Ординатура / Офтальмология / Английские материалы / Handbook of Nutrition and Ophthalmology_Semba_2007

the intestinal lumen. Carotenoids are insoluble in water and must be solubilized within bile acid micelles to facilitate absorption. Micelles with carotenoids are passively absorbed across the brush border of enterocytes. Low levels or absence of dietary fat will greatly reduce the absorption of carotenoids (201,202).

Carotenoids taken in large amounts may interfere with one another’s absorption (203, 204). β-carotene in large amounts can interfere with the absorption of lutein (203,204). Healthy men who took purified β-carotene in capsules (12 and 30 mg) daily for 6 wk showed significant declines in plasma lutein concentrations, suggesting that pharmalogical doses of β-carotene can interfere with lutein absorption or metabolism (205). The absorption and metabolism of carotenoids may also be affected by intake of vitamin E, by alcohol intake, malabsorption, intestinal parasites, thyroid status, and liver disease (199). Vitamin A, iron, and zinc status may affect the carotenoid absorption and metabolism (199). Consumption of alcohol has been reported to increase plasma α-carotene and β- carotene concentrations and decrease lutein/zeaxanthin concentrations in nonsmoking, premenopausal women (206). Plasma carotenoid concentrations appear to respond fairly rapidly to changes in dietary intake of carotenoids. In eleven healthy subjects, plasma carotenoid concentrations fell by about 60% after 2 wk on a low-carotenoid diet (207).

Carotenoids that are taken up by enterocytes may by secreted into lymph unchanged or may be subject to enzymatic cleavage, which may occur centrally or asymmetrically. β-carotene, for example, may be cleaved centrally by β-carotene 15,15'-dioxygenase or by excentric cleavage mechanisms (208,209). Some β-carotene is converted to vitamin A within enterocytes. Excentric cleavage of carotenoids can result in a variety of aldehyde, alcohol, and epoxide metabolites, and the functions, if any, of these derivatives are largely unknown (159). Carotenoids are transported in lymph within chylomicrons to the general circulation. Lipoprotein lipase hydrolyzes much of the triglyceride in the chylomicron, which yields a chylomicron remnant that is taken up largely by hepatocytes (159). Hepatocytes incorporate dietary carotenoids into lipoproteins, and under fasting conditions, up to 75% of hydrocarbon carotenoids in plasma are found in the low-density lipoprotein (LDL) fraction (210). Under fasting conditions, α-carotene, β-carotene, and lycopene are found primarily in the LDL fraction and lutein and zeaxanthin are found in the high-density lipoprotein (HDL) fraction (209). The estimated total body content of carotenoids is 140 mg, of which 84% is found in adipose tissue and 10% is found in the liver (210). The relative concentrations of carotenoids in various tissues in the human body are shown in Table 5 (211–214). The retina contains the highest concentration of carotenoids found in the human body.

Experimental animal studies involving carotenoids are limited because absorption of carotenoids is relatively poor in rodents such as rats, mice, and hamsters (208). In addition, other species such as chicks, rabbits, pigs, and sheep break down β-carotene in the gastrointestinal tract and absorb little β-carotene intact (208). In contrast, humans can absorb a small amount of β-carotene intact and can accumulate relatively large concentrations of carotenoids. The ferret, Mustela putorius, appears to absorb carotenoids in a manner similar to humans, and the ferret has been used as a model for β-carotene metabolism (208).

5.3.6. GENERAL FUNCTIONS OF CAROTENOIDS

The carotenoids are perhaps best described as being conditionally essential nutrients, as suboptimal health may result from low intake of particular carotenoids. By definition,

Table 5

Reported Concentrations of Mixed Carotenoids in Human Tissues

aLutein plus zeaxanthin in perifoveal retina, per g protein.

carotenoids are not essential nutrients, as a low or absent intake of carotenoids, in the presence of an adequate intake of preformed vitamin A, do not result in signs of a deficiency disease and death. Lutein and zeaxanthin might be considered to be conditionally essential nutrients, as strong evidence is accumulating that these two carotenoids are essential for eye health (215). The best-documented function of carotenoids for human health is the role of provitamin A carotenoids as precursors to vitamin A (159). Carotenoids may play a role as antioxidants (216,217), as immune enhancers (218), as mediators of gap junction communication (219), and may influence reproduction. Carotenoids have been described as being both prooxidants and antioxidants (217). β-carotene has been shown to act as a prooxidant, but this may occur under experimental conditions of high oxygen tension or high carotenoid concentrations that might not be relevant to human physiology (217). In humans, in vivo studies suggest that dietary carotenoids may reduce some laboratory biomarkers for oxidative stress, such as plasma malondialdehyde concentrations (considered a marker for lipid peroxidation) and 8-OhdG (considered a marker for DNA damage) (217). Potential roles for carotenoids in the retina are presented in detail under Subheading 5.3.9.

