The substance commonly referred to as Vitamin D is really a group of several similar molecules whose functions in the body are

essential to human health. Vitamin D is endogenously produced and altered to maintain homeostasis levels of calcium and phosphorus. It also has an important role in disease prevention due to its control of gene expression. Vitamin D Production Vitamins are usually considered to be substances that must be ingested, but the human body has its own method to produce Vitamin D endogenously. Vitamin D and its derivatives are secosteroids: they have the characteristic four-ring steroid structure with the B-ring severed. The breaking of this ring occurs when vitamin D is formed. When the skin is exposed to sunlight, UV rays break a C-C bond in the second ring of 7-dehydrocholesterol to form previtamin D3. Heat then isomerizes this molecule to produce cholecalciferol (D3), stretching out the B-ring to form a carbon chain between what were previously the A and C-rings. This chain is fixed in an extended position due to the two double bonds it contains that were formed with the electrons previously contributing to the C-C bond that was broken. The body regulates the amount of D3 that it creates by having two alternate pathways for previtamin D3 to proceed. Additional light causes previtamin D3 to form tachysterol and lumisterol. These two molecules remain in the skin and later revert back to previtamin D3 in the absence of light, allowing for further production of D3 after the original D3 is transported away from the skin. Continued exposure to UV light also results in the photoconversion of excess D3 to suprasterols I and II and 5,6 transvitamin D.1 This complete process ensures that individuals who have regular exposure to sunlight will be provided with adequate but not excessive amounts of vitamin D. In cases where individuals are unable to attain enough exposure to sunlight, vitamin D can also be

consumed. Certain edible plants undergo a similar light-induced process to convert ergosterol to ergocalciferol (D2) which can then be consumed. The physiological actions of D 2 after absorption are analogous to those of D3, so the two molecules will henceforth be referred to simply as D.

Figure 1 Photoconversion of 7-dehydrocholesterol to previtamin D3 and heat isomerization to cholecalciferol.

Figure 2 Photoconversion of ergosterol to previtamin D 2 and isomerization to ergocalciferol.

Transport and Modification As a lipophilic molecule, D is not soluble in the blood on its own and requires a protein carrier.2 After its consumption or production in the skin, it is bound to vitamin D binding protein (DBP) for transport. From there it is either taken to the liver or stored in the adipose (body fat) tissues for later use. In the liver, cytochrome P450 containing enzymes add a hydroxyl group to the position 25 carbon to form 25-hydroxyvitamin D (25-OH-D), the primary circulating form of vitamin D. This molecule then binds to DBP again and re-enters the bloodstream. From there it

can enter the kidneys for its second alteration. In the proximal nephronal tubules, the enzyme CYP27B1 hydroxylates 25-OH-D at the position 1 carbon to form 1,25(OH)2D, the most biologically active form of vitamin D. Unlike the previous hydroxylation, which occurs relatively freely, the second hydroxylation is very closely regulated.3

Figure 3 25-OH-D3 (left) and 1,25(OH)2D3 (right)

Calcium Homeostasis One of the key roles of vitamin D is the regulation of serum Ca2+. The amount of calcium in the blood is vital to many of the bodys processes such as muscle contraction, neurological activity, and bone growth. The Ca2+ concentration in the blood is carefully monitored by the parathyroid gland. If the concentration dips too low, parathyroid hormone (PTH) is released into the bloodstream. Within minutes, PTH reaches receptors along the nephrons of the kidneys. This triggers the activation of CYP27B1 which then hydroxylates 25-OH-D and ultimately raises the plasma concentration of 1,25(OH)D. This active form has many roles, all associated with its affinity for the nuclear receptor protein VDR which is found in many target

cells in tissues that are affected by vitamin D. When VDR binds to 1,25(OH)2D3 it is able to interact with cell DNA to either upregulate or downregulate expression of certain genes.4 With relation to calcium homeostasis, this process initiates the uptake of calcium from food in the small intestine and stimulates osteoblasts to transfer calcium from the bones to the bloodstream. In addition, production of PTH is downregulated and consequently, the production of 1,25(OH)2D is slowed. The production of the enzyme CYP24, which is responsible for the catabolism of vitamin D, is upregulated. A similar process takes place to regulate concentrations of PO43- in the bloodstream. Vitamin D Catabolism

Figure 4 The C-24 oxidation pathway. Beginning with 1,25(OH)2D3 and ending with calcitroic acid.

CYP24 systematically oxidizes 1,25(OH)2D via what is known as the C-24 oxidation pathway. Another hydroxyl group is added at the position 24 carbon and is further oxidized to a keto

group. Then the position 23 carbon is hydroxylated and the position 24 and 25 carbons and their attached groups are removed, leaving only an alcohol end group at the position 23 carbon. This alcohol is oxidized to a carboxylic acid via the removal of a proton from the hydroxyl group. These subsequent oxidations cause the molecule to become increasingly polar due to the hydrogen bonding of the hydroxyl groups and the partial negative charge on the oxygen of the keto and carboxyl groups. The final form, called calcitroic acid, is polar enough to be soluble in water and can therefore be excreted by the body.3 Potential for Toxicity Due to the careful regulation of the active form of vitamin D, it would seem that an excessive intake of vitamin D containing foods would have no adverse biological effects. However, vitamin D toxicity is observed. In those affected with toxicity, the concentration of the active form is comparable to normal levels, but the concentration of 25-OH-D is present in very high concentrations. The exact cause of toxicity symptoms in this state has not been conclusively determined. The most plausible explanation is that 25-OH-D, which has a higher affinity for DBP than 1,25(OH)2D, overwhelms the DBP in the bloodstream, resulting in more free-floating 1,25(OH)2D that is easily able to bind to VDR.2 The overall concentration of 1,25(OH)2D is normal, but the amount able to induce the transcription of genes is elevated beyond normal levels. 1. www.endotext.org; Bikle, D., Vitamin D: Production, Metabolism, and Mechanisms of Action 2. Jones, G. AJCN 2008; Vol. 88, No. 2, 582S-586S. 3. Jones, G., Strugnell, S., DeLuca HF. Physiol Rev 1998; vol. 78: 11932310.

4. 3. Liao, J., Ozono, K., et al. PNAS 1990; vol. 87: 9751-9755. 5. Holick, M. Vitamin D: Physiology, Molecular Biology, and Clinical Applications. 2nd ed., 2010. Humana Press.