Jan A Lute in Reprint

The Journal of the American Nutraceutical Association
Vol. 4, No. 2, Summer 2001
www.ana-jana.org Reprint
The Role of Lutein in Human Health

Andrew Shao, PhD Technical Services Manager Vitamins and Dietary Supplements Kemin Foods, L.C., Des Moines, Iowa
A Peer-Reviewed Journal on Nutraceuticals and Nutrition Mark Houston, MD Editor-in-Chief

ISSN-1521-4524
E V I E W
R T I C L E
The Role of Lutein in Human Health

Andrew Shao, PhD Technical Services Manager Vitamins and Dietary Supplements Kemin Foods, L.C., Des Moines, Iowa
ABSTRACT Lutein is a unique dihydroxy-carotenoid (or xanthophyll) present in many plants consumed in the human diet. In humans, as in plants, lutein is believed to function in two ways: rst as a lter of high energy blue light, and second as an antioxidant that quenches photo-induced free radicals and reactive oxygen species (ROS). Epidemiologic evidence suggests that lutein consumption is inversely related to eye diseases such as age-related macular degeneration (AMD) and cataracts. This is supported by the nding that lutein (and a related compound, zeaxanthin) are specically and selectively deposited in the macula lutea, an area of the retina responsible for central and high acuity vision. Macular pigment, a yellow color in the center of the macula, functions as a lter of the high energy blue light that protects the sensitive rods and cones, and is comprised solely of lutein and zeaxanthin. Human intervention studies show that lutein supplementation results in increased macular pigment. This suggests that lutein supplementation may protect against AMD. There is also evidence suggesting that lutein may have a protective effect against other chronic diseases, such as certain cancers and cardiovascular disease. However, further research is needed to determine optimal lutein doses. The following paper represents a comprehensive review of the available evidence supporting a benecial role for lutein in human health.
INTRODUCTION Carotenoids are a class of compounds responsible for the yellow and red pigments present in many commonlyconsumed fruits and vegetables with large amounts found in green leafy vegetables such as spinach.1,2 Hundreds of these compounds exist in nature, yet only a handful have been detected in human serum (Table 1) and tissues.3,4 These select few may have some biologic function in humans. Consequently, their consumption may play a role in maintaining human health.(5,6) Many observational epidemiologic studies have shown an inverse relationship between carotenoid intake and serum levels, and risk for diseases such as cancer and cardiovascular diseases.5 While these studies suggest that carotenoids may protect against chronic disease, they have not rmly established a basis for the biologic plausibility that they are involved in human health. For the majority of the carotenoids present in the human body, little investigation has been done on specic function or tissue deposition. In addition, intervention studies have primarily focused Table 1. Distribution of the major carotenoids in human serum Carotenoid Lutein Lycopene -carotene -carotene Phytouene -cryptoxanthin -carotene -cryptoxanthin Phytoene Anhydrolutein Zeaxanthin -carotene Neurosporene % Distribution in Serum 20 20 10 10 8 8 6 4 4 3 3 2 2
* Correspondence: Andrew Shao, PhD Kemin Foods, LC 600 East Court Avenue, Suite A Des Moines, IA 50309 Phone: 515-248-4000 Fax: 515-248-4051 Email: ashao@keminfoods.com
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on the use of -carotene and its effect on various forms of cancer, and have been met with equivocal results.7-9 Lutein is a well-known carotenoid found readily in the human diet, serum, and tissues (Table 1).10 Similar to other carotenoids, epidemiologic data supports the hypothesis that lutein intake is inversely associated with chronic diseases, such as cancer of the breast11-13 and colon,14-16 and ocular diseases such as cataracts17-20 and AMD.21-22 Lutein has also been shown to be selectively and specically deposited in ocular tissues such as the macula, supporting the biologic plausibility of lutein as a bioactive carotenoid.23 Furthermore, macular pigment optical density (MPOD), which consists entirely of the carotenoids lutein and zeaxanthin, may be a potential biologic marker of both lutein status and macular health.24 These ndings and others have helped to establish lutein as a unique carotenoid, and are reviewed extensively in this article. Lutein in nature Carotenoids were originally thought to serve solely as vitamin A precursors in the human body, but this has since been shown to be limited primarily to the hydrocarbon carotenoid, -carotene (Figure 1).25 Research over several decades has revealed that carotenoids are capable of far more than provitamin A activity. They are known to act naturally in plants in two important ways: rst in a photoprotective manner by absorbing damaging blue light from sunlight; second as a quencher of photo-induced free radicals and reactive oxygen species (ROS).26,27 Figure 1. Cleavage of -carotene to form retinal and retinol (vitamin A).Note that certain xanthophylls such as lutein do not possess provitamin A activity.
Lutein, and a related compound zeaxanthin, are classied together in nature as dihydroxy xanthophylls, possessing two hydroxyl groups. In contrast, hydrocarbon carotenoids such as -carotene and lycopene possess no oxygen atoms (Figure 2).28,29 The hydroxyl groups render lutein and zeaxanthin more polar than the hydrocarbon carotenoids, and may contribute to their unique role in ocular tissues. Lutein is found extensively in the human diet, primarily in dark, leafy green vegetables such as spinach and kale.30 Although puried and crystallized lutein displays a distinct orange-yellow color (Figure 3), its color is not evident in green leafy vegetables due to a masking effect by chlorophyll. Lutein intake appears to be declining in the US to between 1.5 and 2 mg/day, likely due to a decrease in the consumption of dark greens.31 II. LUTEIN AND EYE HEALTH Age-related macular degeneration AMD, a degradation of the central portion of the retina (the macula lutea), is the principal cause of blindness among people age 65 and older.32 The macula is located in the posterior portion of the retina and possesses the highest concentration of photoreceptors responsible for central vision and high resolution visual acuity.33 It is a circular area 5-6 mm in diameter with the fovea located at its center (Figure 4). Age-related macular degeneration can be classied into two categories: (1) early (or dry AMD) characterized by accumulation of soft drusen (oxidatively damaged cells and their components), and depigmentation of Figure 2. Hydrocarbon carotenoids and xanthophylls. Shown top to bottom are lycopene, -carotene, zeaxanthin, and lutein.
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the retinal epithelium, and (2) late (or wet AMD) is characterized by neovascularization of the macula and retina, and accumulation of scar tissue.34 Advanced AMD often leads to irreversible blindness, and there is currently no effective treatment.35 Many factors contribute to an increased risk for AMD, including age, cigarette smoking, female sex, light iris color, family history, sunlight exposure, and poor nutritional status (Table 2).36,37 Epidemiological evidence supporting a protective effect of lutein against AMD In 1988 Goldberg et al. analyzed a cross-sectional sample from the National Health and Nutritional Examination Survey (NHANES), which used questionnaires to assess nutrient intake in AMD cases and controls with healthy maculae. It was found that diets high in fruits and vegetables were inversely associated with AMD risk.38 Such diets are also high in many carotenoids, including lutein.30 In 1992 the Eye Disease Case-Control Study Group obtained personal, medical, physiological, biochemical, and ocular data on 421 AMD patients and 615 controls. Serum carotenoids (lutein, zeaxanthin, -carotene, acarotene, cryptoxanthin, and lycopene) were found to be inversely related with AMD risk.21 Further analysis showed that prevalence of AMD among those in this sample with total serum carotenoid concentrations 2.39 mol/L was 66% lower than the prevalence among those with levels 1.02 mol/L.21 Although these studies provided a basis for the hypothesis that dietary carotenoids in general may Figure 3. Puried crystalline lutein. Puried lutein crystals isolated from marigold ower extract. Photo courtesy of Kemin Foods.
have a protective effect against AMD, lutein and zeaxanthin (and their metabolites) are the only carotenoids found in the macula, and constitute the entire macular pigment.33 This suggests that the observed protective effects of high fruit and vegetable intake and high carotenoid consumption may be due solely to lutein and zeaxanthin intake. Figure 4. The human eye. Shown is the macula lutea, located in the mid portion of the retina.
