone, pro-drug, and pro-biotic refer to compounds that are inactive when administered but become fully active when they split or cleave, releasing their active component, as in pro-insulin. Such a process does not happen in the activation of vitamin D. It is the same parent vitamin D molecule that gets hydroxylated (converted) to form 25(OH)D (calcifediol) in the liver. It then gets further hydroxylation in renal tubular and peripheral target cells to form 1,25(OH)2D (calcitriol)—the most active form. Therefore, VITAMIN D is neither a pro-drug, pro-hormone, nor hormone but is a vitamin.

Hormones are produced in a cluster of cells or an (endocrine) organ. The final product from these cells—the hormone—is secreted into the bloodstream and acts on cells located distally. Vitamin D is synthesized in skin cells following exposure to ultraviolet B (UVB) rays. 7-dehydrocholesterol is converted to pre-vitamin D and isomerized to form vitamin D within skin cells. “Vitamin D” does not bind to a receptor (receptors are a complex protein with an effector system generating signals) with high affinity and has no known endocrine functions. Therefore, vitamin D is not a hormone, and the skin is not an endocrine organ (DOI: 10.3390/nu15163623). The vitamin D metabolite that binds to a receptor is calcitriol. Although commonly, it is called a vitamin D receptor, it should be re-named as calcitriol receptor (CTR) (DOI: 10.3390/biomedicines11061542).

Vitamin D is a fat-soluble compound that cannot be freely transported in an aqueous solution like blood. Therefore, as with other lipid-soluble molecules, vitamin D (and also calcifediol and calcitriol) gets attached (binds) to vitamin D-binding protein (VDBP; a large protein in the blood), before they are released into the circulation. Vitamin D is predominantly transported to the liver, where 25-hydroxylation occurs to form 25(OH)D (calcifediol)—the precursor for 1,25(OH)2D (calcitriol). Vitamin D and 25(OH)D also get into peripheral target cells, which are hydroxylated to form calcitriol, as illustrated in the diagram above. Calcifediol is a vitamin D metabolite but not a hormone (DOI: 10.3390/ nu15173842).

Calcifediol that reaches renal tubular cells (kidneys) gets further hydroxylated at the 1α-position of its carbon rings, generating 1,25(OH)2D calcitriol. The portion of calcitriol that is secreted from renal tubular cells into the circulation then acts on distally located cells—thus, by definition, it is a hormone (DOI: 10.3390/nu15163623).

The portion of vitamin D and 25(OH)D that does not enter renal tubular cells is transported via circulation. It diffuses into peripheral target cells, like immune cells, prostate, colon, brain, breast, etc. Vitamin D and 25(OH)D convert directly within these cells (i.e., inside these cells) to form the non-hormonal calcitriol. This portion of calcitriol does not secrete back into the circulation; in these circumstances, it is not a hormone. Instead, once bound to the calcitriol receptors (CTR) in the cell, it acts on the genome to modulate DNA. Intracellular calcitriol is also a critical signaling molecule, initiating autocrine/intracrine and paracrine functions (of vitamin D) within those cells. This portion of non-hormonal vitamin D is critical for the genomic and some non-genomic functions of vitamin D. (DOI: 10.1016/j.jsbmb.2006.12.078)

During genomic and metabolic activities and autocrine/intracrine and paracrine signaling processes, calcitriol, magnesium, and other cofactors get consumed (DOI: 10.3390/nu15173842). Therefore, these cells need a continuous supply of micronutrients, particularly vitamin D and magnesium, for proper physiological functions.

• Can vitamin D3 be metabolized within cells or tissues outside the liver?
• Why is daily and weekly vitamin D administration better than less frequent administration, like once every three months?
• Is measuring Vitamin D3 or 1,25(OH)2D clinically essential or valuable?
• Are there conditions requiring measurement of calcitriol in blood?
• What are the specific indications for measuring calcitriol?

* The above is a scientific discussion and should not be considered medical advice. Regarding clinical or personal issues, Prof. Wimalawansa advises readers to consult her/his physician.

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