Vitamin A is available in dietary sources as either preformed vitamin A or as provitamin A carotenoids. Rich dietary sources of preformed vitamin A include egg yolk, liver, butter, cheese, whole milk, and cod-liver oil. In animal foods, vitamin A is mostly in the form of retinyl esters, such as retinyl palmitate. In many developing countries, the consumption of foods containing preformed vitamin A is limited, and provitamin A carotenoids often comprise the major dietary source of vitamin A (134). The major provitamin A carotenoids consist of a-carotene and P-carotene, found in such foods as dark green leafy vegetables, carrots, sweet potatoes, mangoes, and papayas, and P-cryptoxanthin, found in foods such as oranges, tangerines, and kiwi fruit. Recent studies show that the bioavailability of provitamin A carotenoids is probably lower than previously believed (135,136). Many factors can affect the absorption and utilization of carotenoids, including the digestibility of the food matrix, food particle size, fat level, presence of vitamin E, amount of carotenoids in the meal, and the presence of deficiencies of iron, zinc, and vitamin A (137).
Antiquity Night blindness described in Hippocratic writings, Epidemics VI (4), and ingestion of liver described as treatment by Celsus in De Medicina (5) 17-18th century Night blindness encountered in indigenous populations worldwide (6,8-10) 1816 Magendie shows that dogs fed sugar and water developed corneal ulcers and died (15)
1824-1849 Corneal ulcers described in poorly fed infants (16-19)
1855-1863 Conjunctival alterations described by Mecklenburg (25), von Huebbenet 26),
Mendes (27), and Bitot (20) 1881 Lunin shows substance in milk is necessary for survival in mice (28)
1911 Stepp extracts lipids from milk with alcohol ether that support life (32,33)
1912 Hopkins shows "accessory factors" in milk are essential for life (31)
1913 McCollum and Davis extract lipids from cod-liver oil with ether that support life (34); Osborne and Mendel show butter-fat contains something essential for life (35)
1911-1920 Bloch and Blegvad describe epidemic of xerophthalmia with high mortality among Danish children during period when butter unavailable to the poor (48-52)
1920-1940 More than 30 trials conducted of vitamin A as prophylaxis or treatment to reduce morbidity and mortality of measles, puerperal sepsis, and other conditions (56)
1931 Karrer describes structure of vitamin A (42,43)
1932 Ellison discovers that vitamin A supplementation reduces mortality in children with measles (57) 1930-1950 High consumption of cod-liver oil in households in Europe and the United States
1932 Outcry in British House of Commons over bill to tax cod-liver oil over fear it would make cod-liver oil too expensive for the poor and increase morbidity and mortality among British children (62-64) 1937 Vitamin A crystallized (44)
1939 Fortification of margarine with vitamin A recommended in the United
1947 Synthesis of vitamin A (45,46)
1948 Ramalingaswami shows vitamin A therapy reduces severity of diarrhea (86) 1951 Role of vitamin A in visual cycle shown by Wald (47)
1960s Interdepartmental Committee on Nutrition for National Defense surveys show vitamin A deficiency highly prevalent in some developing countries 1963 International conference in Bellagio, Italy on "How to Reach the Pre-School
Child" concludes that mortality among children with xerophthalmia is high (96)
1965 Western Hemisphere Nutrition Congress concludes vitamin A deficiency accounts for substantial blindness and mortality among children (99)
1966 Special Milk Program authorized
1968 Relationship between vitamin A deficiency and infection recognized by
Scrimshaw, Taylor, and Gordon (109) 1970s India and Indonesia commence national programs to distribute high-dose vitamin A capsules to preschool children (120-122) 1974 International Vitamin A Consultative Group organized
1983 Sommer reports Bitot spots and night blindness are associated with increased mortality (128)
1980-1990s Clinical trials show that vitamin A supplementation reduces morbidity and mortality of preschool children from diarrheal disease (130)
3.2.2. Digestion and Absorption of Vitamin A in Foods
In the stomach, foods containing vitamin A and carotenoids undergo proteolysis and are released from protein. The presence of fat in the small intestine stimulates the secretion of cholecystokinin, which stimulates the secretion of bile from the gall bladder and the secretion of pancreatic enzymes. Retinyl esters and carotenoids are insoluble in water and within the small intestine are solubilized within bile acid micelles. The presence of fat in the small intestine improves the absorption of retinol and carotenoids by increasing the size and stability of the micelles. In the gut lumen, dietary retinyl esters are hydro-lyzed to retinol (138) and then undergo reesterification during absorption (139). The pancreatic enzyme, pancreatic triglyceride lipase, plays an important role in hydrolysis of retinyl esters (140). The brush border membrane in the gut also has hydrolytic activity (141,142) that has been attributed to intestinal phospholipase B (143). Carboxylester lipase was usually considered to be involved in hydrolysis of retinyl esters, but recent work in the carboxylester lipase knockout mouse shows that dietary retinyl ester digestion is not affected by absence of this pancreatic enzyme (144).
