Retinol metabolism, oxidative

Vitamin A (retinol) (Fig. 7.12) and its metabolic oxidation products assume a critical physiological role in growth, development and differentiation of epithelial tissue, the maintenance of vision, and as well in spermatogenesis and the normal development of the placenta and the foetus. (allE)-Retinoic acid and (13Z)-retinoic acid are important medicaments for the treatment of acne and psoriasis the former has also demonstrated complete remission in most cases of acute promyelocytic leukemia (APL). 

The metabolism of a provitamin A carotenoid such as P-carotene is depicted in Figure 2. The major pathway involves cleavage by a 15,15 -central dioxygenase that results in the formation of retinal, which can either be reduced to retinol or oxidized to retinoic acid (see Napoli, this volume). This process occurs in the cytoplasm of many cell types, and produces two... 

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

Vitamin Ai (retinol) is derived in mammals by oxidative metabolism of plant-derived dietary carotenoids in the liver, especially -carotene. Green vegetables and rich plant sources such as carrots help to provide us with adequate levels. Oxidative cleavage of the central double bond of -carotene provides two molecules of the aldehyde retinal, which is subsequently reduced to the alcohol retinol. Vitamin Ai is also found in a number of foodstuffs of animal origin, especially eggs and dairy products. Some structurally related compounds, including retinal, are also included in the A group of vitamins. 

The leveisal of the oxidative pathway of vitamin A (retinol —r retinal —>-retinoic add) does not occur in the body, When retinoic acid is feci to animals, even in relatively large doses, there is no storage and, in fact, die molecule is rapidly metabolized and cannot be found several hours after administration. The metabolic products have not been fully identified. Several fractions from liver or intestine, isolated after administering retinoic add marked with carbon-14, have been shown to have biological activity. 

Plants are the major source for dietary provitamin A. As mammals and humans cannot synthesize carotenoids, dietary provitamin A is obtained from plant sources that contain carotenoids having 2,6,6-trimethyl-l-cyclohexen-l-yl rings, such as P-carotene. More than 600 carotenoids have been identified in plants and algae, which together biosynthesize about 0.1 billion tons of carotenoids each year. However, only about ten carotenoids, including P-carotene, are nutritionally significant members of the provitamin A class that can be oxidatively metabolized to retinal in mammals and humans by such organs as the intestine, liver, and kidney and then reduced to retinol. 

Retinoic acid is a metabolic product of vitamin A that supports the growth and differentiation of epithelial tissues. Retinoic acid is formed in the cytosol by the reversible oxidation of retinol to retinal, and the irreversible oxidation of retinal to retinoic acid. There is controversy as to whether retinal is oxidized by retinal dehydrogenase, which is linked to NAD+, or by retinal oxidase. 

Figure 2.3. Oxidative cleavage of j6-carotene by carotene dioxygenase (EC 1.14.99.36), and onward metabolism of retinaldehyde catalyzed by retinol dehydrogenase (EC 1.1.1.105) and retinaldehyde oxidase (EC 1.2.3.11).

ChenH, Howald WN, and Juchau MR (2000) Biosynthesis of all-fraws-retinoic acid from all-fraws-retinol catalysis ofall-trfl s-retinol oxidation by human P-450 cytochromes. Drug Metabolism and Disposal 28, 315-22. 

Retinol is metabolized by the same enzymes that oxidize ethanol. As a result, prolonged use of ethanol, which induces those degradative enzymes, results in the breakdown of retinol to toxic metabolites. Ethanol also interferes with the conversion of beta-carotene, a precursor to vitamin A, to retinol. Thus, ethanol both promotes a deficiency of vitamin A and enhances its toxicity and that of beta-carotene. ... 

The interaction between alcohol and vitamin A is complex. They have overlapping metabolic pathways a similar 2-step process is involved in the metabolism of both alcohol and vitamin A, with alcohol dehydrogenases and acetaldehyde dehydrogenases being implicated in the conversion of vitamin A to retinoic acid. Alcohol appears to act as a competitive inhibitor of vitamin A oxidation. In addition, chronic alcohol intake can induce cytochrome P450 isoenzymes that appear to increase the breakdown of vitamin A (retinol and retinoic acid) into more polar metabolites in the liver, which can cause hepatocyte death. So chronic alcohol consumption may enhance the intrinsic hepatotoxicity of high-dose vitamin A. Alcohol has also been shown to alter retinoid homoeostasis by increasing vitamin A mobilisation from the liver to extrahepatic tissues, which could result in depletion of hepatic stores of vitamin A. ... 

Vitamin A (retinol) is a fat-soluble vitamin important for the maintenance of skin, bone, and blood vessels, as well as for the promotion of vision (Theodosiou et al. 2010). It is obtained from the diet either as all-trans-retinol, retinyl esters, or P-carotene (Blomhoff and Blomhoff 2006) and is stored in the liver (Moise et al. 2007). Vitamin A is converted to retinoic acid (RA), which is formed mainly through intracellular oxidative metabolism by retinal dehydrogenases (RALDHs) (Lampen et al. 2000). RA plays important roles in embryonic development, organogenesis, tissue homeostasis, cell proliferation, differentiation, and apoptosis (Theodosiou et al. 2010). In adult mammals, RALDH is found in intestinal epithelial cells (lECs) and gut associated-dendritic cells (DCs) from Peyer s patches and mesenteric lymph nodes (Iwata 2004, Coombes et al. 2007). Gut-associated DCs and lECs can metabolize vitamin A to RA in vitro (Lampen 2000), which indicates they may be a source of RA in gut mucosa. RA binds to two families of nuclear receptors, RA receptor (RAR) isotypes (a, p, and y) and retinoic X receptor (RXR) isotypes (a, p, and y). RAR and RXR form heterodimers and interact with retinoic acid response elements (RAREs) within the promoters of retinoic acid responsive genes (Blomhoff and Blomhoff 2006). RAR is ubiquitously expressed and up-regulated by RA. RXR also... 

After the uptake of retinol and -carotene into the mucosal cell, a number of metabolic events occur. For -carotene these events include the dioxygenase cleavage of carotene to form retinaldehyde, which is then reduced to retinol. These reactions have been discussed in detail earlier in this chapter. Data have also been reported that suggest that a small portion of newly biosynthesized (or dietary) retinaldehyde may be oxidized in the mucosal cell to retinoic acid (Dl), which is then transported to the liver via the portal vein (see below) (Fidge et al., 1968). 

Metabolism—Foods supply vitamin A in the form of vitamin A, vitamin A esters, and carotenes. Almost no absorption of vitamin A occurs in the stomach. In the small intestine, vitamin A and beta-carotene are emulsified with bile salts and products of fat digestion and absorbed in the intestinal mucosa. Here, much of the conversion of beta-carotene to vitamin A (retinol) takes place. There are wide differences in species and individuals as to how well they utilize the carotenoids. Their absorption is affected by several factors, including the presence in the small intestine of bile, dietary fat, and antioxidants. Bile aids emulsification fat must be absorbed simultaneously and antioxidants, such as alpha-tocopherol and lecithin, decrease the oxidation of carotene. Also, the presence of enough protein of good quality enhances the conversion of carotene to vitamin A—a matter of great importance in developing countries where protein is limited in both quantity and quality. 

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