Retinol

Retinol (RET-uh-nol) is the scientific name for vitamin A, a vitamin found only in animals. It occurs as a yellowish to orange powder with a slight brownish cast and is a relatively stable compound. Retinol is converted in the body from an alcohol to the corresponding aldehyde, retinal (C2oH280), one of the primary chemical compounds involved in the process by which light is converted to nerve impulses in the retina of the eye. Vitamin A is also required for a number of other biochemical reactions in the body, including growth and development of tissue and maintenance of the immune system. 

Vitamin A is synthesized in animal bodies through a variety of pathways. One important source of vitamin A is a group of related compounds called the carotenes, substances responsible for the yellowish or orangish appearance of 

Retinol. Red atom is oxygen white atoms are hydrogen and black atoms are carbon. Gray sticks indicate double bonds. PUBLISHERS RESOURCE GROUP 

The chemical structure of retinol was determined in 1931 by Swiss chemist Paul Karrer (1889-1971), and the compound 

Animals that live in very who eats it.Vitamin 

Retinol, or vitamin A, is a necessary nutrient in all higher animals. It plays an important role in vision, in the maintenance of epithelial cell layers, in spermatogenesis, and in fetal development. Retinol must be obtained from 

and 13 -cA-retinoic acid (or isotretinoin), which is used as an anti-acne drug. 

Tazarotene is a synthetic retinoid that mediates cell differentiation and proliferation [19]. Tazarotene, a pro-drug of tazarotenic acid,has recently been proven effective as a treatment for photodamaged skin [11]. 

In general, retinoids are also well tolerated in darker skin types however, retinoid dermatitis may cause post-inflammatory hyperpigmentation. In addition, progressive hyperpigmenta- 

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Van Aalten, D.M.F., Findlay, J.B.C., Amadei, A., Berendsen,H.J.C. Essential dynamics of the cellular retinol-binding protein. Evidence for ligand-induced conformational changes. Protein Engin. 8 (1995) 1129-1136. 

Carotenoids absorb visible light (Section 13 21) and dissipate its energy as heat thereby protecting the organism from any potentially harmful effects associated with sunlight induced photochemistry They are also indirectly involved m the chemistry of vision owing to the fact that p carotene is the biosynthetic precursor of vitamin A also known as retinol a key substance m the visual process... 

Ref. 2. Vitamin A is reported as retinol [68-26-8] equivalents/L. RE = 1 /ig of all trans-i.etSio 6 )lg of all /ra j -(3-carotene, and 12 )lg of other provitamin A cartenoids, with older definitions giving 3.33 lU vitamin A from retinol and 10 lU vitamin A activity from -carotene. 

The stmcture of vitamin A [11103-57-4] and some of the important derivatives are shown in Figure 1. The parent stmcture is aH-Zra/ j -retinol [68-26-8] and its lUPAC name is (all-E)-3,7-dimethyl-9-(2,6,6-trimethyl-l-cyclohexen-l-yl)-2,4,6,8-nonatetraen-l-ol (1). The numbering system for vitamin A derivatives parallels the system used for the carotenoids. In older Hterature, vitamin A compounds are named as derivatives of trimethyl cyclohexene and the side chain is named as a substituent. For retinoic acid derivatives, the carboxyl group is denoted as C-1 and the trimethyl cyclohexane ring as a substituent on C-9. The stmctures of vitamin A and -carotene were elucidated by Karrer in 1930 and several derivatives of the vitamin were prepared by this group (5,6). In 1935, Wald isolated a substance found in the visual pigments of the eye and was able to show that this material was identical with Karrer s retinaldehyde [116-31-4] (5) (7). 

Fig. 1. Vitamin A and derivatives retinol (1), retinyl acetate [127-47-9] (2), retinyl palmitate [79-81-2] (3), and retinyl propionate [7069-42-3] (4).

Because of the presence of an extended polyene chain, the chemical and physical properties of the retinoids and carotenoids are dominated by this feature. Vitamin A and related substances are yellow compounds which are unstable in the presence of oxygen and light. This decay can be accelerated by heat and trace metals. Retinol is stable to base but is subject to acid-cataly2ed dehydration in the presence of dilute acids to yield anhydrovitamin A [1224-18-8] (16). Retro-vitamin A [16729-22-9] (17) is obtained by treatment of retinol in the presence of concentrated hydrobromic acid. In the case of retinoic acid and retinal, reisomerization is possible after conversion to appropriate derivatives such as the acid chloride or the hydroquinone adduct. Table 1 Hsts the physical properties of -carotene [7235-40-7] and vitamin A. 

Property Retinol Retinyl acetate Retinyl palmitate Retinyl propionate o p-carotene... 

In the BASF synthesis, a Wittig reaction between two moles of phosphonium salt (vitamin A intermediate (24)) and C q dialdehyde (48) is the important synthetic step (9,28,29). Thermal isomerization affords all /ra/ j -P-carotene (Fig. 11). In an alternative preparation by Roche, vitamin A process streams can be used and in this scheme, retinol is carefully oxidized to retinal, and a second portion is converted to the C2Q phosphonium salt (49). These two halves are united using standard Wittig chemistry (8) (Fig. 12). 

Biological, spectroscopic, and chromatographic methods have been used to assay vitamin A and the carotenoids. Biological methods have traditionally been based on the growth response of vitamin A—deficient rats. The utiUty and shortcomings of this test have been reviewed (52,53). This test has found apphcabiUty for analogues of retinol (54,55). Carotenoids that function as provitamin A precursors can also be assayed by this test (56). 