Table 2. Risk factors for AMD Parameter Age Smoking Body fat Female sex Hypothesis Accumulation of photo-oxidative damage Increase in amount of free radicals; depletes body of antioxidants Increased storage, less utilization of xanthophylls Increased storage, less utilization of xanthophylls due to body fat Decreased capacity to lter damaging blue light Genetic component to susceptibility Increased amount of damaging blue light Insufficient antioxidant supply Increased source of PUFAs promoting lipid peroxidation Lower melanin content, less protection against blue light
Light iris color Family history Sunlight exposure Poor nutritional status Fat intake Caucasians
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The true ground-breaking epidemiological study showing a direct relationship between lutein intake and AMD risk was reported by Seddon et al. in 1994. Among the specic carotenoids, lutein and zeaxanthin were most strongly associated with decreased AMD risk (57% lower risk for highest quintile of lutein intake, 6mg/day, relative to the lowest quintile, 0.5 mg/day).22 Consistent with this nding was the inverse association between intake of spinach and collard greens, two foods richest in lutein and zeaxanthin, and AMD risk. This suggests that individuals decient in lutein intake are at higher risk for AMD. Subsequent epidemiological studies have not reported such striking relationships, with an inverse association between lutein intake and serum levels and AMD risk being marginal at best.39,40 However, it should be acknowledged that many of these study outcomes may be affected by unaccounted for physiologic and nonphysiologic confounders. For example, Mares-Perlman et al. reported finding no relationship between lutein intake and AMD risk, but a weak association between serum levels and AMD risk in a group of NHANES III subjects.40 This inconsistency may be due to effects of bioavailability, unreported carotenoid supplementation by subjects, and even inaccuracies in the nutrient content of reported foods, all of which would contribute to diluting relationships by increasing variability. Thus, while future epidemiological studies (ideally prospective in nature) should take these confounders into account, the available evidence supports the hypothesis that lutein plays a protective role against AMD. Biologic plausibility and mechanism of action Light-induced retinal damage depends largely on wavelength, exposure time, and power level, with blue light (440 nm) requiring 100 times less energy to cause damage than orange light (590 nm).41 Because of its molecular structure, lutein does not absorb UV light (maximum absorption at 446 nm, at the blue range of the electromagnetic spectrum). Rather, all UV light entering the eye is absorbed by the lens. Elevation of blood oxygen levels in monkeys exposed to blue light is associated with increased macular damage, suggesting that the basic mechanism of photo-induced damage involves free radicals produced by light and reactive oxygen species. 42 Characteristics of the macular pigment make it well suited to serve as a lter of incoming blue light, such as its orientation (back of the retina), and its absorption spectrum (420-460 nm). It is well accepted that the macular pigments primary purpose is to function in a photoprotective manner by ltering out damaging blue light.24 Indeed, Hammond et al. revealed that, in older subjects, the strongest positive association between MPOD and visual sensitivity was observed at 440 nm (vs. 550 nm) light.43 In a recent report by Beatty et al., macular pigment was shown to be signicantly inversely related to age and predisposition
to AMD in a group of 46 subjects.44 These ndings from human studies suggest that the macular pigment serves to protect the ocular cells of the macula, and that age-related decreases in MPOD may increase susceptibility to macular degeneration. Perhaps the most compelling piece of evidence supporting a protective role for lutein in AMD is its selective and specic deposition in the macula. Of all the carotenoids found in human serum, only lutein and zeaxanthin (and their metabolites) are located in the macula, with their concentration being greatest at the center of the fovea, diminishing with increasing eccentricity (Figure 4).45 A number of studies have reported that lutein and zeaxanthin are solely responsible for macular pigment.23,46,47 Not surprisingly, these two xanthophylls absorb light of the characteristic blue wavelength.48 Researchers have discovered what is believed to be an intermediate metabolite in the conversion of lutein to zeaxanthin, meso-zeaxanthin, in the macula.49 This suggests that in addition to having its own biologic activity, lutein may act as a precursor of zeaxanthin. As a highly vascularized tissue possessing a high concentration of polyunsaturated fatty acids (PUFAs), the macula is particularly susceptible to free radical oxidative damage.33 The presence of oxidative metabolites in the macula50 suggests that lutein may also offer protection to the cells of the macula by acting as an antioxidant. Several investigators have published reviews proposing that antioxidants, including lutein and zeaxanthin, help to inhibit drusen formation and preserve macular health by acting as free radical quenchers (Figure 5).28,34 Use of retinal pigment epithelium (RPE) cells in culture as an in vitro model has shown that treatment with antioxidants, including zeaxanthin, dramatically decreased oxidative stress-induced lipid peroxidation and apoptosis (cell death).51 Thus, the available evidence supports the notion that lutein and zeaxanthin comprise the macular pigment, and provide photochemical protection to the macula. While it is clear that lutein and zeaxanthin comprise the macular pigment, which in turn is proposed to protect the cells of the macula from photo oxidative damage, little has been done to investigate whether or not the concentrations of lutein and zeaxanthin in the macula, per se, are associated specically with AMD risk in humans. A group that includes two of the worlds leaders in ophthalmology research, Dr. Richard Bone and Dr. John Landrum, addressed this issue in a recent publication. Investigators obtained donor eyes from AMD patients and control subjects, and measured the concentrations of lutein and zeaxanthin in the central regions of the retina (area including and surrounding the macula). Within the inner region (area most closely surrounding the macula), those subjects possessing the highest quartile of concentration were 99.9% less likely to have AMD relative to those with the lowest quartile (Figure 6).52 This study was the rst to specical-
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Figure 5. Proposed model for AMD protection by antioxidants. (From Winkler 1999.) Oxidation Photoxidation Oxidants Free Radicals Reactive Oxygen Species Lipid Peroxides Oxidized Proteins DNA Breaks
Disease
Dark Sunglasses Macular pigment (Lutein/zeaxanthin)
Antioxidants/Enzymes Carotenoids Lutein Glutathione Vitamins C & E
Repair/Replace
ARMORY OF PROTECTANTS
Figure 6. Odds ratio (risk) for AMD as a function of lutein concentration quartile in the inner region of the fovea in AMD cases vs. controls. Retinas were collected from donor eyes (AMD patient cases, n = 56; and controls, n = 56) and analyzed for lutein and zeaxanthin concentration by HPLC. The above gure is representative of data collected from concentrations in the inner part of the fovea, where the relationship was strongest. *95% CI; p = 0.0005 for trend. From Bone et al. 2001.
Figure 7. Binding of various carotenoids to XBP. Indicated carotenoids were added at 4 M concentrations to xanthophyll-binding protein (XBP) preparations from human peripheral retina. Shown is the mean SEM for the peak A260/A280 ratio (measurement of binding) determined by gel ltration chromatography; n = 3 5. From Yemelyanov et al. 2001.
