D Illustration Receptor Vitamin
Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D 2 (or ergocalciferol) and vitamin D 3 (or cholecalciferol). Vitamin D obtained from sun exposure, food, and supplements, is biologically inert and must undergo two hydroxylation reactions to be activated in the body. Calcitriol (1,25-Dihydroxycholecalciferol) is the active form of vitamin D found in the body. The term vitamin D also refers to these metabolites and other analogues of these substances.
Calcitriol plays an important role in the maintenance of several organ systems. However, its major role is to increase the flow of calcium into the bloodstream, by promoting absorption of calcium and phosphorus from food in the intestines, and reabsorption of calcium in the kidneys; enabling normal mineralization of bone and preventing hypocalcemic tetany. It is also necessary for bone growth and bone remodeling by osteoblasts and osteoclasts.
Without sufficient vitamin D, bones can become thin, brittle, or misshapen. Deficiency can arise from inadequate intake coupled with inadequate sunlight exposure; disorders that limit its absorption; conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders; or, rarely, by a number of hereditary disorders. Vitamin D deficiency results in impaired bone mineralization and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis.
Vitamin D plays a number of other roles in human health including inhibition of calcitonin release from the thyroid gland. Calcitonin acts directly on osteoclasts, resulting in inhibition of bone resorption and cartilage degradation. Vitamin D can also inhibit parathyroid hormone secretion from the parathyroid gland, modulate neuromuscular and immune function and reduce inflammation.
Forms
Several forms (vitamers) of vitamin D have been discovered (see table). The two major forms are vitamin D 2 or ergocalciferol, and vitamin D 3 or cholecalciferol. These are known collectively as calciferol . Vitamin D 2 was chemically characterized in 1932. In 1936 the chemical structure of vitamin D 3 was established and resulted from the ultraviolet irradiation of 7-dehydrocholesterol.
Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken. The structural difference between vitamin D 2 and vitamin D 3 is in their side chains. The side chain of D 2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24.
Vitamin D 2 (made from ergosterol) is produced by invertebrates, fungus and plants in response to UV irradiation; it is not produced by vertebrates. Little is known about the biologic function of vitamin D 2 in nonvertebrate species. Because ergosterol can more efficiently absorb the ultraviolet radiation that can damage DNA, RNA and protein it has been suggested that ergosterol serves as a sunscreening system that protects organisms from damaging high energy ultraviolet radiation.
Vitamin D 3 is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–300 nm, with peak synthesis occurring between 295-297 nm. These wavelengths are present in sunlight when the UV index is greater than 3. At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D 3 can be made in the skin after only ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. However, season, geographic latitude, time of day, cloud cover, skin cover, skin color, smog, and sunscreen affect UV ray absorption and vitamin D synthesis. For example, sunlight exposure from November through February in Boston is insufficient to produce significant vitamin D synthesis in the skin. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and excess vitamin D simply degrades as fast as it is generated.
Both vitamin D 2 and D 3 are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene. In humans, D 3 is as effective as D 2 in vitamin D hormone activity in circulation, although others state that D 3 is more effective than D 2 . However, in some species, such as rats, vitamin D 2 is more effective than D 3 .
Biochemistry
Vitamin D is a prohormone, meaning that it has no hormone activity itself, but is converted to the active hormone 1,25-D through a tightly regulated synthesis mechanism. Production of vitamin D in nature always appears to require the presence of some UV light; even vitamin D in foodstuffs is ultimately derived from organisms, from mushrooms to animals, which are not able to synthesize it except through the action of sunlight at some point in the synthetic chain. For example, fish contain vitamin D only because they ultimately exist on calories from ocean algae which synthesize vitamin D in shallow waters from the action of solar UV.
Production in the skin
The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer, thinner epidermis. The epidermis consists of five strata ; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale.
Cholecalciferol is produced photochemically in the skin from 7-dehydrocholesterol; 7-dehydrocholesterol is produced in relatively large quantities in the skin of most vertebrate animals, including humans. The few exceptions are some bat species, mole rats, cats, and dogs, which produce little vitamin D. In most animals the highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum. The production of pre-vitamin D 3 is therefore greatest in these two layers, whereas production in the other layers is less.
Synthesis in the skin involves UVB radiation, which effectively penetrates only the epidermal layers of skin. While 7-dehydrocholesterol absorbs UV light at wavelengths between 270–300 nm, optimal synthesis occurs in a narrow band of UVB spectra between 295-300 nm. Peak isomerization is found at 297 nm. This narrow segment is sometimes referred to as D-UV. The two most important factors that govern the generation of pre-vitamin D 3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7-dehydrocholesterol deep in the stratum basale and stratum spinosum.
A critical determinant of vitamin D 3 production in the skin is the presence and concentration of melanin. Melanin functions as a light filter in the skin, and therefore the concentration of melanin in the skin is related to the ability of UVB light to penetrate the epidermal strata and reach the 7-dehydrocholesterol-containing stratum basale and stratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 µg/cm² of skin) are available in the stratum spinosum and stratum basale of the skin to meet the body's vitamin D requirements, and melanin content does not alter the amount of vitamin D that can be produced. Thus, individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. The amount of time an individual requires to produce a given amount of vitamin D may also depend upon the person's distance from the equator and on the season of the year.
In some animals, the presence of fur or feathers blocks the UV rays from reaching the skin. In birds and fur-bearing mammals, vitamin D is generated from the oily secretions of the skin deposited onto the fur and obtained orally during grooming.
In 1923, Harry Goldblatt and Katherine Soames established that when 7-dehydrocholesterol (a precursor of vitamin D in the skin) is irradiated with light, a form of a fat-soluble vitamin is produced. Alfred Fabian Hess and Mildred Weinstock further substantiated that "light equals vitamin D". Adolf Windaus, at the University of Göttingen in Germany, received the Nobel Prize in Chemistry in 1928, for his work on the constitution of sterols and their connection with vitamins. In 1930s, he clarified further the chemical structures of the vitamins D.
Synthesis mechanism (form 3)
Mechanism of action
After vitamin D is produced in the middle layers of skin or consumed in food, it is converted in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH) 2 D), the physiologically active form of vitamin D (when "D" is used without a subscript it refers to either D 2 or D 3 ). This physiologically a
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