5.3.7. REQUIREMENTS FOR CAROTENOIDS

Currently, there is insufficient evidence to define dietary reference intakes for the major dietary carotenoids, although sufficient data exist to support existing recommendations for increased consumption of fruits and vegetables (220).

5.3.8. ASSESSMENT OF CAROTENOID STATUS

Serum or plasma carotenoid concentrations are considered the best indicator of carotenoid status (220), but this laboratory assay requires analysis by high performance liquid chromatography and storage of plasma or serum samples at −70°C. In NHANES III (1988–

Fig. 8. Zeaxanthin isomers. (After ref. 227.)

1994), the median concentrations of lutein + zeaxanthin (not separated in this laboratory procedure) for 40-yr-old adults was 0.35 μmol/L with a 5th and 95th percentile of 0.16 and 0.72 μmol/L, respectively (159). Food frequency questionnaires can be used to assess dietary intake of carotenoids. In older adults, reasonable correlations have been described between estimated intakes of α-carotene, β-carotene, β-cryptoxanthin, and lycopene and their respective plasma concentrations, but correlations were weak for lutein/zeaxanthin (221). Correlations between plasma carotenoids and dietary intake estimated by food frequency questionnaires may be better among younger than older adults (222).

5.3.9. ROLE OF CAROTENOIDS IN THE RETINA

Macular pigment consists primarily of two carotenoids, lutein and zeaxanthin (223– 226). These carotenoids have an intense coloration due to extensive conjugation in the polyene chain (85) and give the macula its yellowish color. Zeaxanthin is found as two isomers, 3R, 3'R-zeaxanthin and meso-zeaxanthin (227) (Fig. 8). Zeaxanthin and meso- zeaxanthin differ in relation to the stereochemistry of the secondary hydroxyl groups at the 3' position. Lutein, zeaxanthin, and meso-zeaxanthin represent about 36%, 18.%, and 18% of the total carotenoid content of the retina (85). Several minor carotenoids, consisting of additional isomers of both lutein and zeaxanthin, have also been identified in retinal extracts (228). In the inner macula, the concentration of zeaxanthin is approximately twice that of lutein, but lutein becomes the dominant carotenoid with increasing eccentricity from the fovea (229). Studies in primates show that there is a high degree of symmetry in the lutein and zeaxanthin concentrations in corresponding sections of the retinas between the left and right eyes of individual animals (230). The distribution of macular pigment stereoisomers in the human retina has been mapped. In the adult retina, the concentration of lutein increases and the concentration of meso-zeaxanthin decreases with radial distance from the fovea (229). The concentration of macular pigment reaches almost 1 mM within the central macula, which is about three times the concentration of carotenoids in normal human sera (85). In the primate retina, the highest concentrations of macular pigment are located in the inner retinal layers (231,232) (Fig. 9).

Fig. 9. Cross-sections of a rhesus macaque macula showing the distribution of macular pigment (dark region). Highest concentrations of macular pigment are in the inner retinal layers, lying between incipient light and the photoreceptors. (Reprinted from ref. 252, with permission of Investigative Ophthalmology & Visual Science.)

Serum lutein and zeaxanthin concentrations have been positively correlated with macular pigment density in human subjects (233). A high concentration of lutein has been described in subretinal fluid in subjects with rhegmatogenous retinal detachment, which supports the hypothesis that lutein is transported from the blood into the retina (234). The isomer meso-zeaxanthin is found in human serum in extremely low concentrations, and it is not clear whether meso-zeaxanthin in the plasma is the source for meso-zeaxanthin in the retina (85). It has been hypothesized that a yet undescribed isomerase converts lutein to meso-zeaxanthin by migration of the 4',5' double bond in lutein to the 5',6' position to form meso-zeaxanthin (229). In the human eye, iris, ciliary body, and retinal pigment epithelium and choroid also contain high concentrations of carotenoids, accounting for about one-half of the eye’s total carotenoids and about 30% of the total lutein and zeaxanthin found in the eye (235). Carotenoids have been reported to bind to tubulin with the receptor axon layer of the fovea (236), specifically to the paclitaxel-binding site of the β-tubulin subunit of microtubules in the primate retina (237). Other reports show that lutein and zeaxanthin are associated with rod outer segments in the peripheral retina of humans

Fig. 10. Comparisons of the mean total concentrations of lutein and zeaxanthin in the inner, medial, and outer regions of the retina in donor eyes with age-related macular degeneration and control eyes. (Reprinted from ref. 239, with permission of Investigative Ophthalmology & Visual Science.)