ly examine the relationship between lutein and zeaxanthin concentration in the macular region and AMD risk in humans. Such a relationship has not been reported for any other carotenoid. Although research at the cellular level directed at dening luteins mechanism of action in the macula is in its infancy, initial studies offer encouraging insights. The group headed by Dr. Paul Bernstein from the University of Utah addressed this issue by isolating and purifying a puta-
tive xanthophyll-binding protein (XBP) from human retina tissue. Using a combination of ion-exchange and gel-ltration chromatography, this group isolated two putative xanthophyll-binding proteins from human macular tissue of 25 and 55 kDa, respectively, with the former likely being a truncated form of the latter.53 The XBP was shown to bind selectively and specically to the xanthophylls (lutein, zeaxanthin, -cryptoxanthin) with the highest affinity being for lutein (Figure 7). In contrast, other plasma-binding pro-
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teins, such as albumin and low-density lipoprotein had little or no affinity for any of the carotenoids. These data are the rst to demonstrate the presence of a specic lutein-binding protein in ocular tissues. It is the rst insight into establishing a potential transport pathway for lutein from the serum and/or retina to the macula. Nutritional importance of lutein in AMD Although epidemiological studies offer strong support for the notion that lutein consumption may be inversely related to AMD risk, they are associative, and do not test causality. Controlled intervention studies are needed to determine whether lutein consumption per se results in a direct health benet. Due to the lengthy nature of AMD development, it is very costly to test this using the disease as the endpoint. Thus, for nutritional intervention studies, scientists have turned to using macular pigment as a surrogate biomarker for lutein action. As previously discussed, MPOD, readily measured in animals and humans, is well accepted as a marker of macular health.24 One of the rst lutein nutritional intervention studies was performed on rhesus monkeys, a well-known human model, by Malinow et al. in 1980.54 Monkeys maintained on a standard laboratory diet containing lutein possessed normal MPOD levels, and drusen was nearly undetectable. However, monkeys maintained on a xanthophyll-free diet possessed no macular pigment, a high level of drusen in the pigment epithelium, and serum xanthophylls were undetectable. This study has been followed by a recent report by Neuringer et al. showing once again that maintaining rhesus monkeys on a xanthophyll-free diet results in zero macular pigment. They also showed that repleting the monkeys
with a diet supplemented with 6 mg/kg/day lutein and 2.2 mg/kg/day zeaxanthin, restored MPOD to near normal levels in 6 to 12 months.55 These studies provide evidence from a well-utilized human model that lutein and zeaxanthin are required for macular pigment, and that they must be obtained from the diet. Controlled intervention studies in humans have now begun to appear in the literature (summarized in Table 3). Collectively, these studies have shown that providing lutein to humans from foods,56,57 marigold ower extract (lutein esters),58,59 or purified/crystalline lutein from marigold owers,60 results in signicant increases in serum lutein and MPOD in normal subjects. While serum lutein levels typically increase within hours of ingestion, several or more weeks are required before increases in MPOD are detected. However, as shown by Johnson et al. (Figure 8) the MPOD density and serum lutein do follow the same pattern, suggesting that the increase in MPOD is supplied by serum lutein obtained from supplementation.57 In contrast to lutein serum levels, the MPOD remains elevated for at least two months after supplementation. Doses as low as 2.4 mg lutein/day (puried form of lutein supplement) for six months increased MPOD by 10% (Figure 9).60 As expected, the bioavailability of lutein from vegetables, such as spinach is lower than puried lutein (Johnson et al. 2000 vs. Landrum et al. 1997), but greater than lutein esters. The largest response per mg in both serum lutein and MPOD was observed with puried crystalline lutein (Table 3). Human intervention studies examining visual function as an endpoint to dietary supplementation are ongoing. The largest of these prospective, randomized, placebo-controlled studies, the Age-Related Eye Disease Study
Table 3. Summary of human intervention studies investigating the effect of lutein on serum and MPOD responses. Study n Supplement Dose (mg/day) Product/Form Supplementation Period (weeks) Peak Response (% increase/mg lutein or lutein esters) MPOD Time to Peak (weeks) 2.6% 0.4% 0.8% 4.1% 4 25 16 24+
Serum Time to Peak (weeks) Johnson et al. 2000 Landrum et al. 1997 Berendschot et al. 2000 Landrum et al. 2000 7 2 8 24 10.2 60* 20* 2.4 Spinach/corn (lutein) Lutein esters Lutein esters Purified lutein 15 20 12 24 9.3% 1.4% 4% 43.3% 4 17 4 24+
*Based on 2:1 lutein ester to lutein equivalency ratio. Peak response refers to the highest levels attained in the study. +Peak response not assessed; increases based on pre- and post-supplementation values only.
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Figure 8. Effect of 10 mg lutein/day (from spinach and corn consumption) on serum lutein and MPOD. Normal subjects ingested a diet supplemented with spinach (60g/day) and corn (150 g/day), equivalent to about 10 mg/day lutein, for 15 weeks. Serum lutein and MPOD were measured periodically. Shown is mean SEM for n = 7 subjects; *p < 0.05 vs. wk 0 for serum; p < 0.05 vs. wk 0 for MPOD. From Johnson et al. 2000.
* * *
Figure 9. Effect of 2.4 mg/day supplemental lutein on serum levels and MPOD. Normal subjects were supplemented with 2.4 mg puried lutein/day for six months. Serum lutein and MPOD were measured pre- and post-supplementation. Shown is mean SEM for n = 24 subjects; * p < 0.05. From Landrum et al. 2000.
(AREDS), was initiated prior to luteins emerging role, and thus does not contain lutein or zeaxanthin supplements. Smaller trials, including case-studies that incorporated lutein as a supplement are nearing completion, and some have been published already. In 1999, Dr. Stuart Richer reported improvements of up to 92% in 14 AMD patients assessed by various visual acuity tests following diets containing ve ounces of spinach (equivalent to approximately 14 mg lutein) and supplemented with puried lutein 4-7 times/week for up to a year.61 However, this study was not placebo-controlled and did not address changes in macular pathology. A recent study from a group in Milan, Italy, showed that supplementation of AMD patients with a daily vitamin/antioxidant cocktail that included 15 mg of lutein for eighteen months resulted in a 2-fold higher improvement in visual acuity relative to the placebo group.62 No changes were observed in the number and size of drusen from either group. Further human intervention studies are needed to better dene the protective effects of lutein supplementation on AMD and visual acuity. Two expert researchers, Dr. Stuart Richer and Dr. Max Snodderly, have ongoing double-blind, placebo-controlled human intervention studies. Their results will help determine the safety and efficacy of lutein supplementation on visual acuity in patients with AMD. Lutein and other eye diseases: cataracts and retinitis pigmentosa Cataracts are prevalent in 40% of US adults over age 75.63 and their extraction is one of the most frequent and costly surgeries performed on the elderly.64 Cataracts are characterized by the presence of an ocular opacity, partial or complete in one or both eyes, on or in the lens or capsule, often impairing vision or causing blindness. The cause is
likely due to the oxidation of proteins, and subsequent precipitation of these damaged proteins in the lens of the eye.65 As is the case with AMD, a number of epidemiological studies have reported that lutein intake and/or serum levels are inversely associated with cataract risk.66,67 In 1992, Hankinson et al. used a prospective cohort to show that specifically spinach consumption (high in lutein), as opposed to carrots (high in -carotene) was inversely related to cataract extraction.17 Three recent prospective studies all showed that of the carotenoids analyzed, only the intake of lutein and zeaxanthin were inversely associated with cataract extraction (20-50% risk reduction).18,20 In addition, while total serum carotenoids were not related to nuclear cataract, there was at least a marginal inverse association with serum lutein reported by Lyle et al.68 Results of these studies are summarized in Table 4. With respect to biologic plausibility, if lutein does confer a protective effect against cataracts, one would expect it deposited in the lens of the eye. In a manner parallel to that with AMD, research has shown that of the handful of carotenoids found in serum, once again it is the xanthophylls that are selectively deposited in the lens. A group from the USDA Human Nutrition Research Center on Aging at Tufts University reported that lutein and zeaxanthin were the only carotenoids detected in the lens of the human eye.69 A group at the University of Utah headed by Dr. Paul Bernstein showed recently that lutein is present in other ocular tissues as well, including the retinal pigment epithelium and ciliary body.70 While other carotenoids that occur readily in the serum were detected, lutein was present anywhere from 2- to 7-fold higher than -carotene or lycopene.70 This once again reinforces the importance of lutein relative to other carotenoids in eye health. Though a strong case can be made for a protective effect of lutein
