A’-Dehydrocholesterol

P450 7A1 has also been demonstrated to convert lathosterol to 7-ketolathosterol (the immediate precursor of cholesterol in the normal pathway) to 7-ketoeholesterol and a trace of the 7,8-epoxide [1777]. The reaction with A -dehydrocholesterol is proposed to be responsible for the high level of the oxysterol 7-ketocho-lesterol in individuals with Smith-Lemli-Opitz syndrome [1777], and the ketone is formed in a direct reaction (carbocationic intermediate, with hydride transfer) rather than via rearrangement of the epoxide [1777], The relevance of this reaction has been demonstrated in Smith-Lemli-Optiz syndrome and cerebrotendinous xanthomatosis patients [1778],... 

Vitamin D, also called calciferol, is related to the steroids. It arises from A - -un-saturated sterols, the provitamins, by ultraviolet irradiation (cf. the diagram of formulas in Chapt. XIV-4). Thus, vitamin D2 (ergocalciferol) arises from ergos-terol vitamin D3 (cholecalciferol) from A -dehydrocholesteroI. In this connection it is important that A -dehydrocholesterol is concentrated in the skin and therefore exposed to irradiation. 

A steroid very closely related structurally to cholesterol is its 7 dehydro derivative 7 Dehydrocholesterol is formed by enzymatic oxidation of cholesterol and has a conju gated diene unit m its B ring 7 Dehydrocholesterol is present m the tissues of the skin where it is transformed to vitamin D3 by a sunlight induced photochemical reaction... 

Infants maybe sensitive to doses of vitamin A [11103-57-4] in the range of 75,000—200,000 lU (22.5—60 mg), although the toxic dose in adults is probably 2—5 million lU (90.6—1.5 g). Intakes in this range from normal food suppHes without oral supplements are simply beyond imagination (79). Vitamin D [1406-16-2] toxicity is much more difficult to substantiate clinically. Humans can synthesize active forms of the vitamin in the skin upon irradiation of 7-dehydrocholesterol. Toxic symptoms are relatively nonspecific, and dangerous doses seem to He in the range of 1000—3000 lU/kg body wt (25—75 flg/kg body wt) (80). Cases of toxicity of both vitamins E and K have been reported, but under ordinary circumstances these vitamins are considered relatively innocuous (81). 

Vitamins are classified by their solubiUty characteristics iato fat-soluble and water-soluble groups. The fat-soluble vitamins A, E, and K result from the isoprenoid biosynthetic pathway. Vitamin A is derived by enzymic cleavage of the symmetrical C q beta-carotene, also known as pro-vitamin A. Vitamins E and K result from condensations of phytyldiphosphate (C2q) with aromatic components derived from shikimic acid. Vitamin D results from photochemical ring opening of 7-dehydrocholesterol, itself derived from squalene (C q). 

P-Hydroxy steroids which contain the 5,7-diene system and can be activated with uv light to produce vitamin D compounds are called provitamins. The two most important provitamins are ergosterol (1) and 7-dehydrocholesterol (3). They are produced in plants and animals, respectively, and 7-dehydrocholesterol is produced synthetically on a commercial scale. Small amounts of hydroxylated detivatives of the provitamins have been synthesized in efforts to prepare the metaboHtes of vitamin D, but these products do not occur naturally. The provitamins do not possess physiological activities, with the exception that provitamin D is found in the skin of animals and acts as a precursor to vitamin D, and synthetic dihydroxalated... 

The molecular extinction coefficients (at various wavelengths) of the four main components of the irradiation are shown in Table 5. The absorption of light above 300 nm is favored by tachysterol. A yield of 83% of the previtamin at 95% conversion of 7-dehydrocholesterol can be obtained by irradiation first at 254 nm, followed by reirradiation at 350 nm with a yttrium aluminum garnet (YAG) laser to convert tachysterol to previtamin D. A similar approach with laser irradiation at 248 nm (KrF) and 337 nm (N2) has also been described (76). 

