Vitamin D

Author: David Baorto, MD, PhD
Date Written: 2011-02-19

General summary

Vitamin D is a prohormone that is involved in calcium and phosphate homeostasis, bone formation, and immune regulation. The determination of vitamin D is complex because it is not a single component, but has two major forms, each of which has several metabolic stages leading to an active end product. Vitamin D3, also known as cholecalciferol, is the form that occurs naturally in humans and is produced in the skin of vertebrates from 7-dehydrocholesterol exposed to UV B radiation from the sun. Vitamin D3 can also be obtained from certain dietary animal products and supplementation. Vitamin D2, also known as ergocalciferol, is introduced into humans primarily by commercial supplementation. It is produced by UV irradiation of ergosterol, a substance that occurs in yeast, molds and certain plants.

Despite their distinct origins, both vitamin D2 and D3 share similar chemical structure, metabolic activation in humans, and presumably bioactivity as well, although the literature suggests that vitamin D2 is biologically inferior. Their structures differ only by a side chain, and the starting forms of both in humans, cholecalciferol and ergocalciferol, are hormonally inactive. Both undergo hydroxylation to 25-hydroxyvitamin D (2 or 3) in the liver, followed by further conversion to the active hormone, 1,25-dihydroxyvitamin D (2 or 3) in the kidney (or the placenta during pregnancy). 25-hydroxyvitamin D3 is also known as calcidiol, while the active form 1,25-dihydroxyvitamin D3 is also known as calcitriol. It is more difficult to find trivial name forms for the vitamin D2 group, although IUPAC recommends ercalcitriol for the active form of D2 (see nomenclature table).

"Vitamin D" based Name Trivial Name
Vitamin D2 ergocalciferol
Vitamin D3 cholecalciferol
25-Hydroxyvitamin D2 -none found-
25-Hydroxyvitamin D3 calcidiol
1,25-dihydroxyvitamin D2 ercalcitriol
1,25-dihydroxyvitamin D3 calcitriol

Measurement of the vitamin D parent compound, whether D3 or D2, has limited clinical value because, with a half-life of about one day, the value reflects mostly recent sun exposure or intake (there may be a utility in assessing absorption from the gut). Vitamin D status is generally determined by measuring the intermediate 25-hydroxyvitamin D form, the major circulating form with a half-life of 2-3 weeks. Whether there is a value to distinguishing the relative contribution of 25-hydroxyvitamin D2 compared to D3 depends on the objective. Understanding vitamin D status generally requires a total number; however, the need to assess response to supplementation with vitamin D2, for example, may be helped with distinct reports on both forms. The active hormone, 1,25-dihydroxyvitamin D (2 or 3), has a short half- life of 4-6 hours, and its concentration is tightly regulated. This makes it a poor candidate for assessing nutritional vitamin D status, although its measurement has utility in differential diagnosis of hyper and hypocalcemia and bone and mineral disorders.

An alternative metabolism pathway in the kidney yields a 24,25-dihydroxyvitamin D form. This is the most prevalent dihydroxylated metabolite in circulation, but (unlike the 1,25-dihydroxyvitamin D forms), it is not hormonally active. The physiological role of 24,25-dihydroxyvitamin D is unclear, although it has been suggested that the active hormone may self-modulate by shunting toward this pathway.

Specific parts

Vitamin D3

Vitamin D plays important roles in maintaining calcium and phosphate levels, and in immune regulation, but its determination is complex due to multiple metabolic intermediates and two major forms. Vitamin D3, also known as cholecalciferol, is the parent compound of one of the two major families of vitamin D (D2 and D3). Vitamin D3 is the form of vitamin D that is endogenously produced in the skin of vertebrates (including humans) upon exposure to sunlight (specifically UV B). It can also be obtained from dietary animal products, or dietary supplements. Vitamin D3, whether produced endogenously or ingested, is a prohormone form that is not active until further metabolism first to 25-hydroxyvitamin D3 (in the liver), then finally to 1,25-hydroxyvitamin D3 (in the kidney or placenta) . Measurement of the vitamin D parent compound, whether D3 or D2, has limited clinical value because, with a half-life of about one day, the value reflects mostly recent sun exposure or intake (there may be a utility in assessing absorption from the gut). Vitamin D status is generally determined by measuring the intermediate 25-hydroxyvitamin D form, the major circulating form with a half-life of 2-3 weeks. The need to assess response to supplementation with vitamin D2, for example, may be helped with distinct reports on both forms.