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Table 4. Summary of epidemiological studies investigating lutein and cataract risk Study Hankinson et al. 1992 Chasan-Tabar et al. 1999 Brown et al. 1999 Lyle et al. 1999 Lyle et al. 1999 Parameter Assessed Spinach intake Endpoint Assessed Incidence of cataract extraction Incidence of cataract extraction Incidence of cataract extraction Incidence of nuclear cataract Incidence of nuclear cataract Comparison Consumption 5 times/week vs. 1 time/month 13.7 vs. 1.1 mg/day lutein Outcome risk 39% risk 22%
Carotenoid intake
Carotenoid intake Antioxidant intake Serum carotenoids
7.0 vs. 1.3 mg/day lutein 1.3 vs. 0.3 mg/day lutein 0.4 vs. 0.18 mol/L lutein
risk 19% risk 50% risk 30%*
*not statistically significant against cataracts, whether lutein supplementation has a direct effect on this disease remains to be established. More data are required from prospective epidemiological studies and from double-blind, placebo-controlled intervention studies especially, to better dene the role of lutein in cataracts. Retinitis pigmentosa (RP), is a degenerative disease characterized by atrophy of the retinal pigment, that leads to damage of the photoreceptors and eventually blindness.71 There are few, if any, treatments available, although supplementation with high doses of vitamin A has been shown to slow the degenerative process.72 One internet study suggests that lutein supplementation improves visual acuity in RP patients. Sixteen RP patients recruited and maintained in the study via the internet were supplemented with 40 mg lutein/day for 9 weeks. Using computer-simulation, patient self-tested visual acuity improved signicantly.73 While these data are subjective, they suggest that lutein may have a protective effect against RP. Double-blind, placebo-controlled intervention studies are forthcoming. Collectively, these data suggest that lutein may not only be protective against AMD, but may play an important role in eye health in general. This is particularly apparent in light of the ndings reported by Bernstein et al. showing how lutein levels outnumber other well-known carotenoids in several ocular tissues.70 III. LUTEIN AND CHRONIC DISEASE: CANCER, HEART DISEASE, AND IMMUNE FUNCTION In addition to their potential role against eye disease, carotenoids have been hypothesized to have a role in the prevention of cancer.5 At the cellular level, environmental and metabolically-derived free radicals and reactive oxygen species are believed to cause oxidative damage to DNA, inducing mutations in key genes that control cell growth (see Figure 5).74,75 As photoprotectors, carotenoids act as absorbers of blue light and as barriers to photo-induced free radical production.76 As antioxidants, they are believed to protect cellular DNA by quenching free radicals and reactive oxygen species, and by replenishing other antioxidants.74,77 Finally, evidence suggests carotenoids exert antiproliferative and differentiating effects that may prevent transformed cells from becoming cancerous.78-80 As a relatively new member of the carotenoid family, the protective role of lutein against cancer has not been fully established. Fruit and vegetable intake has been the focus of most research testing this hypothesis, with -carotene being the main carotenoid of interest. However, a growing body of evidence suggests that lutein may have protective effects against cancers of the breast, colon, lung, skin, cervix, and ovaries.5 Table 5 summarizes the available evidence supporting a protective role of lutein in various cancers. Breast cancer Breast cancer is the most common form of cancer in women of developed countries, afflicting one in eight US women.81 The largest body of evidence linking lutein intake and decreased cancer risk comes from studies on breast cancer. In 1996 Freudenheim et al. conducted the rst casecontrol study showing a 53% decreased risk for breast cancer for lutein and zeaxanthin intakes in the highest quartile ( 7.2 mg/day) vs. the lowest ( 3.6 mg/day).11 Consistent with these results is another case-control study by Longnecker et al. showing that consumption of spinach or carrots more than twice weekly was associated with half the
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Table 5. Summary of lutein effects on cancer Cancer Breast Colon Lung Skin Cervix Ovarian Tissue Yes Yes Yes Yes Yes Yes Deposition Epidemiology Showing Inverse association Intake & serum Intake Intake & serum NA Intake & serum Intake Intervention Studies Inhibition of mammary tumor development* Inhibition of colon carcinoma propagation* NA Inhibition of UV-induced erythema and dermatitis NA NA
NA = research not available; *based on animal and/or cell culture studies risk of developing breast cancer relative to those who did not consume these vegetables.82 This is consistent with a subsequent prospective study by Zhang et al. showing that women with intakes of lutein and zeaxanthin in the highest quintile (9 mg/day) had a signicant 21% decrease in breast cancer risk relative to those in the lowest quintile (2mg/day).13 Two studies have also reported an inverse association between serum lutein and breast cancer risk.12,83 As is the case with other carotenoids, deposition of lutein in tissues of interest helps to substantiate a hypothesis of bioactivity. Lutein is readily present in both breast tissue and breast milk.84,85 While intervention studies examining the effect of lutein supplementation on breast cancer are absent, studies have shown that increasing carotenoid intake increases serum lutein levels,86,87 which correlate well with breast tissue levels.88 This suggests that increasing lutein intake from foods or supplements increases the amount deposited in breast tissue. Currently no human intervention studies have examined the effect of lutein supplementation on breast cancer incidence or progression. However, a recent study by Brown et al. reported at the Association for Research in Vision and Ophthalmology 2001 Annual Meeting showed that the inhibition of mammary tumor development in mice on a high-lutein diet was due to a decrease in tumor angiogenic (blood vessel growth) activity.89 Reducing the blood supply to tumors is known to effectively shrink their size. These data from mice indicate that not only may lutein exert anticancer effects, but does so when consumed in the diet. Colon cancer While it has decreased slightly in recent years, colon cancer is a leading cause of death in the US.90 As with breast cancer, a number of epidemiological studies have revealed an inverse relationship between lutein intake and colon cancer.16,91,92 In the most recent US-based study (Slattery et al. in 2000), of all carotenoids analyzed, lutein intake had the strongest inverse relationship with colon cancer risk.16 Subjects consuming the highest quintile of lutein (3 mg/day) had a 35% decreased risk for colon cancer relative to those in the lowest quintile (0.3 mg/day). Lutein also accumulates in colonic epithelial cells in subjects consuming a diet rich in vegetables.93 This helps to establish a basis for the biologic plausibility for lutein and colon cancer prevention or protection. Lung cancer More Americans die from lung cancer than any other cancer.94 Data from epidemiologic studies support a protective effect of fruit and vegetable consumption on lung cancer risk.95 However, researchers have proceeded cautiously when examining whether or not lutein has a benecial effect on lung cancer in light of intervention studies that showed that -carotene supplementation increased cancer incidence in smokers.8,96 Inverse associations have been reported between lutein intake and serum levels and lung cancer risk in both retrospective case-control studies and prospective cohorts.97-102 The strongest association for lutein was reported by De Stefani et al. who showed that subjects consuming lutein in the highest quartile ( 3.2 mg lutein/day) had nearly half the risk of lung cancer relative to those in the lowest quartile (< 1 mg/day).100 Oxidative stress from smoke may play an important role in lung carcinogenesis.103-105 The protective effect of carotenoids and other antioxidants may be related to their ability to scavenge free radicals contained in smoke.106 Concurrently, smoking depletes the body of these important antioxidants107 as smokers tend to have lower plasma levels of antioxidants relative to nonsmokers.108 Even exposure to passive smoke is associated with lower serum carotenoid
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Figure 10. Effect of carotenoid supplementation on UV-induced

skin redness (erythema). Subjects were given a carotenoid supplement that included 0.12 mg lutein daily for 12 weeks. Dorsal skin was then exposed to UV light, and erythema was measured 24-hours later. Each subject served as their own control. Shown is the mean SD for n = 20 subjects; *p < 0.05 vs. control. From Stahl et al. 2000.
Figure 11. Effect of lutein supplementation on UV-induced inammation in mice. Mice were fed a standard laboratory diet containing no lutein, 0.04% lutein, or 0.4% lutein, respectively. 24 hours after exposure to UVB irradiation (ears), ear swelling was assessed. Shown is the mean SEM from n = 10 mice per group; *p = 0.025 vs. control diet. From Faulhaber et al. 2001.
