A Ray of Health

Hello people,

Today, I will be writing about how vitamin D is produced and what happens to it in the body.

What is vitamin D?

Vitamin D is actually not a real vitamin (I know the name is a bit deceiving). Vitamins are molecules that cannot be generated by the human organism. Our bodies, however, can make vitamin D from cholesterol. In order to produce it, however, our skin has to be exposed to sunlight or UV light (part of the spectrum of sunlight).

Hold on! UV light gives you cancer!

I know it is counter-intuitive. First of all, vitamin D was shown to greatly reduce overall cancer incidence and was shown to be particularly beneficial for breast, colorectal, skin cancers and some forms of leukemia. All this to say that vitamin D protects you from getting cancer. However, the UV exposure of your skin should not be too long.

For how long should I go tanning to get enough vitamin D, but not cancer?

The answer to this question lies in the chemistry of vitamin D production in the skin, which requires both UV light and heat (coming from the UV/sunlight). If there is too much heat (getting a bit of a sunburn), however, vitamin D is actually degraded, so tanning for long periods of time is counterproductive. I would say that 15min per day of full body exposure during the summer is enough to get enough vitamin D.

Figure 1: Ozone layer aborbs UV spectrum of sunlight. The angle at which the sun rays hit the earth surface during winter is such that it passe through more ozone farther north or south of the equator resulting in more UV light being absorbed and less passing through to help us produce vitamin D in our skin.

What do you mean by “during the summer”? How about during winter?

It is all about the UV. Please refer to figure 1 to grasp the situation better. Winter is fine too… if you live near the equator. The farther south or north you get, the more the UV spectrum of the sunlight is filtered by the ozone layer, which is especially bad during winter times. The angle of the sun is such that the sunlight passes through the most ozone layer giving the least amount of UV. This is the reason why sometimes tanning beds are prescribed in Sweden in order for people to get enough vitamin D.

Except from UV light, how can I obtain vitamin D?

Vitamin D is contained in limited dietary sources (a separate post will list those). These are fatty fish (like mackerel, salmon, cod, etc.). In north America, the milk and some other dairy products are supplemented with vitamin D (these dosages are probably not high enough to see many of the beneficial effects of this compound). Also supplements could be taken.

Figure 2: Vitamin D Metabolism and Physiology. Vitamin D is made in the skin and is then activated in the liver and kidneys to exert its physiological effects. Vitamin D could also be obtained from the diet and follows the same path as the skin-produced vitamin D. (Nat Rev Nephrol. 2009 Dec;5(12):691-700)

The vitamin D obtained through the diet or made in the skin exposed to UV light has no physiological effects, however. It has to be activated. First, it is transported through the blood to the liver, where it is modified (fig. 2). This modified form of vitamin D is referred to as 25(OH)D3. Of all the forms of vitamin D, 25(OH)D3 is the form that is the highest in human blood (yes, even higher than vitamin D itself). It is for this reason that 25(OH)D3 is referred to circulating vitamin D. 25(OH)D3 then goes to the kidneys where it is modified again to give the active form of vitamin D. This active form is responsible for the actions of vitamin D in our organism and is referred to as 1,25(OH)2D3. In summary, vitamin D has to be activated in the liver and kidney in order to have physiological effects. The activation step in the liver is always on, but the step in the kidneys is regulated by different signals. I will make a new post on how the activation in the kidneys is regulated.

What vitamin D supplements are there and how much should I take?

Once again, I promise to dedicated an entire post to vitamin D supplementation and concentrations, and their effects on disease. I will give some basic recommendations here.

There are several forms of vitamin D supplements. One of them is vitamin D (it could also be designated D3 or Vitamin D3). This is the same form of the vitamin as the one we produce in our skin when exposed to UV light or the form that we obtain from fatty fish. I take 2000 IU daily (IU=international units). I know people (experts in the vitamin D field) that take 6000 units all-year-round and have been doing so for more than 10 years and are still fine. Taking 2000IU per day should be enough to maintain vitamin D levels in the blood high enough to prevent some forms of cancer and increase calcium absorption and bone health. I think I will provide a separate post discussing vitamin D concentrations and their effects on diseases treatment and prevention.

The other form of Vitamin D supplements that I have seen is 1,25(OH)2D3. This is the active form of the vitamin. In other words, if you take vitamin D supplements, you still need your liver and kidneys to activate it. If you take 1,25(OH)2D3, it is already active. Needless to say that you should take a lot less. In fact, I would not recommend healthy people to take 1,25(OH)2D3. It is meant for people with kidney problems that cannot carry out the activation step in the kidneys.