(238), and the concentrations of lutein and zeaxanthin in rod outer segment membranes is 2.7 times more concentrated in the perifoveal compared with the peripheral retinal region (231). The mean total concentrations of lutein and zeaxanthin in the inner, medial, and outer regions of the retina are lower in human eyes with age-related macular degeneration compared with control eyes (239) (Fig. 10).

Macular pigment absorbs and attenuates blue light (240). Currently, the hypothesis that has received the most active investigation is that macular pigment serves to protect the retina from excessive oxidative stress (85). The functions of macular pigment may also include the reduction of chromatic aberration (241), thus, an alternative or perhaps complementary hypothesis is that macular pigment improves visual resolution by absorbing short-wave light (242). Older adults showed a differential loss of sensitivity of short-wave- length-sensitive-cone (S-cone) in the retinal periphery compared with younger adults, suggesting that macular pigment may protect the fovea from light damage (243).

Macular pigment density has been studied in detail in humans using noninvasive psychophysical measurements with tabletop devices that employ light-emitting diodes (244). In a study of 217 subjects, macular pigment density appeared to decline with age, and lower macular pigment density was sgnificantly lower in women than men, was lower

Fig. 11. Relationship of macular pigment optical density to plasma lutein and zeaxanthin concentrations for men (r = 0.62) and females (r = 0.30). (Reprinted from ref. 247, with permission of Elsevier.)

in those with light versus dark colored irises, and was low among current smokers who smoked >10 cigarettes per day (245). Macular pigment density appears to be well correlated between the two eyes of the same individual (246). Males have been shown to have higher macular pigment densities than females, despite similar plasma carotenoid concentrations (247). Plasma lutein and zeaxanthin concentrations were positively correlated with macular pigment density among both men and women (247) (Fig. 11). Visual sensitivity appears to be preserved in older adults who have high macular pigment density (248). Among individuals with stable dietary patterns, macular pigment densities appear to change little over time (249). Studies in monozygotic twins suggest that macular pigment density may vary according to dietary intake (250).

There have not been many experimental animal studies of carotenoid deprivation, partly because of the limitations mentioned under Subheading 5.3.5. In one study, monkeys raised on a xanthophyll-free diet showed a total loss of macular pigment that was accompanied by an increase in drusen-like bodies at the level of pigment epithelium (251). Another study showed that no detectable macular pigment and practically no plasma xanthophylls were found in monkeys raised on semipurified diets without carotenoids, and clinical histopathology showed vacuolated retinal pigment epithelial cells that corresponded to window defects in the retinal pigment epithelium (252).

5.3.10. INTERVENTION STUDIES WITH CAROTENOIDS

Some pilot intervention studies have used carotenoids to increase macular pigment or improve vision. Spinach and corn are rich and easily accessible dietary sources of lutein and zeaxanthin. In one trial, 13 subjects received spinach and corn, spinach alone, or corn alone, and increases in macular pigment density were seen in most, but not all, subjects after 4 wk (253). In another study, two subjects consumed lutein esters, equivalent of 30 mg of free lutein per day, for 140 d. Over the first 40 d, serum concentrations of lutein increased 10-fold, and macular pigment density increased by 21% and 39% in the two subjects (254). The investigators estimated that lutein supplementation may have produced a 30–40% reduction in blue light reaching the photoreceptors, Bruch’s membrane, and the retinal pigment epithelium (254). In another dietary intervention study, seven subjects consumed spinach and corn daily for 15 wk, and macular pigment density and carotenoid concentrations in serum, buccal mucosal cells, and adipose tissue were measured at baseline, 4, 8, and 15 wk and 2 mo postintervention (255). Daily consumption of spinach and corn resulted in a significant increase in macular pigment density at 4 wk compared to baseline. In a crosssectional study, lutein concentrations in adipose tissue and macular pigment were compared between 13 women and 8 men. There was a significant positive correlation between lutein concentrations and adipose tissue and macular pigment among men, but a negative correlation among women, suggesting that there may be sex differences in lutein metabolism (255). Lutein supplementation of 20 mg lutein ester/day increased macular pigment optical density in patients with age-related maculopathy (256).

In a small uncontrolled study, 14 male patients with atrophic age-related macular degeneration received 5 oz of spinach, four to seven times per week (257). Short-term improvement in visual function was found in one or both eyes (257). Lutein supplementation was associated with short-term visual improvement among subjects with retinitis pigmentosa and related retinal degenerations who were recruited and followed via the internet (258). In another study of lutein supplementation, 20 mg/d, for 58 patients with retinitis pigmentosa or Usher syndrome, serum lutein concentrations increased significantly by 6 mo, but only about half of the patients showed an increase in macular pigment density (259). Carotenoid extracts from the Gou Zi Qi berry (Lycium chinense) contain high concentrations of zeaxanthin, and retinal zeaxanthin increased after supplementation in rhesus monkeys (260). Recently, a clinical trial was conducted with 90 adults at a Veterans Administration hospital who had atrophic age-related deteneration (261). Participants were randomized to receive lutein, 10 mg/d, or lutein 10 mg/d in combination with an antioxidant, multivitamin and mineral supplement, or a placebo for 12 mo. There was a small improvement in Snellen equivalent visual acuity by 5.4 letters in the lutein only group and 3.5 letters in the lutein plus antioxidant, multivitamin, and mineral supplement group compared with placebo (261). Some studies that have attempted to increase macular pigment or improve vision by dietary modification and supplementation are highlighted in Table 6.

