Vitamin D’s beginnings to fame and importance in health

Preventing Rickets

Vitamin D was discovered between 1910–1940 when something in the cod liver oil was preventing rickets from expressing in dogs. Just so everyone is on the same page, rickets is the improper absorption of calcium and calcification, which causes bowed legs (Figure 1).

Figure 1. Normal legs (left) and bowed legs from rickets (right).

In 1914, Dr. Edward Mellanby mistakenly thought the substance in cod liver oil that was given to dogs that prevented the development of rickets was Vitamin A. It was in 1922 when Elmer McCollum and Marguerite Davis identified the substance as Vitamin D through an elimination technique that removed the vitamins presented in the cod liver oil. Most of the 1910s-1930s was identifying the structure of Vitamin D and it’s production through irradiation. For example, irradiating food fortified the rodent feed to prevent the onset of rickets.

In 1969 Mark Haussler and Tony Norman identified the metabolites and cycle of Vitamin D metabolism in the body (Figure 2). And several scientists started identifying the Vitamin D metabolites in the metabolic pathway in human cell lines.

What is the metabolic pathway for Vitamin D?

Figure 2. Metabolic breakdown of provitamin D3, inactive Vitamin D3, 25-hydroxyvitamin D3, and active D3.

Figure 3. Ergocalciferol (Vitamin D2)

Figure 4. Cholecalciferol (inactive Vitamin D3)

Vitamin D is called the “sunshine” vitamin because it requires UVB (in this case, coming from sunlight) to breakdown cholesterol into downstream forms of Vitamin D. Once an inactive form of Vitamin D3 reaches the liver, then the serum typically expresses the pre-hormone, calcifediol, before it gets activated in the kidneys (Figure 2).

Some of you may heard of Vitamin D2, and so where does Vitamin D2 play a role in all of this? Vitamin D2 or ergocalciferol is typically produced in plants and fungi and it mimics cholecalciferol, which is the inactive form of Vitamin D3 (Figure 3 and Figure 4, respectively). When treated for rickets, both Vitamin D2 and D3 show elevated levels of calcifediol in their serum (Figure 5, Thatcher et al., J Bone Miner Res, 2010). What they failed to mention was that children with rickets taking Vitamin D2 showed lower levels of calcifediol in their serum in comparison to Vitamin D3.

Figure 5. Vitamin D2 or D3 administered to children with rickets show increased levels of calcifediol.

Figure 6. Provitamin D2

Figure 7. Provitamin D3

Okay lets take a few steps back and put on our chemistry hats. Failure to acknowledge the difference between Vitamin D2 and D3 is literally ignoring the amount of work put into understanding the chemical, structural, biological difference of these compounds and potentially different outcomes.

If we look at the provitamin (precursor substrate) of Vitamin D2 and D3, you can see already structural differences between them; some more subtle than others. Vitamin D2 contains an extra methyl group and the double bond in comparison to Vitamin D3 (Figure 3 and 4, respectively). And you can see the same difference in the precursors or the provitamins for Vitamin D2 and D3.

So what does all this chemistry mean? The proteins or receptors, such as the vitamin D receptor (VDR) that binds onto Vitamin D2 or D3 with a different affinity or various strength. And in fact, Dr. Bruce Hollis found just that; Vitamin D and its metabolites binds onto VDR at lower affinity (Hollis, 2002). Another study found that treated groups needed to take 2.5x more Vitamin D2 in order to achieve similar serum levels in comparison to those taking Vitamin D3 (Houghton, Vieth, 2006).

Now the version of Vitamin D matters, but what about the dosage? Vitamin D dosages matter for people of different weight. In fact, those at risk for obesity have a higher chance of having lower levels of Vitamin D (Figure 8, Abdelkarem, et al., 2016). And even when provided the same dosages of Vitamin D, patients that were obese had less Vitamin D in their serum (Figure 9). Another study demonstrated that BMI corresponded to levels of Vitamin D in their serum (Figure 10).

Figure 8. Obese groups show higher distribution of those at risk of low Vitamin D levels in the serum.

Figure 9. Given the same dosage of Vitamin D, obese group has less Vitamin D levels in their serum.

Figure 10. Low Vitamin D levels correspond to increase in BMI.

The dosages and versions or isoforms (e.g. Vitamin D2 versus Vitamin D3) are all very well studied, but it’s only been recently that Vitamin D has been taken more seriously and more people have started to recognize it’s importance. Take Vitamin D Council, which is a nonprofit with a mission to educate people on the importance of Vitamin D and provide recent studies related to health and disease. This education needs to be implemented for health professionals who need support in receiving up-to-date health information for their patients. I can elaborate more on this topic in another article.

Vitamin D treatment for Prostate Cancer

If you want a perfect overview as to why Vitamin D plays a role in cancer at all, I advise reading this great review (Feldman, et al., 2014). Pretty much I’ll be summarizing some of the work presented in the review and how we got to implement Vitamin D as part of the treatment for prostate cancer.

One of the first studies identified that low Vitamin D levels may increase the risk of prostate cancer by simply mapping incidents of prostate cancer mortality to UVB levels in the U.S. (Schwartz and Hulka, 1990). It was during this time, investigators started to identify Vitamin D pathways and its relationship with prostate cancer. This study identified how the expression of VDR and increase treatment with Vitamin D3 elicit antiproliferative and differentiating action of these prostate cancer cell lines (Skowronski et al., 1993).

Vitamin D hydroxylase activity in prostate cells were less than in normal prostate cells (Schwartz, et al., 1998). The mechanism behind this is Vitamin D3 inhibits growth and invasion by upregulating nuclear receptors and hydroxylase in the human prostate cancer cells. Around this time, Dr. Feldman and colleague were the first to implement Vitamin D3 treatment to patients with prostate cancer (Gross et al., 1998). Results showed decrease in prostate specific antigen (PSA).

Delving deeper into the mechanism of Vitamin D treatment, this study looked directly at the treatment of human prostate adenocarcinoma cells with Vitamin D, and demonstrated inhibition of cell proliferation (Blut, et al., 2000). This also corresponded to decrease in the expression of Bcl-2 which induces apoptosis or triggering cell death (Figure 11).

Figure 11. Low number of cells correspond to 100nM of Vitamin D administered (white columns).

Low vitamin D levels increase the odds of the prostate cancer diagnosis (Figure 12, Murphy, et al., 2014) .

Figure 12. Low hydroxylase activity levels in patients during prostate cancer diagnosis.

So much has been done in understanding the mechanism of Vitamin D in human metabolism and most importantly in health and medicine. It is no wonder the vitamin worth giving attention. But, what about the other vitamins and nutrients and how it plays a role in the early beginnings of your health? If this the pathway of Vitamin D deficiency, what other deficiencies are worth pursuing to overcome these severe health outcomes?