Retinol cleavage

A small but variable proportion of the carotenoids with one or two P-ionone rings (mainly P-carotene) are cleaved in the enterocytes to produce retinol (vitamin A). This process is very tightly controlled, so that too much vitamin A is not produced, although the control mechanism is not clear. Some cleavage of P-carotene can also occur in the liver, but this does not account for the turnover of P-carotene in the body. Small amounts of carotenoids are subject to enterohepatic circulation, but this does not account for losses. 

In intestinal cells, carotenoids can be incorporated into CMs as intact molecules or metabolized into mainly retinol (or vitamin A), but also in retinoic acid and apoc-arotenals (see below for carotenoid cleavage reactions). These polar metabolites are directly secreted into the blood stream via the portal vein (Figure 3.2.2). Within intestinal cells, retinol can be also esterified into retinyl esters. 

The a-, (3- and y-carotenes, which are found in most plants, are vitamin A provitamins and are converted to vitamin A alcohol (all- ran,v-retinol), which is usually called vitamin Aj (Figure 12.8) by oxidative mid-point cleavage. Retinol and its fatty acid esters are the main forms in which vitamin A is stored in animals and humans, and its oxidation product, 1 1-c/s-retinal (vitamin A, aldehyde), is required for the visual process. 

The central cleavage of P-carotene 1 is most likely the major pathway by which mammals produce the required retinoids il), in particular, retinal 2, which is essential for vision and is subsequently oxidized to retinoic acid 3 and reduced to retinol 4. An alternative excentric cleavage of 1 has been reported involving scission of the double bond at C7-C8 producing P-8 -apocarotenal 5 (2a,2b) which is subsequently oxidized to 2 (Fig. 1) (2c). The significance of carotene metabolites such as 2, 3 and 4 to embryonic development and other vital processes such as skin and membrane protection is a major concern of medicinal chemistry. 

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. 

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... 

Transport to the liver Retinol esters present in the diet are hydrolyzed in the intestinal mucosa, releasing retinol and free fatty acids (Figure 28.19). Retinol derived from esters and from the cleavage and reduction of carotenes is reesterified to long-chain fatty acids in the intestinal mucosa and secreted as a component of chylomicrons into the lymphatic system (see Figure 28.19). Retinol esters contained in chylomicrons are taken up by, and stored in, the liver. 

In no instance did the synthetic retinoid possess as great an inhibitory capacity as do retinol or retinyl acetate. In addition, the provitamin g-carotene had no effect on mutagenicity of 2-fluorenamine in Salmonella regardless of the carcinogen activation system (Tables III and IV). Thus, 3-carotene would apparently require enzymatic cleavage to vitamin A in order to have an effect in this ijri vitro bioassay and exerts no role by itself in modulating the metabolism of chemical carcinogens in the model system. 

The fat-soluble vitamins include vitamin A (retinol), a colorless compound resulting from cleavage of /3-carotene, vitamin D3 (cholecalciferol) a steroid, and vitamins E and K (tocopherols and menadione and their derivatives, respectively), which consist of isoprene and phenolic-quinone components. 

In addition to oxidation of retinol, retinoic acid may be formed by the /3-oxidation of apo-carotenals arising from the asymmetric cleavage of /3-carotene (Section 2.2.2.1). 

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).

Figure 2.4. Potential products arising from enzymic or nonenzymic symmetrical (a) or asymmetric (b to d) oxidative cleavage of, 6-carotene. Apocarotenals can undergo side chain oxidation to yield retinoic acid, but cannot form retinaldehyde or retinol.

---