Provitamin D. The molecular extinction coefficient of 7-dehydrocholesterol at 282 nm is 11,300 and is used as a measure of 7-dehydro isomer... 

A flow diagram for the manufacturing process is shown in Figure 8. First, ether solution containing 7-dehydrocholesterol is recirculated through a quartz uv reactor, and the ether is distilled off. Methanol is added to the 7-dehydrocholesterol—vitarnin mixture, and the remaining ether is... 

Photochemical ting opening of 7-dehydrocholesterol derivatives which have ting A or the side chain modified (142,143). 

FIGURE 18.37 (a) Vitamin D3 (cholecalciferol) is produced in the skin by the action of sunlight on 7-dehydrocholesterol. The successive action of mixed-function oxidases in the liver and kidney produces 1,25-dihydroxyvitamin D3, the active form of vitamin D. 

Chloroform-methanol extracts of Borrelia burgdorferi were used for the identification of lipids and other related components that could help in the diagnosis of Lyme disease [58]. The provitamin D fraction of skin lipids of rats was purified by PTLC and further analyzed by UV, HPLC, GLC, and GC-MS. MS results indicated that this fraction contained a small amount of cholesterol, lathosterol, and two other unknown sterols in addition to 7-dehydrocholesterol [12]. Two fluorescent lipids extracted from bovine brain white matter were isolated by two-step PTLC using silica gel G plates [59]. PTLC has been used for the separation of sterols, free fatty acids, triacylglycerols, and sterol esters in lipids extracted from the pathogenic fungus Fusarium culmorum [60]. 

In more recent studies the use of HPLC allowed isolation and counting of individual sterols after administration of labelled precursors. The sterols isolated from mantles and viscera of the nudibranch Doris verrucosa were identified as cholestanol, cholesterol, 24-dehydrocholesterol and 7-dehydrocholesterol [103]. After injection of dl-[2-14C]-mevalonic acid DBED salt, cholesterol (57) and 7-dehydrocholesterol (58) were isolated as the acetates by reversed phase HPLC. Both sterols were found significantly labelled specific radioactivity associated with 7-dehydrocholesterol was higher by one order of magnitude than that associated with cholesterol. This fact would indicate either that the reduction of the A1 double bond of 7-dehydrocholesterol to afford cholesterol occurs at a low rate, or that the cholesterol found in D. verrucosa comes partly from a dietary source. 

Several procedures for the synthesis of calcitriol have been reported in the literature. Parren et Uskokovic and others (10-18) have described lengthier syntheses utilizing more readily available starting materials. A typical reaction scheme, utilizing 1 a, 25-diacetoxy-7-dehydrocholesterol as the starting material, is shown in Figure 6. 

The active vitamins are produced by conversion of provitamins by ultraviolet light. Ergosterol, a yeast sterol, is converted to its active form, ergocalciferol (vitamin D2), and 7-dehydrocholesterol, which is found in many natural foods and is also synthesized in man, is converted to cholecalciferol (vitamin D3). Fish liver oils are virtually the only source of vitamin D3 in nature. The most active form of vitamin D3 is 1,25-dihydroxycholecalciferol and this is produced by the hydroxylation of cholecalciferol at position 25 in the liver and then at position 1 in the kidney. 

The precursor, 7-dehydrocholesterol is converted by a non-enzymatic reaction to cholecalciferol (calciol). This reaction occurs in skin exposed to sunlight due to irradiation by UV-B light at a wavelength of about 300 nm. Cholecalciferol is transported via carrier proteins to the liver where hydroxylation at carbon-25 occurs in a reaction catalysed by a microsomal cytochrome P450 hydroxylase to form calcidiol. This compound travels to the kidney attached to specific binding proteins, where another cytochrome P450 enzyme, mitochondrial 1-a-hydroxylase, introduces a second hydroxyl group in to the molecule to form the active calcitriol. 