Retinol is absorbed in the intestine by both a saturable, carrier-mediated process and a nonsaturable, simple passive diffusion process (145-147). It has been hypothesized that a retinol transporter, not yet characterized, exists on the luminal side of the enterocyte (148). In the cytoplasm of the enterocyte, free retinol appears to be sequestered by cellular retinol-binding protein (CRBP) II, a 16-kDa polypeptide with a single retinoid binding site (149). CRBP II will bind all-trans-retinol, 13-cis-retinol, and all-trans-retinal, but not other cis isomers of retinol (150). CRBP II is found in high concentrations in the small intestine (151,152), and upregulation of CRBP II mRNA occurs during pregnancy and lactation (153) and during retinoid deficiency in the rat model (154). CRBP I is also present in enterocytes, but at a much lower concentration than CRBP II (155).
The uptake of ^-carotene by enterocytes appears to occur by simple passive diffusion (156), and a saturable, carrier-mediated process has also been proposed (150). Within the enterocyte, ^-carotene is either absorbed intact and passes into the portal circulation, undergoes enzymatic cleavage by ^-carotene 15,15'-dioxygenase to retinal (157-160), or is converted to retinoic acid (161,162). P-carotene can be cleaved centrally via P-carotene 15,15'-dioxygenase or may undergo excentric cleavage in which P-apocarotenals are produced (163-165). In the rat model, central cleavage appears to be the dominant form of oxidation of P-carotene, although small amounts of P-apocarotenals (8', 10', 12', and 14') were detected (166). In the presence of oxidative stress, P-carotene 15,15'-dioxygenase may be downregulated with more formation of excentric cleavage products (167,168). Retinal is reduced to retinol by retinal reductase activity that is present in microsomes (169).
The two sources of retinol in the enterocyte (retinol that is absorbed directly by the enterocyte and retinol generated through cleavage of P-carotene and subsequent reduction of retinal to retinol) have the same metabolic pathway of esterification with long-chain fatty acids and release into the lymphatic circulation. In the enterocytes, lecithin-retinol acyltransferase (LRAT) and acyl-CoA-retinol acyltransferase (ARAT) are thought to be involved in the esterification of retinol, with retinyl esters formed by LRAT targeted for secretion in chylomicrons and retinyl esters formed by ARAT targeted for storage (148). The four main retinyl esters are produced in a proportion of about 8:4:2:1 for retinyl pal-mitate, retinyl stearate, retinyl oleate, and retinyl linoleate (170,171). The amount and type of fatty acids ingested with preformed vitamin A in the diet can modulate the pattern of retinyl esters that are secreted in chylomicrons (172). Chylomicrons are spherical lipoprotein particles of 75-450 nm in diameter that are composed of triacylglycerols, unesterified and esterified cholesterol, phospholipids, apolipoproteins, unesterified and esterified retinol, carotenoids, and other fat-soluble vitamins. The assembly of chylomicrons occurs in the endoplasmic reticulum and requires apoB48, microsomal triglyceride transfer protein, phospholipids, and triglycerides (173,174). The secretion of retinyl esters is dependent on the secretion of chylomicrons and is one of the last steps in the molecular assembly of chylomicrons (175). Intraluminal factors such as pH, bile, and fatty acids modulate the secretion of retinyl esters into the lymphatic and portal circulation (176). Chylomicrons are secreted by exocytosis from the basolateral surface of the enterocyte into the mesenteric and then thoracic duct lymphatic circulation and on into the general circulation.
3.2.3. Uptake and Storage of Vitamin A in the Liver and Other Tissues
In the general circulation, chylomicrons are converted to chylomicron remnants in a process that involves both the hydrolysis of the chylomicron triacylglycerols by lipoprotein lipase, an enzyme located on the luminal surface of capillary endothelial cells (177), and the transfer of apolipoproteins, phospholipids, and carotenoids to other lipoproteins or cell membranes. Most of the retinyl esters contained in the chylomicrons do not transfer to other lipoproteins and are largely cleared by the liver (178,179). Other tissues take up retinyl esters, such as the mammary gland during lactation (180-182), muscle, adipose tissue, and kidneys (183), lung (184), and blood leukocytes (185). Chylomicron remnants are rapidly removed from the circulation by the liver. In normal healthy humans, it is generally thought that the liver contains about 90% of the body stores of vitamin A; however, the distribution of vitamin A stores during deficiency and disease states is unclear (186). The liver absorbs most of the retinyl esters in chylomicrons (187,188). Chylomi-cron remnants are removed by the liver between the endothelial cells and hepatocytes within the space of Disse (189). The chylomicron remnants bind to receptors on the hepa-
tocytes such as low-density lipoprotein (LDL) receptor and apo E (190), or chylomicron remnant receptor (189).