Vitamin D2 is also available. This form of vitamin D is produced in plants. For all practical purposes, however, it has the same effect as vitamin D (or vitamin D3).

So the basic concept to remember here is that you get vitamin D from direct skin exposure to UV light. Vitamin D is then activated in the liver and kidneys and serves to protect from cancer, cardiovascular disease, osteoporosis and rickets. It also enhances calcium absorption necessary for bone health.

Thanks for reading.

Greetings readers,

Today, I will introduce you to the basics of Vitamin D metabolism in the human body. I suspect this will be a bit boring, but it is a necessary step we need to go through in order to fully understand the effects of this vitamin regarding human health, longevity and possibly fitness (controversial reports).

Everybody knows that vitamin D is important for adequate calcium absorption. Since its discovery in the early 20^th century and the eradication of nutritional rickets¹, many aspects of its beneficial health effects have been elucidated, but many more remain to be investigated. Quite a lot is known about its metabolism. First of all, I would like to point out that vitamin D is not a “real vitamin”. By definition vitamins are organic compounds that are required for various physiological processes, but cannot be produced by the organism. Vitamin D can be obtained through limited dietary sources (mostly fatty fish) and be made in the skin directly exposed to ultraviolet B light (UVB). Just to clarify, UVB and UVA is ultraviolet light with slightly different wavelengths.

Figure 1: Vitamin D Metabolism and Physiology. After synthesis of Vitamin D3 in the skin or its absorption through the diet, it is transported by DBP to liver and kidneys where it undergoes two sequential hydroxilations to yield the hormonally active form, 1,25(OH)2D3. 25(OH)D3 and 1,25(OH)2D3 induces the gene expression of 24-hydroxylase, which results in its degradation.

In skin exposed to UVB light, pro-vitamin D₃ or 7-dehydrocholesterol, is converted to pre-vitamin D₃ (fig. 1)^2,3. Chemically, a C-C bond of 7-dehydrocholesterol (pro-vitamin D₃) is broken giving rise to pre-vitamin D₃. Pre-vitamin D₃ then isomerises to vitamin D₃ in a process stimulated by heat (fig. 2)⁴. Vitamin D₃ thus produced in the skin or dietary vitamin D₃ absorbed in the intestine then enters the circulation³. Vitamin D₃ in the circulation does not exist in free form. It is bound by vitamin D₃ binding protein (DBP)². DBP is a Gc-globulin that is abundant in serum. It binds the lipophilic vitamin D₃ and transports it through the bloodstream to other organs and tissues⁵.

Figure 2: Vitamin D Metabolism. Under the action of UVB (ultraviolet B) light, a C-C bond in Pro-vitamin D3 (7-dehydrocholesterol) is broken giving rise to Pre-vitamin D3. Under the action of heat, Pre-vitamin D3 is converted to to vitamin D3 relieving steric hindrance. Vitamin D3 then is converted to the hormonally active form, which is 1,25(OH)2D3 or Calcitriol, by the sequential action of a hepatic and renal enzymes as discussed in the text.

Vitamin D₃ needs to be activated through chemical modifications. The first one takes place in the liver. The vitamin D₃ molecule is hydroxylated at the 25^th position to give 25-hydroxyvitamin D₃ [25(OH)D₃]. This is the major circulating form of vitamin D. It determines the status of vitamin D in the body: sufficiency, insufficiency or deficiency. The enzyme responsible for this modification is a hepatic vitamin D₃ 25-hydroxylase encoded by the gene CYP27A1 (fig. 1)³. CYP27A1 is a cytochrome P450 enzyme and is mitochondrial. There are other enzymes that perform the same function – e.g. the microsomal CYP2R1².

25(OH)D₃ is still not hormonally active. It is bound by DBP and is transported to the kidneys. The DBP/25(OH)D₃ complex interacts with the receptor magalin^6,7 and is internalized in cells of the proximal tubules where it is hydroxylated at carbon 1. This form of vitamin D, 1,25(OH)₂D₃ or 1,25-alpha-dihydroxyvitamin D₃, is the hormonally active form of vitamin D. The enzyme responsible for the 1-alpha hydroxylation (the 1-alpha-hydroxylase) is encoded by the gene CYP27B1, also a member of cytochrome P450 family. The renal 1-alpha-hydroxylase is regulated by calcium and phosphate homeostatic signals such as parathyroid hormone and FGF23 (a separate post will deal with this). There is ample evidence, however that CYP27B1 is expressed in other tissues enabling the local production of the hormonal form of vitamin D [1,25(OH)₂D₃]⁸ from circulating 25(OH)D₃ independently of the regulation cues stated above. 1,25(OH)₂D₃ could be bound to DBP, but with a much lower affinity compared to vitamin D₃ or 25(OH)D₃.