5.4. Vitamin E

5.4.1. INTRODUCTION

Vitamin E is a term used to describe a group of lipid soluble tocol and tocotrienol derivatives that are considered to have vitamin E activity. There are eight naturally occurring forms of vitamin E, but α-tocopherol appears to be the most biologically relevant form

of vitamin E for human health (220). Vitamin E is thought to function as an antioxidant and appears to protect polyunsaturated fatty acids from oxidative damage. Although vitamin E has been implicated in the pathogenesis of age-related macular degeneration, a recent large clinical trial shows that high-dose vitamin E supplementation alone has no effect on the incidence of age-related macular degeneration (262).

5.4.2. HISTORICAL BACKGROUND

In 1922, Herbert McLean Evans (1882–1971) and Katherine Scott Bishop (1889–1976) demonstrated the existence of a dietary factor that was essential for reproduction in rats (263). This factor became known as the “antisterility vitamine” or “X factor,” and was later named vitamin E by Barnett Sure (1891–1960) in 1924 (264). Following the isolation of pure vitamin E, the name tocopherol was proposed, from the Greek, tokos (offspring) and pherein (to bear) with the suffix -ol, signifying an alcohol (265). A large international symposium on vitamin E was organized in London in 1939 by the Society of Chemical Industry (266).

5.4.3. BIOCHEMISTRY OF VITAMIN E

The eight naturally occurring forms of vitamin E are α-, β-, γ-, and δ-tocopherol and α-, β-, γ -, and δ-tocotrienol. The tocopherols consist of a chromanol ring with a long saturated (phytyl) side chain, and the tocotrienols consist of chromanol ring with an unsaturated side chain. Because the β-, γ-, and δ-tocopherols and α-, β-, γ -, and δ-tocotrienols are not converted to α-tocopherol by the α-tocopherol transfer protein in the liver, these seven other natural forms of vitamin E are not considered to contribute towards the vitamin E requirement of humans. The liver maintains concentrations of α-tocopherol in plasma, and the only stereoisomers that are maintained are RRR-α-tocopherol (2,5,7,8-tetramethyl- 2R-(4'R, 8'R, 12' trimethyltridecyl)-6-chromanol), which occurs in foods, and 2R-stereo- isomeric forms of α-tocopherol that are found in synthetic all racemic-α-tocopherol which include “d-α-tocopherol” (220) (Fig. 12). 2S-stereoisomers of synthetic, all racemic-α- tocopherol are not maintained in human plasma (267,268) or tissues (220) and do not contribute towards the vitamin E requirements of humans. γ -tocopherol, found in human plasma in low concentrations, is not transported to tissues but is metabolized and and excreted.

5.4.4. DIETARY SOURCES OF VITAMIN E

The richest food sources of vitamin E are certain oils, such as wheat germ oil, sunflower oil, and safflower oil, sunflower seeds, almonds, peanut butter, wheat germ and margarine. The vitamin E content of some common foods is shown in Table 7 (269). Beef, chicken, fish, and most fruits and vegetables have little vitamin E. Rich sources of RRR-α-toco- pherol, the most important source of vitamin E for humans, are wheat germ oil, safflower oil, and sunflower oil, whereas corn and soy oils are richer in γ-tocopherol. Vitamin E supplements are often labeled as “natural vitamin E” or “d-α-tocopherol” and consist of RRR-α-tocopherol that has been manufactured by methylation of γ-tocopherol found in vegetable oils.

5.4.5. ABSORPTION, STORAGE, AND METABOLISM OF VITAMIN E

The absorption of vitamin E is facilitated by biliary and pancreatic secretions and the formation of micelles in the gastrointestinal lumen (Fig. 13). As with other lipids, vitamin E

Fig. 12. Isomers of α-tocopherol.

is emulsified in the stomach and small intestine and mixed with bile acids and pancreatic secretions. The vitamin E in supplements is usually manufactured in the form of tocopheryl esters, which require pancreatic esterases for hydrolytic cleavage. Vitamin E is passively absorbed across the brush border of enterocytes in the small intestine. Enterocytes secret vitamin E to chylomicrons in the lymph, and the enterocytes do not appear