Retinyl esters are hydrolyzed by retinyl ester hydrolase (191), and within the hepato-cyte, retinol is found within endosomes (192). Retinol is transferred to the endoplasmic reticulum, where it binds to retinol-binding protein (RBP). The retinol and RBP complex is translocated to the Golgi complex and then secreted from the hepatocyte (186). Retinol is transferred from hepatocytes to stellate cells (193), and most of the vitamin A stored within the liver is found in stellate cells (194-196), where it is stored as retinyl esters in lipid droplets (186). Some retinol bound to RBP is not taken up by stellate cells and enters the blood (186). Circulating retinol may leave and enter the liver many times in a process known as retinol recycling (197). Two enzymes, LRAT and CRAT, can esterify retinol in stellate cells, of which LRAT is considered the more important enzyme for retinol esterification (198). In vitamin A-deficient rats, LRAT activity is low in the liver but is rapidly upregulated after an oral dose of retinol, suggesting that low LRAT activity may be a mechanism by which retinol is made available for secretion to plasma and delivery to target tissues during a state of vitamin A deficiency (198,199).
Carotenoids are also delivered to tissues via chylomicrons, and carotenoids accumulate in high concentrations in adipose tissue. Higher doses of P-carotene were associated with higher serum concentrations of all-trans retinoic acid in rabbits (200). P-carotene can be converted to all-trans retinoic acid in the intestine, testes, lung, and kidney without retinol as an obligatory intermediate (162,201). The processing of carotenoids from chy-lomicron remnants by the liver has not been well characterized.
The major form of circulating retinol in the blood is as retinol bound to RBP (202), and about 95% of plasma RBP is associated with transthyretin (TTR) in a one-to-one molar ratio. RBP is a single-polypeptide chain with a molecular weight of about 21,000 and a binding site for one molecular of all-trans retinol (203). In addition to retinol, other forms of retinoids found in plasma include all-trans retinoic acid (204), 13-cis-retinoic acid, 13-cis-4-oxoretinoic acid (205,206), all-trans retinyl P-glucuronide, and all-trans retinoyl P-glucuronide (207). The relative concentrations of various retinoids in human plasma are retinol (1-2.5 ^mol/L), retinyl esters (0.03-0.3 pmol/L), retinoic acid (0.003-0.03 ^mol/ L) and retinyl P-glucuronide (0.002-0.01 pmol/L) (207,208). Other retinoids such as 9-cis-retinoic acid, 9,13-di-cis-retinoic acid, and 14-hydroxy-4,14-retro-retinol have been described in human plasma after consumption of liver (209). Retinoic acid also circulates bound to albumin (210). Some insight into the importance of RBP transport of retinol has come from a study of two siblings who had two point mutations in the RBP gene, and normal growth and development but extremely low concentrations of plasma retinol, plasma RBP, and night blindness (211). These observations suggest that retinyl esters in chylomicrons, retinoic acid bound to albumin, and other circulating forms of vitamin A may provide a sufficient supply of vitamin A to most tissues except the retina (211).
Retinol is released from the liver into the circulation in the form of holo-RBP (all-trans retinol bound with RBP in a 1:1 molecular complex). Under normal circumstances, plasma retinol concentrations are usually maintained at what is considered a normal homeostatic level, or "set-point" for individuals (212). This level may vary from individual to individual, but is usually in a concentration of about 1-3 pmol/L in healthy adults. Plasma retinol concentrations will decrease when hepatic retinol stores become inadequate, and this usually occurs when there is insufficient dietary intake of vitamin A for a prolonged period. Plasma retinol concentrations will increase to high levels above the normal range when vitamin A intake is excessive. Various disease states can decrease plasma retinol concentrations, including protein-energy malnutrition (213,214), hypothyroidism (215), zinc status (216), and inflammation and infection (217), or increase plasma retinol concentrations, such as renal disease (218).
Retinol is recycled between the liver and peripheral tissues, as shown by kinetic studies (219). In rats, about 90% of retinol that left the circulation was recycled and not irreversibly metabolized (219). The recycling of retinol appears to be tightly regulated and dependent on the amount of hepatic vitamin A, and extrahepatic tissues contribute a large proportion to the retinol that circulates in plasma (219,220). The half-life of holo-RBP is about 12 h (221). As noted earlier, a large portion of dietary carotenoids pass into the circulation intact within chylomicrons. It is estimated that there are more than 40 dietary carotenoids that may be absorbed, metabolized, and/or utilized by the human body (222). The main dietary carotenoids found in human plasma include a-carotene, P-caro-tene, P-cryptoxanthin, lutein, zeaxanthin, and lycopene, but other carotenoids and their oxidation products have been identified in human plasma (223). Most carotenoids in the plasma are transported by LDLs, and carotenoids can be delivered to peripheral cells that express the LDL receptor (224).
Retinol is taken up by peripheral tissues in a processs that has not been well characterized. Some cells, such as retinal pigment epithelial cells and parenchymal and stellate cells of the liver, have specific surface receptors for RBP (225). Circulating all-trans retinoic acid is taken up by cells, as it is able to move through cell membranes in an uncharged state and enter cells. In steady-state tracer studies in rats, the percentage of alltrans retinoic acid derived from the plasma was high for the liver and brain, but lower for the spleen and eyes (226). All-trans retinoic acid may act on cells through retinoy-lation, or the acylation of all-trans retinoic acid by protein (227-229). All-trans retinoic acid may be incorporated into proteins of cells through posttranslation modification in which a retinoyl-CoA intermediate is formed and is followed by the transfer and covalent binding of the retinoyl moiety to protein (230).
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