Absorption and Metabolism of Carotenoids

Carotenoids are absorbed passively, dissolved in lipid micelles; various studies have estimated the biological availability and absorption of dietary carotene as between 5% to 60%, depending on the nature of the food, whether it is cooked or raw, and the amount of fat in the meal. In addition, much of the carotene in foods is present as crystals that may not dissolve to any significant extent in intestinal contents (Parker, 1989; 1996; Parker etal., 1999; Hickenbottom et al., 2002; Ribaya-Mercado, 2002; Tanumihardjo, 2002; Yeum and Russell, 2002).


Figure 2.3. Oxidative cleavage of p-carotene by carotene dioxygenase (EC, and onward metabolism of retinaldehyde catalyzed by retinol dehydrogenase (EC and retinaldehyde oxidase (EC




Figure 2.3. Oxidative cleavage of p-carotene by carotene dioxygenase (EC, and onward metabolism of retinaldehyde catalyzed by retinol dehydrogenase (EC and retinaldehyde oxidase (EC

Although the generally accepted factors for calculating retinol equivalence of dietary carotenoids are that 1 f g of retinol is provided by 6 f g of p-carotene or 12 fig of other provitamin A carotenoids, feeding studies suggest that 1 fig of retinol is provided by 26 f g of p-carotene from dark green leafy vegetables (with a range of 13 to 76 fg), or 12 fg from yellow and orange fruits (with a range of 6 to 29 f g) (Castenmiller and West, 1998; West and Castenmiller, 1998). A number of studies have shown that increasing the consumption of dark green leafy vegetables as a means of increasing vitamin A intake in children in developing countries is unlikely to provide a significant improvement in nutritional status. These studies provide the rationale for the retinol activity equivalents that are half the traditional retinol equivalents (Section 2.1.3). Carotene Dioxygenase As shown in Figure 2.3, p-carotene and other provitamin A carotenoids undergo oxidative cleavage to retinaldehyde in the intestinal mucosa, catalyzed by carotene dioxygenase. Retinaldehyde binds to the intracellular retinoid binding protein (CRBP II), and is reduced to retinol by a microsomal dehydrogenase, then esterified and secreted in chylomicrons together with retinyl esters formed from dietary retinol.

As discussed in Section, only a relatively small proportion of carotene undergoes oxidation in the intestinal mucosa, and a significant amount of carotene enters the circulation in chylomicrons. Novotny and coworkers (1995) reported a study in one subject given an oral dose of [2H]f-carotene dissolved in oil; 22% was absorbed - 17.8% as carotene and 4.2% as retinoids. Their results suggest that nonintestinal carotene dioxygenase is important in retinoid formation, because there was a late disappearance of labeled carotene from the circulation and the appearance of labeled retinoids.

There is some hepatic cleavage of carotene taken up from chylomicron remnants, again giving rise to retinaldehyde and retinyl esters; the remainder is secreted in very low-density lipoproteins and may be taken up and cleaved by carotene dioxygenase in extrahepatic tissues. During and coworkers (1996) reported the activity of carotene dioxygenase in various tissues: liver (25% of the specific activity in intestinal mucosa), brain (2.5% of intestinal activity), and lungs (1% of intestinal activity), with some activity also in the kidneys. The carotene 15,15-dioxygenase gene is expressed in duodenal villi, the liver, lungs, and kidney tubules (Wyss et al., 2001).

Central oxidative cleavage of f-carotene, as shown in Figure 2.3, gives rise to two molecules of retinaldehyde, which can be reduced to retinol. However, as noted previously, the biological activity of f -carotene, on a molar basis, is considerably lower than that of retinol, not two-fold higher as might be expected. Three factors may account for this: limited absorption of carotenoids from the intestinal lumen, limited activity of carotene dioxygenase, and ex-centric (asymmetric) cleavage. Limited Activity of Carotene Dioxygenase The intestinal activity of carotene dioxygenase is relatively low, so that in many species (including human beings) a relatively large proportion of ingested f -carotene may appear in the circulation unchanged. In general, herbivores have higher activity of carotene dioxygenase than omnivores. In some carnivores, such as the cat, there is virtually no carotene dioxygenase activity, and cats are unable to meet their vitamin A requirements from carotene (Lakshmanan et al., 1972). Species with high intestinal activity of carotene dioxygenase have white body fat, whereas in species with lower activity, body fat has a yellow tinge. Although the activity of carotene dioxygenase in most species is probably adequate to meet vitamin A requirements solely from dietary carotene, it is low enough to ensure that even very high intakes of carotene will not result in the formation of potentially toxic amounts of retinol (Section 2.5.1).

In animals fed a vitamin A-deficient diet, the activity of intestinal carotene dioxygenase is significantly higher than in animals fed a high intake of carotene or preformed retinol. Dietary protein also affects the intestinal conversion of carotene to retinol, resulting in increased liver retinol stores in animals fed a high-protein diet. In both human beings and experimental animals, feeding a high-protein diet results in increased activity of intestinal mucosal carotene dioxygenase. By contrast, protein deficiency in experimental animals and protein-energy malnutrition in human beings lead to reduced cleavage of carotene to vitamin A (van Vliet et al., 1996; Parvin and Sivakumar, 2000).

Other carotenoids in the diet, which are not substrates, such as canthaxan-thin and zeaxanthin, may inhibit carotene dioxygenase and reduce the proportion that is converted to retinol (Grolier et al., 1997). Similarly, a variety of antioxidants that occur in foods together with carotenoids, including flavo-noids (Section 14.7.2), also inhibit carotene dioxygenase.

A number of studies have reported low serum concentrations of retinol and high concentrations of f-carotene in patients with insulin-dependent diabetes mellitus. Krill and coworkers (1997) showed that up to one-third of nondiabetic first-degree relatives of patients with diabetes also showed a low serum retinol:carotene ratio, implying a genetic predisposition to low activity of carotene dioxygenase, possibly associated with insulin-dependent diabetes. The Reaction Specificity of Carotene Dioxygenase Whereasthe principal site of carotene dioxygenase attack is the 15,15-central bond of f -carotene, there is evidence that asymmetric cleavage also occurs, leading to formation of 8 -, 10 -, and 12-apo-carotenals, as shown in Figure 2.4. These apo-carotenals are metabolized by oxidation to apo-carotenoic acids, which are substrates for f -oxidation to retinoic acid and a number of other metabolites.

Early studies of the reaction specificity of carotene dioxygenase in intestinal mucosal homogenates suggested that it catalyzed both central and asymmetric cleavage (Wang et al., 1991, 1992), although there was evidence that excentric cleavage was nonenzymic. Devery and Milborrow (1994) suggested that there are two enzymes: a cytosolic dioxygenase that acts centrally and a membrane-associated enzyme that catalyzes asymmetric cleavage. Using intestinal homogenates and under conditions to minimize nonenzymic action, there was a near stoichiometric yield of retinaldehyde from f -carotene

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

(Nagao et al., 1996); later studies suggested that excentric cleavage did not occur in the presence of antioxidants, such as a-tocopherol (Yeum et al., 2000). Genetic cloning of an enzyme that catalyzed specifically central cleavage supported the view that excentric cleavage was an artifact (Barua and Olson, 2000; Redmond et al., 2001); however, there is also a mammalian enzyme that catalyzes C9' to 10' cleavage of p-carotene, yielding apo-10-carotenal and p-ionone, an enzyme that also catalyzes cleavage oflycopene (Kiefer et al., 2001). There is some evidence that apocarotenoic acids arising from asymmetric cleavage have effects on cell proliferation independently of actions mediated by RARs (Tibaduiza et al., 2002).

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