Control Control
Carotenoid Carotenoid Supplement Supplement
levels.109 This effect not only predisposes smokers to lung cancer, but decreases macular pigment110 and increases the risk for AMD.111 Increasing intake of green leafy vegetables can increase serum lutein in smokers to levels comparable to those in nonsmokers.112 Thus, smokers especially may require supplementation of their diet with antioxidants to offset the depleting effects of smoking. Skin cancer Skin cancer is a growing concern in the US. With one million cases diagnosed each year, skin cancer is contributing more and more to overall mortality.113 Increased sun exposure (UV light) is thought to be largely responsible. Of all the organ systems in which lutein may have a protective role, none may be more relevant than skin. Carotenoids function in plants as blue light lters and free-radical-scavenging compounds.26 In skin, lutein and other carotenoids may function in a similar manner, either by topical application114 or by ingestion.115 Despite this apparently obvious relationship, very little data are available in the literature. Epidemiologic studies examining relationships between lutein intake or serum levels, sun exposure, and skin cancer risk are unavailable. However, there is some evidence showing that lutein along with other carotenoids may have a protective effect. The presence of lutein in the skin suggests that it may have a biologic function there.116 In a recent study by Stahl et al., subjects who ingested a carotenoid supplement daily for 12 weeks that included 0.12 mg lutein developed signicantly less erythema (skin redness) in response to UV irradiation at week 12 relative to week 0 (Figure 10).117 This study does not establish a direct
link between lutein supplementation and protection of the skin, but it does suggest that lutein may be involved. Higher levels of lutein are present in skin amyloid from subjects suffering from systemic amyloidosis (deposition of glycoproteins in various tissues and organs), relative to normal skin.118 Given that accumulation of these glycoproteins can lead to oxidative damage, accumulation of lutein suggests the presence of a natural defense mechanism that relies on the free-radical-scavenging ability of lutein. The remainder of the evidence comes from cell culture and animal models. Taylor et al. showed that addition of 5 mg lutein to the skin of mice inhibited ultraviolet B radiation (UVB)-induced epidermal cell proliferation and erythema by 50%.119 This is direct evidence that topically-applied lutein exerts photoprotective effects. The recent observation that mice fed a diet supplemented with puried lutein (0.04 or 0.4%, respectively) had significantly decreased UVB induced skin inammation (Figure 11) is the rst of its kind to demonstrate the direct effect of dietary lutein on UVB induced skin damage.120 These ndings suggest that specically dietary sources of lutein may offer a protective effect against oxidative damage induced by UVB light. Furthermore, in a different study the same researchers also showed a decreased UVB induced immunosuppressive response in mice fed puried lutein, suggesting again a protective role of lutein against UVB damage. These ndings support the hypothesis that either topical application or ingestion of lutein protects the skin from UVB-induced damage. This in turn suggests that lutein may play a protective role against skin cancer, primarily as a lter of blue light, but also as a free-radical scavenger. Further
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intervention studies are required to conrm these effects in humans, and determine safe and efficacious doses. Cervical and ovarian cancers In addition to the more common cancers, it appears that lutein intake may be inversely associated with risk of cervical and ovarian cancers. While the research is much less extensive relative to other carotenoids, there are sufficient data to support a role for lutein. Lutein is readily found in both cervical and ovarian tissues,121 and the serum level of lutein from patients with cancerous or precancerous cervical tissue was shown to be lower than that of noncancer subjects.122 This suggests lutein may play a protective role against cervical cancer. However, the majority of the available epidemiologic data do not show such a relationship with cervical cancer as the endpoint. It is possible that lutein may exert its effects earlier in the process of cervical cancer development. Infection by the human papilloma virus (HPV) is believed to be a signicant contributor to cervical carcinogenesis.123 In 1997 Giuliano et al. reported that women who screened negative for HPV had, on average, nearly a 30% higher serum level of lutein than those who had screened positive.124 A similar relationship was found for other carotenoids as well. These data suggest that women with a lower intake of some carotenoids, including lutein, may be more susceptible to HPV infection and subsequent development of cervical cancer. It has been proposed that this effect may be related to the ability of potent antioxidants, such as carotenoids and tocopherols, to maintain a normal immune response, which in turn helps to negate viral infection.124 While studies investigating effects of lutein on ovarian cancer are scarce, there is enough evidence to suggest that it may be protective. In addition to the presence of lutein in ovarian tissue,121 the results from a case-control study released earlier this year by Berton et al. indicate that lutein intake may be inversely associated with ovarian cancer risk.125 Investigators found that lutein consumption of 24 mg/week was associated with a 40% decreased risk for ovarian cancer relative to an intake of less than 4 mg/week. No associations were observed for - and -carotene. When analyzed by food, the data showed a similar relationship between spinach (high in lutein) intake and decreased risk.125 In summary, lutein appears to exert effects at all three stages of cancer progression: acting as a lter of blue light, as a free-radical scavenger to inhibit initiation of DNA damage and subsequent transformation of cells, and as an antiproliferative agent, inhibiting the propagation of cancer cells. However, limitations inherent in epidemiologic studies (i.e., lack of proper controls, recall bias, confounding effects of other nutrients) prevent us from drawing clear conclusions from them regarding independent effects of lutein. The effects observed in these studies are likely due to the combined inuence of many carotenoids and other antioxidants.
In contrast to AMD, a specic role for lutein in cancer has not been as well dened, and human intervention studies are unavailable. However, currently available evidence in the literature suggests that a diet low in lutein may be associated with an increased risk for certain cancers. The notion that lutein may play a protective role against the development of various forms of cancer enforces the need for its increased consumption in the form of foods and/or supplements. Further research is needed to better dene this effect of lutein, and better establish safe and effective doses. Heart disease Cardiovascular disease is the leading cause of death in the US: more people die from this disease than from any other single cause.126 A plethora of epidemiologic studies and research reviews have tested and implicated the intake of antioxidants, such as carotenoids and vitamins C and E, as having an inverse association with and protective effect against heart disease.5,6.127-129 As is the case with cancer, the majority of studies have focused on -carotene, with clinical intervention studies displaying equivocal results.127 Emerging evidence suggests that intake of the hydroxycarotenoids (xanthophylls: lutein, zeaxanthin, and -cryptoxanthin) may be associated with a decreased risk for cardiovascular disease and events associated with it, such as stroke. The two prospective epidemiologic studies examining stroke incidence that have specically included lutein in the analysis (Hirvonen et al. and Ascherio et al.) reported that lutein intake is inversely related to stroke risk.130-131 Of all the carotenoids analyzed by Ascherio et al., only lutein intake was shown to be even marginally inversely related to ischemic stroke risk (37% decreased risk for highest quintile, 6.8 mg/day vs. lowest quintile, 1.3 mg/day; p = 0.1 for trend).130 Hirvonen et al. reported that lutein intake was inversely associated (less than half the risk) with hemorrhagic stroke.131 Until recently, epidemiologic data showing a relationship between serum lutein levels and heart disease were not available. Dwyer et al. reported this year that serum lutein levels were inversely related to arterial wall thickness in a group of subjects from the Los Angeles area over an 18-month follow up period.132 This is consistent with results reported in the same paper indicating that mice supplemented with lutein had signicantly less atherosclerotic lesions than control mice.132 One model to explain heart disease maintains that free radicals and ROS oxidize low density lipoproteins (LDL), which damages the endothelial cells lining the arterial walls. Studies have shown that carotenoids, and specically lutein, inhibit LDL oxidation in vitro.133,134 There are other studies that show marginal effects ex vivo (i.e., supplementation with carotenoids, and analysis of serum samples for LDL oxidation).135,136 Some research also suggests that carotenoids exert their antiatherogenic effect by