Vitamin D hormone is derived from vitamin D (cholecalciferol). Vitamin D can also be produced in the body it is formed in the skin from dehydrocholesterol during irradiation with UV light. When there is lack of solar radiation, dietary intake becomes essential, cod liver oil being a rich source. Metaboli-cally active vitamin D hormone results from two successive hydroxylations in the liver at position 25 ( calcifediol) and in the kidney at position 1 ( calci-triol = vit. D hormone). 1-Hydroxylation depends on the level of calcium homeostasis and is stimulated by parathormone and a fall in plasma levels of Ca or phosphate. Vit D hormone promotes enteral absorption and renal reabsorption of Ca and phosphate. As a result of the increased Ca + and phosphate concentration in blood, there is an increased tendency for these ions to be deposited in bone in the form of hydroxyapatite crystals. In vit D deficiency, bone mineralization is inadequate (rickets, osteomalacia). Therapeutic Liillmann, Color Atlas of Pharmacology... 

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 synthesized in the skin in the presence of ultraviolet light, and it is unusual to become dependent on dietary intake except when exposed to inadequate UV light. The active form of vitamin D is 1,25-dihydroxycholecalciferol (1,25-OHCC), also termed calcitriol. For vitamin D synthesis, cholecal-ciferol (also termed vitamin D3) is synthesized in the skin from cholesterol via 7-dehydrocholesterol, and is 25-hydroxylated in the liver and 1-hydroxylated in the kidney. Dietary vitamin D is actually a mixture of sterols which includes 7-dehydrocholesterol, and is mainly found in fish and eggs. 

The primary supply of vitamin in humans is not obtained from the diet but rather is derived from the ultraviolet photoconversion of 7-dehydrocholesterol to vitamin Ds in skin. Thus, vitamin Dj synthesis varies with the seasons. D3 is a prohormone and requires further metabolic conversion to exert biological activity in its target organs (Fig. 66.2). The liver and the kidney are the major sites of metabolic activation of this endogenous sterol hormone. The initial transformation of D3 occurs in the liver and is catalyzed by the enzyme 25-OH-D3-hydroxylase... 

Cholecalciferol is pure vitamin D3 derived from the ultraviolet conversion of 7-dehydrocholesterol to cholecalciferol. Ergocalciferol vitamin D2) is a sterol derived from yeast and fungal ergosterol. Calcitriol [Rocaltrol, 1,25-(0H)2D3] is the metabolically active vitamin D3 compound. Dihydrotachysterol is a synthetic compound that may act somewhat more quickly than either vitamin D2 or D3. 

Vitamin D is the collective term for a group of compounds formed by the action of ultraviolet irradiation on sterols. Cholecalciferol (vitamin D3) and calciferol (vitamin D2) are formed by irradiation of the provitamins 7-dehydrocholesterol and ergosterol, respectively. The conversion to vitamin D3 occurs in the skin. The liver is the principal storage site for vitamin D, and it is here that the vitamin is hydroxylated to form 25-hydroxyvitamin D. Additional hydroxylation to form 1,25-dihydroxyvita-min D occurs in the kidney in response to the need for calcium and phosphate. A discussion of the role of vitamin D in calcium homeostasis is provided in Chapter 66. 

Z-17(20)-Dehydrocholesterol (231) has been prepared from pregnenolone by two independent routes. Dehydration of a mixture of 20a- and 20/3-hydroxy-cholesterol gave the required compound (231) along with the previously prepared... 

F-17(20)-dehydro-20-cyanopregnene, which may be isomerized in base to the Z-isomer. Elaboration of the side-chain by successive Grignard reaction, reduction, and removal of the 22-hydroxy-group followed. Key steps in two stereospecific syntheses of Z-20(22)-dehydrocholesterol (234) from pregnenolone were (a) stereospecific removal of the 20- and 22-oxygen atoms of (20i ,22S)-20,22-dihydroxycholesterol by conversion into the thiocarbonate (232) and treatment with triethyl phosphite and (b) selective epoxidation of iE -20(22)-dehydrocholes-teryl benzoate to the epoxides (233), which were allowed to react with hexamcthyIdisilane-KOMe in HMPA (see also ref. 179). Syntheses of the 24-... 

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