Skin previtamin

An important group of conjugated diene/triene systems are those in the vitamin D series. The key reactions in the commercial manufacture of vitamin D (and probably also in its formation in skin exposed to daylight) are a photochemical, conrotatory electrocydic ring-opening in the provitamin, and a thermal 1.7-shift of hydrogen in the previtamin so formed (2.23). High conversions to the vitamin are not normally possible because all three species absorb appreciably at the... 

Vitamin D is represented by cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2), which are structurally similar secosteroids derived from the UV irradiation of provitamin D sterols. In vertebrates, vitamin D3 is produced in vivo by the action of sunlight on 7-dehydrocholesterol in the skin. Vitamin D2 is produced in plants, fungi, and yeasts by the irradiation of ergosterol. On irradiation, the provitamins are converted to previtamin D, which undergoes thermal transformation to vitamin D. 

SCHEME II Diagram of the formation of previtamin D3 in the skin, its thermal conversion to vitamin D3, and transport by binding proteins (DBP) in plasma into the general circulation (Reference 17). From ref. 17, copyright 1980 by the AAAS. 

Vitamin D is a fat-soluble vitamin its main function is the maintenance of normal plasma levels of calcium and phosphorus (Zittermann, 2003). Vitamin D3 is synthesized in the skin from 7-dehydrocholesterol on exposure to sunlight (290-315 nm) (Fig. 30-2). The UV light causes a rearrangement of the 5,7 diene bonds in the B ring of 7-dehydrocholesterol, resulting in a break in the B ring to form previtamin D3. 

The skin has a well-documented role in vitamin D metabolism. 7-Dehydrocho-lesterol (provitamin D3) is activated by exposure to ultraviolet radiation in the skin to previtamin D3, which isomerizes to vitamin D3. Recently, further metabolism of 24,25-dihydroxyvitamin D to biologically active 1,25-dihydroxy vitamin D has also been demonstrated in skin, a conversion previously assumed to occur only in the kidney. 

Transport of vitamin D3 away from the dermal junction of skin is accomplished by a 52 kDa serum vitamin D-binding protein (DBP). Serum DBP is a member of the a-fetoprotein-albumin super family [36], DBP has high affinity for vitamin D3, but does not bind to its precursors or the products of previtamin D3 side-reactions, lumisterol and tachysterol [37], Accumulation of 7-dehydrocholesterol in skin occurs in sebaceous glands at the malpighian layer of the epidermis, mostly in the stratum spinosum and stratum basal... 

Biochemistry. Vitamin D is introduced into the bloodstream either from the skin after natural synthesis by the irradiation of 7-dehydrocholesterol stored in the epidermis (172) or by ingestion and absorption of vitamin D2 or vitamin D through the gut wall (40). Between 60 and 80% of the vitamin introduced in the blood is taken up by the Hver, where cholecalciferol is transferred from chylomicrons to a vitamin D-binding protein (DBF), an OC-globulin specific for vitamin D and its metaboHtes but one which does not bind with previtamin D in the skin (173). Cholecalciferol is hydroxylated in the Hver at the C-25 position (51,141,174). This hydroxylation occurs in the endoplasmic reticulum and requires NADPH, a flavoprotein, cytochrome P-450, Mg ", and O2 (175). 25-Hydroxylation also occurs in intestinal homogenates of chicks (176), but does not appear to occur outside the... 

The mechanism responsible for the movement of vitamin D3 from the skin to the blood is not known. In the blorxi. vitamin D3 is bound primarily to an a protein known as vitamin D-binding protein (VDBP). This protein selectively removes vitamin D3 from the skin because it has low alTinity for 7-dchydrochole.sterol. previtamin D3. lumisterol. and tachysterol. 

Vitamin D is associated with biological functions, such as bone formation, immune system responses, cell defences and anti-tumour activity.615,616 Vitamin D comes in two closely related forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), and their metabolites. Both vitamin D2 and D3 occur naturally in some foods. However, vitamin D3 (63) can also be synthesized in skin cells called keratinocytes from 7-dehydrocholesterol (provitamin D 64), which undergoes a photochemical six-electron conrotatory electrocyclic ring opening at 280nm to previtamin D3 (41 see also Scheme 6.8), which spontaneously isomerizes to 63 in a thermal antarafacial hydride [l,7]-sigmatropic shift (Scheme 6.21). Both vitamin D2 and D3 are subsequently converted to active hormone 1,25-D by enzymes in several steps. The recommended daily intake of vitamin D for humans is 5 10 pg per day. For example, 15 ml of fish liver oils and 100 g of cooked salmon contain approximately 35 and 10 pg... 

Vitamin D3 is naturally synthesized in human skin by a spontaneous thermal antarafacial hydrogen [l,7]-sigmatropic shift in previtamin D3, which is produced from 64 upon solar UVB irradiation in the first step.621... 

Vitamin D is produced in skin as a result of ultraviolet irradiation, a phenom enon realized in 1919—1924 It is known that ultraviolet light brings about a photolyas of 5,7-diene sterols giving rise to previtamin D and other photoisomers, lumisterol and tachysterol (Fig. 2). The previtamin D spontaneously isomerizes to vitamin D to yield an equilibrium mixture favoring vitamin D. This photolysis known to occur in organic solvents also occurs in epidermis of skin. Ultraviolet light is known to penetrate to the site of 7-dehydrocholesterol in epidermis Recently, the antirachitic substance produced in rat skin by ultraviolet irradiation has been isolated in pure form and unequivocally identified as vitamin D3 The... 

