Chemistry

Vitamin A and its metabolites comprise a group of more than a dozen molecules that differ in isomeric form, oxidation state, and whether they are unester-ified (free), esterified with a fatty acid, or conjugated.

All-trans-Retinol (Vitamin A Alcohol)

Retinol, the parent molecule of the vitamin A family, is a fat-soluble lipid alcohol (C2oH300, molecular mass 286.4) composed of a methyl substituted cyclohexenyl (/3-ionone) ring, an 11-carbon conjugated tetraene side chain, and a terminal hydroxyl group (Figure 1A, R1). Most of the double bonds can exist in either trans or cis conformation. All-trans-retinol is the most stable and most prevalent form in foods and tissues, but small amounts of other geometric isomers such as 9-cis- and 13-cis-retinol are found in some cells. The terminal hydro-xyl group of retinol can be free or esterified with a fatty acid. Esterification reduces the susceptibility of retinol to oxidation and changes its physical state from a crystalline lipid to an oil. Fatty acid esters of retinol (Figure 1A, R2) are the predominant form of vitamin A in most tissues. In some pharmaceutical products, retinol is present as retinyl acetate. Variant forms of vitamin A are present in some foods and human tissues. For example, vitamin A2, (3,4-didehydroretinol) is present in freshwater fish, and is also a product of retinol metabolism in human skin.

Oxidized Metabolites of Retinol

Figure 2 illustrates key steps in the metabolism of vitamin A. Retinol is oxidized within cells to generate retinal (Figure 1A, R3) and retinoic acid (Figure 1A, R4). 11-cis-Retinal, the isomer of retinal

Retinol (all-trans) and related forms

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Retinol (all-trans) and related forms

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R1 = CH2OH, retinol

R2 = CH2O-fatty acid, retinyl ester

R3 = CHO, retinal

R4 = COOH, retinoic acid

R5 = COO-glucuronide

R1 = CH2OH, retinol

R2 = CH2O-fatty acid, retinyl ester

R3 = CHO, retinal

R4 = COOH, retinoic acid

R5 = COO-glucuronide

Figure 1 (A) Structure of all-trans-retinol and several related forms. (B) Beta-carotene (all-trans) showing the position of 15,15' double bond that through cleavage yields retinal, which can be reduced to form retinal, giving rise to all of the structures indicated in Figure 1A.

Figure 1 (A) Structure of all-trans-retinol and several related forms. (B) Beta-carotene (all-trans) showing the position of 15,15' double bond that through cleavage yields retinal, which can be reduced to form retinal, giving rise to all of the structures indicated in Figure 1A.

Figure 2 Schematic of principal reactions of vitamin A metabolism.

Diet

Carotenoids J«

activation reactions

activation reactions

Retinyl-ß-

Oxidized and glucuronidated

glucuronide

acidic retinoids

conjugation and excretion reactions

Figure 2 Schematic of principal reactions of vitamin A metabolism.

critical for vision, absorbs light maximally at ^365 nm when in organic solvent, but when coupled with a protein, such as opsin, its peak absorptivity is shifted into the visible range of the electromagnetic spectrum (see 'Vision'). In its all-trans isomeric form, retinal is a transient intermediate in the bioconversion of retinol to retinoic acid. Retinoic acid exists in several isomeric forms, two of which (all-trans-retinoic acid and 9-czs-retinoic acid) interact specifically with nuclear receptor proteins.

Numerous metabolites of retinol or retinoic acid are more polar than retinol or retinoic acid due to additional oxidation of the cyclohexenyl ring, often on carbon 4. Some retinoids, particularly retinoic acid and 4-keto-retinoic acid, may be conjugated with glucuronic acid, forming retinyl- or retinoyl-/3-glucuronide (R5); these metabolites are water-soluble and therefore readily excreted. While some polar and water-soluble retinoids possess bioactiv-ity, most show reduced, or no, activity compared to their precursors.

Carotenoids

Carotenoids are produced only by plants and a few microalgae. In plants, they function as accessory light-gathering pigments that enhance the efficiency of photosynthesis. Of the 600 or so carotenoids found in nature, only ^-carotene, a-carotene, and /3-cryptoxanthin have the structural features necessary for vitamin A activity. Beta-carotene is a hydrocarbon (C40H56, molecular mass 536) with two ^-ionone rings, a polyene chain, and structural symmetry around the central 15,15' double bond (Figure 1B). The oxidative cleavage of this bond releases two molecules of retinal, which can be reduced to form vitamin A (retinol). Other isomers of ^-carotene with potential nutritional activity include 9-cis-^-carotene produced by certain microalgae. Other common carotenoids found in fruits and vegetables, such as lycopene, lutein, and zeaxanthin, are absorbable but they lack structural features essential for vitamin A activity.

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