Vitamin D2

Vitamin D plays important roles in maintaining calcium and phosphate levels, and in immune regulation, but its determination is complex due to multiple metabolic intermediates and two major forms. Vitamin D2, also known as ergocalciferol, is the parent compound of one of the two major families of vitamin D (D2 and D3). Vitamin D2 is the form of vitamin D that is not endogenously produced in the skin. It is produced upon UV radiation of ergosterol, which occurs in molds, yeast, and certain plants, and its major introduction into humans is via commercial supplementation. Vitamin D2 is a prohormone form that is not active until further metabolism first to 25-hydroxyvitamin D2 (in the liver), then finally to 1,25-hydroxyvitamin D2 (in the kidney or placenta) . Measurement of the vitamin D parent compound, whether D3 or D2, has limited clinical value because, with a half-life of about 1 day, the value reflects mostly recent sun exposure or intake (there may be a utility in assessing absorption from the gut). Vitamin D status is generally determined by measuring the intermediate 25-hydroxyvitamin D form, the major circulating form with a half-life of 2-3 weeks. The need to assess response to supplementation with vitamin D2, for example, may be helped with distinct reports on both forms.

25-Hydroxyvitamin D, 25-Hydroxyvitamin D2, and 25-Hydroxyvitamin D3

The 25-hydroxyvitamin D intermediate is the major circulating metabolite of vitamin D with a half-life of 2-3 weeks, and it is the most useful measure of vitamin D status. The determination of vitamin D is complex due to multiple metabolic intermediates and two major forms, vitamin D2 and D3. The lack of specification of the form generally indicates that both are included. Vitamin D3 is the form of vitamin D that is endogenously produced in the skin of vertebrates (including humans) upon exposure to sunlight (specifically UV B), whereas vitamin D2 is produced upon UV radiation of ergosterol, which occurs in molds, yeast, and certain plants, and its major introduction into humans is via commercial supplementation, although both D3 and D2 can be included as supplements. The 25-hydroxyvitamin D metabolites of both forms (also known as calcidiol in the case of D3) are produced in the liver from the corresponding parent compound. Whether there is a value to distinguishing the relative contribution of 25-hydroxyvitamin D2 compared to D3 depends on the objective. Understanding vitamin D status generally requires a total number; however, the need to assess response to supplementation with vitamin D2, for example, and other specific cases, may be helped with a distinct reports on both forms.

1,25-Hydroxyvitamin D, 1, 25-Hydroxyvitamin D2, and 1, 25-Hydroxyvitamin D3

1,25-hydroxyvitamin D is the physiologically active form of vitamin D. When metabolically activated to this form, vitamin D plays important roles in maintaining calcium and phosphate levels, and in immune regulation. It increases intestinal absorption of calcium and phosphorus, and in concert with parathyroid hormone increases bone resorption. There are two major forms of vitamin D, each of which can be activated to a 1,25-dihydroxy form (also known as calcitriol in the case of D3 and ercalcitriol in the case of D2). Vitamin D3 is the form of vitamin D that is endogenously produced in the skin of vertebrates (including humans) upon exposure to sunlight (specifically UV B). It can also be obtained from dietary animal products, or dietary supplements. Vitamin D2 is the form of vitamin D that is not endogenously produced in the skin. It is produced upon UV radiation of ergosterol, which occurs in molds, yeast, and certain plants, and its major introduction into humans is via commercial supplementation. Vitamin D, whether produced endogenously or ingested, is a prohormone form that is not active until further metabolism first to 25 hydroxyvitamin D3 (in the liver), then finally to the active 1,25 hydroxyvitamin D3 (in the kidney or placenta). The active hormone, 1,25-dihydroxyvitamin D (2 or 3), has a short half-life of 4-6 hours, and its concentration is tightly regulated. This makes it a poor candidate for assessing nutritional vitamin D status, although its measurement has utility in differential diagnosis of hyper and hypocalcemia and bone and mineral disorders.

24,25-Dihydroxyvitamin D3

24,25-dihydroxyvitamin D3 is a compound which is closely related to 1,25-dihydroxyvitamin D3, the active form of vitamin D3, but (like vitamin D3 itself and 25-hydroxyvitamin D3) is inactive as a hormone. It is produced from 25-hydroxyvitamin D3 by alternative metabolic pathway in the kidney. The physiological role of 24,25-dihydroxyvitamin D is unclear, although it has been suggested that the active hormone may self-modulate by shunting toward this pathway.

References

Houghton, L A, Vieth R. The case against ergocalciferol (vitamin D2) as a vitamin supplement. American Journal of Clinical Nutrition 2006; 84 (4):694-697. PubMed: 17023693.

Morris, H A. Vitamin D: A Hormone for All Seasons - How much is enough? Understanding the New Pressures. Clinical Biochemist Reviews 2005; 26(1):21-32. PubMed: 16278774.

St-Arnaugh, R, Glorieux, F H. 24, 25-Dihydroxyvitamin D—Active Metabolite or Inactive Catabolite? Endocrinology 1998;139:3371-3374. PubMed:9681484.

IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN). Nomenclature of vitamin D. Recommendations 1981. Pure & Appl.Chem. 1982; 54(8): 1511—1516.

Burtis, C A, Ashwood, E R. Tietz Textbook of Clinical Chemistry, 3rd ed.: Saunders; 1994.

Wikipedia: http://en.wikipedia.org/wiki/Vitamin_D

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