Holick, M. R, Maclaughlin, J. A., Doppelt, S. H. 1981. Regulation of cutaneous previtamin D3 photosynthesis in man Skin pigment is not an essential regulator. Science, 211 590-3. 

PROBLEM 20.28 Vitamin D3 (3) is produced in the skin as a result of UV irradiation. It was once believed that 7-dehydro-cholesterol (1) was converted directly into 3 upon photolysis. It is now recognized that there is an intermediate, previtamin D3 (2), involved in the reaction. This metabolic process formally incorporates two pericyclic reactions, 1 — 2 and 2 — 3. Identify and analyze the two reactions. 

In vivo experiments on skin preparates at 37 °C showed that previtamin D was likewise formed by UVB irradiation and was specifically translocated from the skin to the blood by the vitamin D-binding protein, subtracting it from the equilibrium with the previtamin and resulting in essentially quantitative isomerization (see Fig. 4.19). 

Fig. 4.19 (a) Photochemical and thermal reactions occurring with previtamin D at a temperature >20°. (b) Schematic representation of tire photochemical formation of previtamin D3 in the skin ant the subsequent thermal conversion to vitamin D3. In turn, this is bound to the vitamin D-binding protein (DBP) in plasma and transported into circulation... 

Holick L, MacLaughlin JA, Clark MB, Holick SA, Potts JT Jr, Anderson RR, Blank IH, Parrish JA, Elias P (1980) Photosynthesis of previtamin D3 in human skin and the physiologic consequences. Science 210 203-205... 

Vitamin D is essential in the body s calcium metabolism and is formed in the skin from previtamin D, which is in turn synthesised from 7-dehydrocholesterol under exposure to UV light. The deficiency of vitamin D causes rickets, which manifests itself as deformities of the skeleton, enlargements of the head, bending of the spine... 

As shown in Figure 11.6, the steroid 7-dehydrocholesterol (an intermediate in the synthesis of cholesterol that accumulates in the skin but not other tissues), undergoes a non-enzymic reaction on exposure to UV light, yielding previtamin D. This undergoes... 

Although excess dietary vitamin D is toxic, excessive exposure to sunlight does not lead to vitamin D poisoning. There is a limited capacity to form the precursor, 7-dehydrocholesterol, in the skin, and a limited capacity to take up cholecalciferol from the skin. Furthermore, prolonged exposure of previtamin D to UV light results in further reactions to yield biologically inactive compounds. 

Vitamin Dj can be synthesized in the skin or derived from dietary sources. Skin synthesis of vitamin D3 from 7-dehydrocholesterol involves a previtamin D intermediate (Fig. 2), is a nonenzymatic process involving light and heat, and therefore can be mimicked in the test tube. Once the previtamin D is formed in the upper layers of the skin as the result of the reaction of ultraviolet light, it filters down to the lower layers where it is slowly transformed thermally into vitamin D3. Vitamin D3 and its metabolites are primarily hydrophobic and thus require a transport protein to be carried in the aqueous environment of the bloodstream. A specific globulin known as vitamin D binding protein or DBF exists for the purpose of transporting vitamin D3 from the skin to the liver for the first step of activation to carry its initial product, 25-hydroxyvitamin D3 (25-OH-D3) to the kidney for the second step of activation, and also to carry the active form, la,25-(0H)2D3, to its sites of action. 

When the skin is exposed to the ultraviolet radiation of sunlight, part of the store of 7-dehydrocholesterol undergoes a photochemical reaction in the epidermis and the dermis and forms previtamin Dj. Once previtamin D, is formed in the skin, it undergoes a slow temperature-dependent transformation to vitamin D, which takes at least 3 days to complete. Then, the vitamin D-binding protein transports D, from the skin into the circulation. 

An increase in skin pigmentation and zenith angle of the Sim (change in latitude, season, and time of day) and the topical application of a sunscreen can markedly diminish or even prevent the production of vitamin D3 in the skin. Over the age of 65 years, there is a three- to fourfold decline in the synthetic capacity of the skin to produce vitamin D3. Excessive exposure to sunlight cannot cause vitamin D3 intoxication because once previtamin D3 and vitamin D3 are made in the skin, excessive quantities are rapidly destroyed by sunlight (Figure 3). 

Figure 3 A schen atic representation of the photochemical and thermal events that result in the synthesis of vitamin D3 in the skin, and the photodegradation of previtamin D3 and vitamin D3 to biologically inert photoproducis. 7-Dehydrocholesterol (7-DHC) in the skin is converted to previtamin D3 by the action of solar ultraviolet B radiation. Once formed, previtamin D3 is transformed into vitamin D3 by a heat-dependent (AH) process. Vitamin D3 exits the skin into the dermal capillary bbod system and is bound to a specific vitamin D-binding protein (DBF). When previtamin D3 and vitamin D3 are exposed to solar ultraviolet B radiation, they are converted to a variety of photoproducts that have little or no activity on calcium metabolism. (Reproduced with permission from Holick MF (1995) Vitamin D Photobiology, Metabolism, and Clinical Applications. In DeGroot U etal. (eds.) Endocrinology, Srdedn, pp. 990-1013. Philadelphia W.B. Saunders.)...

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