Spectroscopic methods such as uv and fluorescence have rehed on the polyene chromophore of vitamin A as a basis for analysis. Indirectly, the classical Carr-Price colorimetric test also exploits this feature and measures the amount of a transient blue complex at 620 nm which is formed when vitamin A is dehydrated in the presence of Lewis acids. For uv measurements of retinol, retinyl acetate, and retinyl palmitate, analysis is done at 325 nm. More sensitive measurements can be obtained by fluorescence. Excitation is done at 325 nm and emission at 470 nm. Although useful, all of these methods suffer from the fact that the method is not specific and any compound which has spectral characteristics similar to vitamin A will assay like the vitamin... 

More specific methods involve chromatographic separation of the retinoids and carotenoids followed by an appropriate detection method. This subject has been reviewed (57). Typically, hplc techniques are used and are coupled with detection by uv. For the retinoids, fluorescent detection is possible and picogram quantities of retinol in plasma have been measured (58—62). These techniques are particularly powerful for the separation of isomers. Owing to the thermal lability of these compounds, gc methods have also been used but to a lesser extent. Recently, the utiUty of cool-on-column injection methods for these materials has been demonstrated (63). 

The specific role of vitamin A in tissue differentiation has been an active area of research. The current thinking, developed in 1979, involves initial dehvery of retinol by holo-B >V (retinol-binding protein) to the cell cytosol (66). Retinol is then ultimately oxidized to retinoic acid and binds to a specific cellular retinoid-binding protein and is transported to the nucleus. Retinoic acid is then transferred to a nuclear retinoic acid receptor (RAR), which enhances the expression of a specific region of the genome. Transcription occurs and new proteins appear during the retinoic acid-induced differentiation of cells (56). 

Vitamin A is manufactured by Hoffmaim-La Roche (Switzerland), BASF (Germany), and Rhc ne-Poulenc (France), as well as by some smaller suppliers in India, China, and Russia. The worldwide production is estimated to be 2500 to 3000 metric tons. About three-quarters of this production is for animal feed the remainder is for food fortification and pharmaceuticals (qv). The main trade names of feed products are Rovimix, Lutavit, and Microvit. Prices depend on appHcation forms and are approximately 60— 70/10 lU retinol (1995) ie, 200— 233/10 RE. One lU is equivalent to 0.300 )lg of aH-Zra/ j -retinol and 1 RE is equivalent to 1 ) g of all-retinol. 

Retinoic acid (vitamin A acid). Retinol (vitamin A... 

Retinyl acetate [127-47-9] M 328.5, m 57". Separated from retinol by column chromatography, then crystd from MeOH. See Kofler and Rubin [Vitamins and Hormones (NY) 18 315 1960] for review of purification methods. Stored in the dark, under N2 or Ar, at 0°. See Vitamin A acetate p. 574 in Chapter 6. 

Separated from retinol by column chromatography on water-deactivated alumina with hexane containing a very small percentage of acetone. Also chromatographed on TLC silica gel G, using pet ether/isopropyl ether/acetic acid/water (180 20 2 5) or pet ether/acetonitrile/acetic acid/water (190 10 1 15) to develop the chromatogram. Then recrystd from propylene at low temperature. 

Tlie retinol-binding protein binds retinol inside an up-and-down fi barrel... 

The first example is the plasma-borne retinol-binding protein, RBP, which is a single polypeptide chain of 182 amino acid residues. This protein is responsible for transporting the lipid alcohol vitamin A (retinol) from its storage site in the liver to the various vitamin-A-dependent tissues. It is a disposable package in the sense that each RBP molecule transports only a single retinol molecule and is then degraded. 

RBP is synthesized in the hepatocytes, where it picks up one molecule of retinol in the endoplasmic reticulum. Both its synthesis and its secretion from the hepatocytes to the plasma are regulated by retinol. In plasma, the... 

Figure S.3 Schematic diagram of the structure of human plasma retinol-binding protein (RBP), which is an up-and-down P barrel. The eight antiparallel P strands twist and curl such that the structure can also be regarded as two p sheets (green and blue) packed against each other. Some of the twisted p strands (red) participate in both P sheets. A retinol molecule, vitamin A (yellow), is bound inside the barrel, between the two P sheets, such that its only hydrophilic part (an OH tail) is at the surface of the molecule. The topological diagram of this stmcture is the same as that in Figure 5.2. (Courtesy of Alwyn Jones, Uppsala, Sweden.)...

Figure S.4 The binding site for retinol inside the RBP barrel is lined with hydrophobic residues. They provide a hydrophobic surrounding for the hydrophobic part of the retinol molecule.

Figure S.S Amino acid sequence of p strands 2 3 4 in human plasma retinol-binding protein. The sequences are listed in such a way that residues which point into the barrel are aligned. These hydrophobic residues are arrowed and colored green. The remaining residues are exposed to the solvent.

The retinol-binding protein belongs to a superfarnily of protein structures... 

There is a second family of small lipid-binding proteins, the P2 family, which include among others cellular retinol- and fatty acid-binding proteins as well as a protein, P2, from myelin in the peripheral nervous system. However, members of this second family have ten antiparallel p strands in their barrels compared with the eight strands found in the barrels of the RBP superfamily. Members of the P2 family show no amino acid sequence homology to members of the RBP superfamily. Nevertheless, their three-dimensional structures have similar architecture and topology, being up-and-down P barrels. 

Godovac-Zimmerman, J. The structural motif of p-lactoglobulin and retinol-binding protein a basic framework for binding and transport of small hydrophobic molecules Trends Biochem. Sci. 

Newcomer, M.E., et al. The three-dimensional structure of retinol-binding protein. EMBO J. 

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