1,25(OH)₂D₃ enters freely in the cells through the membrane. It exerts non-genomic effects (minutes to an hour) or genomic effects. The latter take at least 1h to observe and involve gene expression regulation. The Vitamin D Receptor (VDR) is required to mediate the genomic effects. VDR is a member of the nuclear receptor family and is activated by 1,25(OH)2D3 to stimulate or repress target gene expression. One of these target genes is CYP24A1, also a member of the cytochrome P450 family. This gene encodes the enzyme 25(OH)D₃/1,25(OH)₂D₃-24-hydroxylase. 1,25(OH)₂D₃ or 25(OH)D₃ 24-hydroxylation is the limiting step in the degradation of vitamin D₃⁹. In this context, 1,25(OH)₂D₃ stimulates its own degradation creating a negative feedback loop. This, along with other regulatory mechanisms, insures a tight control on the actions of vitamin D.

Finally, I would like to discuss the names of the different forms of Vitamin D:

Pro-Vitamin D₃=7-dehydrocholesterol
Pre-Vitamin D₃
Vitamin D₃=cholecalciferol=calciol
25(OH)D₃=25-hydroxyvitamin D₃= calcifediol=25-hydroxychelcalciferol=calcidiol= circulating vitamin D
1,25(OH)₂D₃=1,25-dihydroxycholecacliferol=calcitriol=hormonal vitamin D

Vitamin D₃ is a form of vitamin D produced in vertebrates. I would like to mention that there is another form, vitamin D₂, produced in plants, that has similar properties to vitamin D₃. I will write about the similarities and differences between the two at a later time, but they seem to be modified in a similar fashion and have similar physiological functions.

I discussed above the basics of Vitamin D metabolism. What I did not mention is what role skin complexion has on vitamin D production and how long the skin should be exposed to UVB to get optimal production of vitamin D. Frankly, I think I will create a new entry in my blog that will deal with this, along with epidemiology of vitamin D deficiency-associated diseases, supplementation and concentrations of circulating forms of vitamin D. For now, I will just say that individuals with darker skin produce vitamin D less efficiently than white.

That’s it for now. Thanks for reading.

References:

1 DeLuca, H. F. Evolution of our understanding of vitamin D. Nutrition Reviews 66, S73-S87, doi:10.1111/j.1753-4887.2008.00105.x (2008).

2 Christakos, S., Ajibade, D. V., Dhawan, P., Fechner, A. J. & Mady, L. J. Vitamin D: Metabolism. Endocrinology & Metabolism Clinics of North America 39, 243-253, doi:DOI: 10.1016/j.ecl.2010.02.002 (2010).

3 Doorenbos, C. R. C., van den Born, J., Navis, G. & de Borst, M. H. Possible renoprotection by vitamin D in chronic renal disease: beyond mineral metabolism. Nat Rev Nephrol 5, 691-700 (2009).

4 Jeremy M Berg, J. L. T., Lubert Stryer. Biochemistry. (2002).

5 Zella, L. A., Shevde, N. K., Hollis, B. W., Cooke, N. E. & Pike, J. W. Vitamin D-Binding Protein Influences Total Circulating Levels of 1,25-Dihydroxyvitamin D3 but Does Not Directly Modulate the Bioactive Levels of the Hormone in Vivo. Endocrinology 149, 3656-3667, doi:10.1210/en.2008-0042 (2008).

6 Negri, A. L. Proximal tubule endocytic apparatus as the specific renal uptake mechanism for vitamin D-binding protein/25-(OH)D3 complex (Review Article). Nephrology 11, 510-515, doi:10.1111/j.1440-1797.2006.00704.x (2006).

7 Rowling, M. J., Kemmis, C. M., Taffany, D. A. & Welsh, J. Megalin-Mediated Endocytosis of Vitamin D Binding Protein Correlates with 25-Hydroxycholecalciferol Actions in Human Mammary Cells. The Journal of Nutrition 136, 2754-2759 (2006).

8 Zehnder, D. et al. Extrarenal Expression of 25-Hydroxyvitamin D3-1{{alpha}}-Hydroxylase. J Clin Endocrinol Metab 86, 888-894, doi:10.1210/jc.86.2.888 (2001).

9 Prosser, D. E. & Jones, G. Enzymes involved in the activation and inactivation of vitamin D. Trends in Biochemical Sciences 29, 664-673, doi:DOI: 10.1016/j.tibs.2004.10.005 (2004).