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inhibiting the signaling from damaged endothelial cells that attracts monocytes. Once damaged, the endothelial cells express adhesion molecules on their cell surface that are recognized by monocytes, which engulf the damaged cells in an attempt to destroy them. This step initiates the atherogenic pathway, and development of cardiovascular disease.137,138 Indeed, it has been shown that lutein, -carotene, and lycopene all decrease the expression of adhesion molecules on the surface of interleukin-stimulated human aortic endothelial cells in culture. This results in a decrease in adhesion to subsequently added monocytes.132,139 Immune function Evidence has existed for more than 10 years showing that supplementation with carotenoids, such as -carotene may boost immune function in humans.140,141 While this is a relatively new area of research with respect to lutein, there are compelling data from recent dog and cat model studies. Kim et al. reported that lutein provided in the diet of cats and dogs increased the humoral immunity of both species142,143 In both studies, investigators observed that lutein-supplemented animals signicantly increased lymphocyte and antibody production in response to a vaccination relative to animals on a control diet.142,143 This suggests that lutein boosted the immune function of these animals. More studies are needed to determine if the same effects can be elicited in humans. IV. SUPPLEMENTS AS A SOURCE OF LUTEIN Safety and bioavailability To validate epidemiologic studies linking lutein intake to human health, researchers have begun to perform controlled supplementation studies focusing on bioavailability, tissue deposition, and biomarkers of disease outcome or disease itself. Questions have subsequently arisen concerning the bioavailability of lutein from foods and supplements alike. How bioavailable is lutein from supplements? What factor(s) inuence this? Can supplemental lutein affect the bioavailability of other carotenoids? Bioavailability is dened as both the intestinal absorption and usage of a given nutrient by the body.25 Studies have shown that lutein from supplements appears readily in the plasma (absorption), is deposited in tissues such as the eye, and even results in positive effects on potential disease biomarkers i.e., macular pigment, skin erythema (utilization). Doses as low as 2.4 mg/day have been shown to increase serum lutein levels and increase macular pigment.60 Doses up to 40 mg/day have been shown to improve visual acuity in patients suffering from certain ocular diseases62,73 with no negative side effects or toxic effects reported. Furthermore, a puried lutein product extracted from marigold owers (Kemin Foods, L.C., Des Moines, IA) has just been deter-
mined GRAS (generally recognized as safe for use in certain foods and beverages) by a panel of experts. Thus, it is clear that supplements are a readily bioavailable and safe source of lutein that can be used to increase dietary intake of this nutrient. This is especially important in light of the ndings that consumption of lutein from green leafy vegetables has declined in the US31 and that smokers and patients suffering from chronic diseases often present with low serum antioxidant levels.83,108,144 Several factors can affect carotenoid bioavailability, the majority of which appear to inuence carotenoids from foods.145-147 In contrast to foods, the absorption of supplemental forms of carotenoids are not inuenced by food matrices, cooking, etc.148 However, two important factors affect absorption of supplemental carotenoids, such as lutein. (1) Because lutein is a fat-soluble compound, absorption across the brush-border membrane is dependent on the presence of a small amount of fat (approximately 5g/meal).147 Fat triggers the release of bile acids from the gall bladder which help to disperse the fat (and fat-soluble nutrients and vitamins) into small droplets (micelles) which are readily absorbed by the intestinal cells. Without this small amount of fat (for example, if a carotenoid supplement were taken alone, on an empty stomach), fat-soluble compounds will pass through the gastrointestinal tract unabsorbed.147 (2) As is the case with similarly charged minerals, carotenoids with similar structure can compete for absorption.146,147 This issue has specic relevance to supplements. Often supplemental forms of nutrients are ingested in doses more concentrated than those found in foods, and which are free from the constraining matrix of food (i.e.,water, ber,). It has been proposed that supplement use of carotenoids could disrupt the balance of absorption resulting in decreased bioavailability of certain nutrients,29 as has been shown to occur between lutein and -carotene. However, the effects observed have been inconsistent, with lutein shown to inhibit -carotene absorption and vice-versa.149,150 Moreover, this interaction is so inconsistent to the extent that it varies markedly from individual to individual.151 Hence, inter-carotenoid interactions that exist in the gut may be more pronounced with supplementation. What effect these interactions have on the bodys nutrient status or susceptibility to disease is unknown and warrants further research. Thus, the available evidence supports a clear role for sources of lutein in human health. The studies cited in this review suggest that consumption of lutein from foods or from dietary supplements will result in a health benefit to the public. V. FOCUS FOR FUTURE RESEARCH Establishing lutein as a vitamin By definition, a vitamin is an essential nutrient
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required by the body that must be obtained from the diet.152 Research supporting a protective role for lutein in human health has increased dramatically in the last six years in epidemiologic studies, animal and human intervention trials, and in in vitro cell culture studies. However, as a variety of phytonutrients contained in fruits and vegetables, including carotenoids, and others yet to be identied, are all needed for optimal health and protection from chronic disease, specic carotenoids have not been identied as required and essential nutrients. With the exception of lutein and AMD, there is no disease state that can be linked specically to a deciency in any one carotenoid. With the exception of MPOD, there are no accepted methods for carotenoid status assessment to even begin to determine what a deciency is. No epidemiologic or intervention study shows a consistent inverse relationship with one particular carotenoid and any chronic disease risk or outcome. However, the argument can be made that lutein may be required in the diet to protect from macular degeneration. Humans cannot synthesize lutein, therefore it must be obtained in the diet.26 The fact that lutein and zeaxanthin are the only carotenoids found in the macula suggests that these compounds have a specic function in this tissue.45 The macular pigment is known to be a vital protector of the cells and tissue of the macula from blue light.24 Lutein and zeaxanthin are known to comprise the macular pigment,47 and research showing that lutein is converted to zeaxanthin in the macula suggests that lutein is the required starting material.49 Providing lutein in the diet (either as foods or supplements) increases macular pigment (Table 3), and may increase visual acuity in patients with AMD.61,62 These ndings also suggest that MPOD can not only be used as a biomarker of macular health, but may also be a marker of lutein status. For many nutrients, serum levels are not an accurate reection of nutritional status. Tissue levels verify absorption and are a far better reection of the bodys overall status. However, measurement of tissue levels can be an invasive and impractical method of assessment. MPOD accurately reects the amount of lutein in the macula, and its measurement involves a noninvasive procedure. The gold standard for vitamin classication is the depletion-repletion study.153 Such studies have been performed with lutein using the rhesus monkey model. Feeding monkeys a lutein-free diet (depletion), causes eventual loss of all macular pigment.54,55 Repleting monkeys with lutein and zeaxanthin results in restoration of macular pigment.55 These studies were unable to assess visual acuity nor examine ocular pathology. However, they indicate that lutein is required in the diet for macular pigment, and that a diet low in lutein can result in deciency (as assessed by macular pigment). Because macular pigment is known to be a marker for macular health, this suggests lutein is required in the diet for macular health. No evidence exists to support any such claim for other carotenoids.153
Despite the strides made in lutein research, further studies are still needed in several areas. First, using the rhesus monkey model it may be possible to determine if lutein depletion results in AMD and if the macular pathology can be reversed with lutein repletion. Second, epidemiologic and intervention studies have cited a wide range of lutein doses, with no one amount or range clearly defined. Using MPOD as a lutein status assessment tool, we must better define daily doses of lutein that can be recommended in the human diet. Finally, we must continue to execute human intervention studies to better define efficacy of lutein supplements. REFERENCES
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65. Bron AJ, Vrensen GF, Koretz J, Maraini G, Harding JJ. The ageing lens. Ophthalmologica. 2000;214:86-104. 66. Jacques PF. The potential preventive effects of vitamins for cataract and age-related macular degeneration. Int J Vitam Nutr Res. 1999;69:198-205. 67. Moeller SM, Jacques PF, Blumberg JB. The potential role of dietary xanthophylls in cataract and age-related macular degeneration. J Am Coll Nutr. 2000;19:522S-527S. 68. Lyle BJ, Mares-Perlman JA, Klein BE, et al. Serum carotenoids and tocopherols and incidence of age-related nuclear cataract. Am J Clin Nutr. 1999;69:272-277. 69. Yeum KJ, Taylor A, Tang G, Russell RM. Measurement of carotenoids, retinoids, and tocopherols in human lenses. Invest Ophthalmol Vis Sci. 1995;36:2756-2761. 70. Bernstein PS, Khachik F, Carvalho LS, Muir GJ, Zhao DY, Katz NB. Identication and quantitation of carotenoids and their metabolites in the tissues of the human eye. Exp Eye Res. 2001;72:215-223. 71. Phelan JK, Bok D. A brief review of retinitis pigmentosa and the identified retinitis pigmentosa genes. Mol Vis. 2000;6:116-124. 72. Berson EL. Nutrition and retinal degenerations. Int Ophthalmol Clin. 2000;40:93-111. 73. Dagnelie G, Zorge IS, McDonald TM. Lutein improves visual function in some patients with retinal degeneration: a pilot study via the Internet. Optometry 2000;71:147-164. 74. Kong Q, Lillehei KO. Antioxidant inhibitors for cancer therapy. Med Hypotheses.1998;51:405-409. 75. Ames BN, Gold LS. The causes and prevention of cancer: the role of environment. Biotherapy. 1998;11:205-220. 76. Krinsky NI. Carotenoids and cancer in animal models. J Nutr. 1989;119:123-126. 77. Khachik F, Beecher GR, Smith JC Jr. Lutein, lycopene, and their oxidative metabolites in chemoprevention of cancer. J Cell Biochem Suppl. 1995;22:236-246. 78. Gross MD, Bishop TD, Belcher JD, Jacobs DR Jr. Induction of HL-60 cell differentiation by carotenoids. Nutr Cancer. 1997;27:169-173. 79. Kim JM, Araki S, Kim DJ, et al. Chemopreventive effects of carotenoids and curcumins on mouse colon carcinogenesis after 1,2-dimethylhydrazine initiation. Carcinogenesis. 1998;19:81-85. 80. Nishino H, Tokuda H, Murakoshi M, et al. Cancer prevention by natural carotenoids. Biofactors. 2000;13:89-94. 81. Clavel-Chapelon F, Niravong M, Joseph RR. Diet and breast cancer: review of the epidemiologic literature. Cancer Detect Prev. 1997;21:426-440. 82. Longnecker MP, Newcomb PA, Mittendorf R, Greenberg ER, Willett WC. Intake of carrots, spinach, and supplements containing vitamin A in relation to risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 1997;6:887-892. 83. Ito Y, Gajalakshmi KC, Sasaki R, Suzuki K, Shanta V. A study on serum carotenoid levels in breast cancer patients of Indian women in Chennai (Madras), India. J Epidemiol. 1999;9:306-314.
