Cholecalciferol synthesis

Blood levels of vitamin D are influenced both by dietary intake and the amount of daylight exposure to the skin. Indeed, exposure of the skin to ultraviolet light catalyzes the synthesis of vitamin D3 (cholecalciferol) from 7-dehydrocholesterol thus vitamin D is more like a hormone and not strictly a vitamin. Furthermore, the UV radiation catalyzes the synthesis of ergocalciferol from ergosterol. This latter compound is found in plants, especially yeast and fungi, but the conversion to ergocalciferol... 

Vitamin D is a secosteroid present in the diet but is mainly produced non-enzymatically in the skin from cholesterol under the influence of ultraviolet light. Vitamin D synthesis is promoted by PTH. This is vitamin D3 or cholecalciferol. Vitamin D2, ergocalcif-erol is found in vegetables. Both forms of vitamin D... 

Endogenous vitamin precursor 7-Dehydrocholesterol, an intermediate in cholesterol synthesis, is converted to cholecalciferol in the dermis and epidermis of humans exposed to sunlight. Preformed vitamin D is a dietary requirement only in individuals with limited exposure to sunlight. 

Cholesterol is involved in two major biological processes. It is a structural component of cell membranes (Chap. 6) and the parent compound from which steroid hormones, vitamin D3 (cholecalciferol), and the bile salts are derived. Cholesterol is synthesized de novo in the liver and intestinal epithelial cells and is also derived from dietary lipid. De novo synthesis of cholesterol is regulated by the amount of cholesterol and triglyceride in the dietary lipid. 

Sunlight is not strictly essential for cutaneous synthesis of cholecalciferol, because UV-B penetrates clouds reasonably well complete cloud cover reduces the available intensity by about 50%. It also penetrates light clothing. However, low-intensity irradiation (below 20 ml per cm in vitro) does not result In significant photolysis of 7-dehydrocholesterol to previtamin D. Acute whole-body exposure to UV-B irradiation below 18 ml per cm does not result in any detectable increase in plasma cholecalciferol or calcidiol. In temperate regions (beyond about 40°N or S), the intensity of UV-B is below this threshold in winter, so there is unlikely to be any significant cutaneous synthesis of the vitamin in winter, and plasma concentrations of calcidiol show a marked seasonal variation in temperate regions (Holick, 1995 see Table 3.2). 

Calcidiol la-hydroxylase is not restricted to the kidney, but is also found in placenta, bone cells (in culture), mammary glands, and keratinocytes. The placental enzyme makes a significant contribution to fetal calcitriol, but it is not clear whether the calcidiol 1-hydroxylase activity of other tissues is physiologically significant or not. Acutely nephrectomized animals given a single dose of calcidiol do not form any detectable calcitriol, but there is some formation of calcitriol in anephric patients, which increases on the administration of cholecalciferol or calcidiol. However, thus extrarenal synthesis is not adequate to meet requirements, so that osteomalacia develops in renal failure (Section 3.4.1). The enzyme is inhibited, or possibly repressed, by strontium ions this is the basis of strontium-induced vitamin D-resistant rickets, which responds to the administration of calcitriol or la-hydroxycalciol, but not calciferol or calcidiol (Omdahl and DeLuca, 1971). 

A synthesis of 22,23-epoxyergocalciferol from the 4-phenyl-1,2,4-triazoline-3,5-dione adducts (272) employed the K2CO3-DMSO reaction for deprotection of the A -diene cf. ref. 53). The Reporter observes that the assignment of the 22/3,23/3-configuration is dubious in view of earlier work in this area. " Syntheses have been reported for la,25-dihydroxy-24-nor-cholecalciferol, 25-hydroxy-24 -nor- 5,6- frans-cholecalcif erol, and 2 5 -hydroxy- 24a-homo- 5,6-... 

Some 20% of the daily vitamin D requirement are supplied by food intake, while about 80% are produced via endogenous synthesis through transformation of 7-dehydrocholesterol under the influence of ultraviolet light. Witliin the liver, D3 (= cholecalciferol) is activated by 25-hydroxylation. It is excreted into the bile to become pmrt of an enterohepmtic circulation. In liver cirrhosis, and particularly in cholestasis, this circulation is impaired, so that vitamin D metabolites are activated in larger amounts and excreted in the faeces. The resulting clinical picture is usually a mixture of osteoporosis and osteomalacia. 

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 anti-rachitic factors resulting from the ultraviolet irradiation of cholesterol (40) and ergosterol (41) namely vitamin Dj (42) cholecalciferol and Dj, ergocalciferol (43) respectively are important dietary materials the chemistry of which was only elucidated by the investigations of many chemists (ref.41). Vitamin Dj is most easily derived by semi-synthesis from cholesterol through formation firstly of 7-dehydrocholesterol by reaction with N-bromosuccinimide followed by dehydrobromination with collidine. Ultraviolet light irradiation affords previtamin Dj which is thermally isomerised to the endo compound shown and thence to the exo... 

Fig. 10.10 Calcitriol synthesis in the human body, (a) Numbering of the cholesterol carbon atoms at each end of the molecule and position of oxidation site, (b, c) Isomerization to cholecalciferol. (d) Calcitriol showing the hydroxylation site in the liver (top right) and kidney (bottom left) (Modified from Fig. 27-32 of Biochemistry. L. Stryer, 4th Ed. 1995. W.H. Freeman Co., New York)...

Ergocalciferol (vitamin D2) is formed by irradiation of ergosterol, a plant sterol common in the diet. It differs from cholecalciferol in the side chain attached to the D ring (Figure 37-1). Irradiation of ergosterol is an important commercial method for the synthesis of vitamin D2, which is used for enriching cow s milk. The practice... 

Oxidation of la-hydroxycholecalciferol and la,25-dihydroxycholecalciferol with Mn02 gave the corresponding 1 -oxo-previtamins which could be reduced with LiAlH4 at —25 °C in each case to give a mixture of la-hydroxy- and IjS-hydroxy-previtamins in which the IjS-epimers (285) and (286) predominated. Thermal equilibration allowed the isolation of the 1/3-hydroxy-cholecalciferol and l/ ,25-dihydroxycholecalciferol. A similar independent synthesis of 1/3-hydroxycholecalciferol employed NaBH4 for the reduction... 

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