Vitamin acid Retinoids: Retinol

The successful synthesis of (all- )-retinoic acid (3) was reported by Arens and van Dorp (van Dorp and Arens, 1946) in 1946, but almost 10 years passed before Robeson et aL (1955a) were able to prepare 13-cw-retinoic acid (17). Between 1946 and 1956, a large number of papers were published on successful syntheses of the natural C20 retinoids retinol (1), retinaldehyde (2), and retinoic acid (3), and nine industrial processes for the synthesis of vitamin A were developed during this period (Isler, 1979). 

Vitamin A-active compounds [1] are present in foods of animal origin as retinoids (retinol, retinyl esters, retinylaldehyde, retinoic acid) and in those of plant origin as carotenoids (only carotenoids with one unsubstituted P-ionone ring and with an 11-carbon polyene chain at least are provitamins A). Retinyl palmitate is the main form used as a food supplement [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. 

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). 

Retinoids Vitamin A Carotinoids Retinylesters Retinol Retinal Retinoic acid Vitamin A acid... 

Vitamin A (retinol) and retinoic acid are carotenoid oxidation compounds that are very important for human health. The main functions of retinoids relate to vision and cellular differentiation. With the exception of retinoids, it was only about 10 years ago that other carotenoid oxidation products were first thought to possibly exert biological effects in humans and were implicated in the prevention - or promotion of degenerative diseases. A review on this subject was recently published. ... 

Vitamin A (retinol) is the parent substance of the retinoids, which include retinal and retinoic acid. The retinoids also can be synthesized by cleavage from the provitamin (3-car-otene. Retinoids are found in meat-containing diets, whereas p-carotene occurs in fruits and vegetables (particularly carrots). Retinal is involved in visual processes as the pigment of... 

There are many retinol containing preparations to treat vitamin deficiency states. Retinoids are also used to treat dermatological diseases like acne, psoriasis, Darier s disease, and ichthyosis. Tretinoin, all-trans-retinoic acid, is a topical preparation while isotretinoin or 13-cis-retinoic acid, and etretinate are available for oral administration. 

Retinoid Hormones Retinoids are potent hormones that regulate the growth, survival, and differentiation of cells via nuclear retinoid receptors. The prohormone retinol is synthesized from vitamin A, primarily in liver (see Fig. 10-21), and many tissues convert retinol to the hormone retinoic acid (RA). 

The retinoids, a family of molecules that are related to retinol (vitamin A), are essential for vision, reproduction, growth, and maintenance of epithelial tissues. Retinoic acid, derived from oxidation of dietary retinol, mediates most of the actions of the retinoids, except for vision, which depends on retinal, the aldehyde derivative of retinol. 

Much recent interest has been aroused by the fact that retinoid compounds, including both retinol and retinoic acid, reduce the incidence of experimentally induced cancer. In addition, 13-czs-retinoic acid taken orally is remarkably effective in treatment of severe cystic acne. s However, both vitamin A and retinoic acid in large doses are teratogenic, i.e., they cause fetal abnormalities. The use of 13-cis-retinoic acid during early phases of pregnancy led to a high incidence of major malformations in infants born.1 11 1... 

Structurally, vitamin A and many synthetic retinoids consist of a (3-ionone ring, a polyunsaturated polyene chain, and a polar end group. The polar end group can exist in several oxidation states, as retinol, retinal, or retinoic acid. Retinol and retinyl esters are the most abundant vitamin A forms found in the body (Blaner and Olson, 1994). Retinol can be esterified with long-chain fatty acids (mainly palmitate, oleate, and stearate) to form retinyl esters, which are the body s storage form of vitamin A. Retinol also can undergo oxidation to retinal, which can be oxidized further to retinoic acid. The active... 

Retinoids (e.g. retinoic acid) are involved in development and in metabolic regulation (e.g. through induction of expression of PEPCK, the rate limiting enzyme in gluconeogenesis). Retinoic acid derives from retinol, which in turn derives from ingestion of plant a-, 3- and "/-carotenes and other carotenes. Retinoic acid acts via retinoic acid receptors and retinoid X receptors note that these receptors can heterodimerize in the nucleus with other related hormone receptors such as PPA-Rs. The developmental importance of retinoic acid is underscored by the teratogenicity of retinoic acid and other vitamin A related compounds, notably some compounds developed for anti-acne properties. 

Vitamin A (retinols) plays a role in epithelial function and the retinoic acid derivative, acitretin (Neotigason, orally), inhibits psoriatic hyperkeratosis over 4-6 weeks. Acitretin should be used in courses (6-9 months) with intervals (3-4 months). It is teratogenic, like the other vitamin A derivatives. Rigorous precautions for use in women of childbearing potential are laid down by the manufacturer and must be followed, including contraception for 2 years after cessation, because the drug is stored in the liver and in fat and released over many months. The plasma t) is 3 months. It can cause other serious toxicity (see Vitamin A, p. 739). Tazarotene, a topical retinoid, is of some benefit in mild psoriasis, but is irritant. 

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