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84. Patton S, Caneld LM, Huston GE, Ferris AM, Jensen RG. Carotenoids of human colostrum. Lipids. 1990;25:159-165. 85. Zhang S, Tang G, Russell RM, et al. Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Am J Clin Nutr. 1997;66:626-632. 86. Rock CL, Flatt SW, Wright FA, et al. Responsiveness of carotenoids to a high vegetable diet intervention designed to prevent breast cancer recurrence. Cancer Epidemiol Biomarkers Prev. 1997;6:617-623. 87. McEligot AJ, Rock CL, Flatt SW, Newman V, Faerber S, Pierce JP. Plasma carotenoids are biomarkers of long-term high vegetable intake in women with breast cancer. J Nutr. 1999;129:2258-2263. 88. Yeum KJ, Ahn SH, Rupp de Paiva SA, Lee-Kim YC, Krinsky NI, Russell RM. Correlation between carotenoid concentrations in serum and normal breast adipose tissue of women with benign breast tumor or breast cancer. J Nutr. 1998;128:1920-1926. 89. Brown CM, Park JS, Chew BP, Wong TS. Dietary lutein inhibits mouse mammary tumor growth by regulating angiogenesis and apoptosis. Proc FASEB J. Experiemental Biology Conference. Orlando, Fl. 2001;15:A954. 90. Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin. 2000;50:7-33. 91. Enger SM, Longnecker MP, Chen MJ, et al. Dietary intake of specic carotenoids and vitamins A, C, and E, and prevalence of colorectal adenomas. Cancer Epidemiol Biomarkers Prev. 1996;5:147-153. 92. Levi F, Pasche C, Lucchini F, La Vecchia C. Selected micronutrients and colorectal cancer. a case-control study from the canton of Vaud, Switzerland. Eur J Cancer. 2000;36:2115-2119. 93. Nair PP, Lohani A, Norkus EP, Feagins H, Bhagavan HN. Uptake and distribution of carotenoids, retinol, and tocopherols in human colonic epithelial cells in vivo. Cancer Epidemiol Biomarkers Prev. 1996;5:913-916. 94. Shopland DR. Tobacco use and its contribution to early cancer mortality with a special emphasis on cigarette smoking. Environ Health Perspect 1995;103 (suppl 8):131-142. 95. Ziegler RG, Mayne ST, Swanson CA. Nutrition and lung cancer. Cancer Causes Control. 1996;7:157-177. 96. Patrick L. Beta-carotene: the controversy continues. Altern Med Rev 2000;5:530-545. 97. Le Marchand L, Hankin JH, Kolonel LN, Beecher GR, Wilkens LR, Zhao LP. Intake of specic carotenoids and lung cancer risk. Cancer Epidemiol Biomarkers Prev. 1993;2:183-187. 98. Le Marchand L, Hankin JH, Bach F, et al. An ecological study of diet and lung cancer in the South Pacic. Int J Cancer. 1995;63:18-23. 99. Comstock GW, Alberg AJ, Huang HY, et al. The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity. Cancer Epidemiol Biomarkers Prev. 1997;6:907-916. 100. Stefani ED, Boffetta P, Deneo-Pellegrini H, et al. Dietary antioxidants and lung cancer risk: a case-control study in Uruguay. Nutr Cancer. 1999;34:100-110. 101. Voorrips LE, Goldbohm RA, Brants HA, et al. A prospective cohort study on antioxidant and folate intake and male lung cancer risk. Cancer Epidemiol Biomarkers Prev. 2000;9:357-365.
102. Michaud DS, Feskanich D, Rimm EB, et al. Intake of specic carotenoids and risk of lung cancer in 2 prospective US cohorts [see comments]. Am J Clin Nutr. 2000;72:990-997. 103. Hecht SS, Hoffmann D. N-nitroso compounds and tobaccoinduced cancers in man. IARC Sci Publ. 1991;105:54-61. 104. Hoffmann D, Rivenson A, Chung FL, Hecht SS. Nicotinederived N-nitrosamines (TSNA) and their relevance in tobacco carcinogenesis. Crit Rev Toxicol. 1991;21:305-311. 105. Djordjevic MV, Sigountos CW, Hoffmann D, et al. Assessment of major carcinogens and alkaloids in the tobacco and mainstream smoke of USSR cigarettes. Int J Cancer. 1991;47:348-351. 106. Anderson R. Assessment of the roles of vitamin C, vitamin E, and beta-carotene in the modulation of oxidant stress mediated by cigarette smoke-activated phagocytes. Am J Clin Nutr. 1991;53:358S-361S. 107. Handelman GJ, Packer L, Cross CE. Destruction of tocopherols, carotenoids, and retinol in human plasma by cigarette smoke. Am J Clin Nutr. 1996;63:559-665. 108. Peng YM, Peng YS, Lin Y, Moon T, Roe DJ, Ritenbaugh C. Concentrations and plasma-tissue-diet relationships of carotenoids, retinoids, and tocopherols in humans. Nutr Cancer. 1995;23:233-246. 109. Alberg AJ, Chen JC, Zhao H, Hoffman SC, Comstock GW, Helzlsouer KJ. Household exposure to passive cigarette smoking and serum micronutrient concentrations. Am J Clin Nutr. 2000;72:1576-1582. 110. Hammond BR, Wooten BR, Snodderly DM. Cigarette smoking and retinal carotenoids: implications for age-related macular degeneration. Vision Res. 1996;36:3003-3009. 111. Seddon JM, Willett WC, Speizer FE, Hankinson SE. A prospective study of cigarette smoking and age-related macular degeneration in women [see comments]. JAMA. 1996;276:1141-1146. 112. Chopra M, ONeill ME, Keogh N, Wortley G, Southon S, Thurnham DI. Inuence of increased fruit and vegetable intake on plasma and lipoprotein carotenoids and LDL oxidation in smokers and nonsmokers. Clin Chem. 2000;46:1818-1829. 113. Ko CB, Walton S, Keczkes K, Bury HP, Nicholson C. The emerging epidemic of skin cancer. Br J Dermatol. 1994;130:269-272. 114. Dreher F, Maibach H. Protective effects of topical antioxidants in humans. Curr Probl Dermatol. 2001;29:157-164. 115. Heinrich U, Weibusch M, Tronnier H. Photoprotection from ingested carotenoids. Cosmetics and Toiletries. 1998;113:61-70. 116. Wingerath T, Sies H, Stahl W. Xanthophyll esters in human skin. Arch Biochem Biophys. 1998;355:271-274. 117. Stahl W, Heinrich U, Jungmann H, Sies H, Tronnier H. Carotenoids and carotenoids plus vitamin E protect against ultraviolet light-induced erythema in humans. Am J Clin Nutr. 2000;71:795-798. 118. Bruch-Gerharz D, Stahl W, Gerharz CD, et al. Accumulation of the xanthophyll lutein in skin amyloid deposits of systemic amyloidosis. J Invest Dermatol. 2001;116:196-197. 119. Taylor EJ, Evans FJ. Anti-psoriatic action of lutein demonstrated by inhibition of rat photodermatitis. J Pharm Pharmacol. 1998;50:78. 120. Faulhaber D. Lutein inhibits UVB radiation-induced tissue
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swelling and suppression of the induction of contact hypersensitivity (CHS) in the mouse. J Invest Dermatol. Society of Investigative Dermatology Conference. Washington, DC. 2001. 121. Peng YM, Peng YS, Lin Y. A nonsaponication method for the determination of carotenoids, retinoids, and tocopherols in solid human tissues. Cancer Epidemiol Biomarkers Prev. 1993;2:139-144. 122. Peng YM, Peng YS, Childers JM, et al. Concentrations of carotenoids, tocopherols, and retinol in paired plasma and cervical tissue of patients with cervical cancer, precancer, and noncancerous diseases. Cancer Epidemiol Biomarkers Prev. 1998;7:347-350. 123. Schiffman MH. New epidemiology of human papillomavirus infection and cervical neoplasia. J Natl Cancer Ins.t 1995;87:1345-1347. 124. Giuliano AR, Papenfuss M, Nour M, Caneld LM, Schneider A, Hatch K. Antioxidant nutrients: associations with persistent human papillomavirus infection. Cancer Epidemiol Biomarkers Prev. 1997;6:917-923. 125. Berton ER, Hankinson SE, Newcomb PA, et al. A populationbased case-control study of carotenoid and vitamin A intake and ovarian cancer (United States). Cancer Causes Control. 2001;12:83-90. 126. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature. 1993;362:801-809. 127. Pryor WA, Stahl W, Rock CL. Beta carotene: from biochemistry to clinical trials. Nutr Rev. 2000;58:39-53. 128. Ford ES. Variations in serum carotenoid concentrations among United States adults by ethnicity and sex. Ethn Dis. 2000;10:208-217. 129. Kritchevsky SB. beta-carotene, carotenoids and the prevention of coronary heart disease. J Nutr. 1999;129:5-8. 130. Ascherio A, Rimm EB, Hernan MA, et al. Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann Intern Med. 1999;130:963-970. 131. Hirvonen T, Virtamo J, Korhonen P, Albanes D, Pietinen P. Intake of avonoids, carotenoids, vitamins C and E, and risk of stroke in male smokers. Stroke. 2000;31:2301-2306. 132. Dwyer JH, Navab M, Dwyer KM, et al. Oxygenated carotenoid lutein and progression of early atherosclerosis: the Los Angeles atherosclerosis study. Circulation. 2001;103:2922-2927. 133. Chopra M, Willson RL, Thurnham DI. Free radical scavenging of lutein in vitro. Ann N Y Acad Sci. 1993;691:246-249. 134. Chopra M, Thurnham DI. Effect of lutein on oxidation of low-density lipoprotein (LDL) in vitro. Proc Nutr Soc. 1994;53:1993. 135. Dugas TR, Morel DW, Harrison EH. Dietary supplementation with beta-carotene, but not with lycopene, inhibits endothelial cell-mediated oxidation of low-density lipoprotein. Free Radic Biol Med. 1999;26:1238-1244. 136. Linseisen J, Hoffmann J, Riedl J, Wolfram G. Effect of a single oral dose of antioxidant mixture (vitamin E, carotenoids) on the formation of cholesterol oxidation products after ex vivo LDL oxidation in humans. Eur J Med Res.1998;3:5-12. 137. Alexander RW. Theodore Cooper Memorial Lecture. Hypertension and the pathogenesis of atherosclerosis. Oxidative stress and the mediation of arterial inammatory response: a new perspective. Hypertension. 1995;25:155-161.
138. Marui N, Offermann MK, Swerlick R, et al. Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. J Clin Invest. 1993;92:1866-1874. 139. Martin KR, Wu D, Meydani M. The effect of carotenoids on the expression of cell surface adhesion molecules and binding of monocytes to human aortic endothelial cells. Atherosclerosis. 2000;150:265-274. 140. Ringer TV, DeLoof MJ, Winterrowd GE, et al. betacarotenes effects on serum lipoproteins and immunologic indices in humans. Am J Clin Nutr. 1991;53:688-694. 141. Prabhala RH, Braune LM, Garewal HS, Watson RR. Inuence of beta-carotene on immune functions. Ann N Y Acad Sci. 1993;691:262-263. 142. Kim HW, Chew BP, Wong TS, et al. Dietary lutein stimulates immune response in the canine. Vet Immunol Immunopathol. 2000;74:315-327. 143. Kim HW, Chew BP, Wong TS, et al. Modulation of humoral and cell-mediated immune responses by dietary lutein in cats. Vet Immunol Immunopathol. 2000;73:331-341. 144. Howard AN, Williams NR, Palmer CR, et al. Do hydroxycarotenoids prevent coronary heart disease? A comparison between Belfast and Toulouse. Int J Vitam Nutr Res. 1996;66:113-118. 145. Furr HC, Clark RM. Intestinal absorption and tissue distribution of carotenoids. J Nutr Biochem. 1997;8:364-377. 146. Williams AW, Boileau TW, Erdman JW. Factors inuencing the uptake and absorption of carotenoids. Proc Soc Exp Biol Med. 1998;218:106-108. 147. van Het Hof KH, West CE, Weststrate JA, Hautvast JG. Dietary factors that affect the bioavailability of carotenoids. J Nutr. 2000;130:503-506. 148. Castenmiller JJ, West CE, Linssen JP, van het Hof KH, Voragen AG. The food matrix of spinach is a limiting factor in determining the bioavailability of beta-carotene and to a lesser extent of lutein in humans. J Nutr. 1999;129:349-355. 149. van den Berg H, van Vliet T. Effect of simultaneous, single oral doses of beta-carotene with lutein or lycopene on the beta-carotene and retinyl ester responses in the triacylglycerol-rich lipoprotein fraction of men. Am J Clin Nutr. 1998;68:82-89. 150. van den Berg H. Effect of lutein on beta-carotene absorption and cleavage. Int J Vitam Nutr Res. 1998;68:360-365. 151. Kostic D, White WS, Olson JA. Intestinal absorption, serum clearance, and interactions between lutein and beta-carotene when administered to human adults in separate or combined oral doses. Am J Clin Nutr. 1995;62:604-610. 152. Stark C. Translating biochemical and physiological requirements into practice. In: Stipanuk MH, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia, Pa: W. B. Saunders Company; 2000:945-959. 153. National Academy of Sciences. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, D. C.: National Academy Press, 2000.
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D I T O R I A L
Lutein An Opportunity For Improved Eye Health

Stuart Richer, OD, PhD, FAAO* Chief, Optometry- Eye Clinic/Operative and Invasive Procedures DVA Medical Center, and Clinical Associate Professor, Family Medicine, FUHS/Chicago Medical School, North Chicago, Illinois
Dr. Andrew Shao is among few scientists, and even fewer clinicians, who appreciate the weight of evidence and emerging potential for improved eye health and vision in the aging industrialized population centers of the world. In his article: The Role of Lutein in Human Health, Dr. Shao devotes his review to a neglected dihydroxy carotenoid that plays both preventative and therapeutic roles in optimizing eye health. Lutein as well, shows early promise in cardiovascular health and myriad cancers. I have devoted a good part of my career to the study of Age Related Macular Degeneration (ARMD). It remains the leading cause of untreated vision loss in aging western Caucasian societies, accounting for 45 % of all visual disability in the US.1,2 ARMD is three times more common than glaucoma. Unlike glaucoma, however, there is no medical treatment for the most common dry atrophic form of the disease, which affects 90% of all visually disabled people. ARMD is a bilateral disease, gradually robbing a person of critical central visual function the vision each of us requires to read or drive a car. Increasing age is associated with increasing prevalence of ARMD in all studies,1-4 with approximately 60 % of 90- year-olds and above effected.5 ARMD has increased in Britain in the last 60 years, ruling out genetic predisposition as the primary etiologic factor.4 It has begun to emerge in Japan as the Japanese shift to a * Correspondence: Stuart Richer, OD, PhD, FAAO Chief, Optometry- Eye Clinic/Operative and Invasive Procedures DVA Medical Center, North Chicago, IL 60064 Phone: (847) 688-1900 ext. 85406 Fax: (847) 578-6924 E-mail: Stuart.Richer@Med.VA.Gov
more westernized diet.3 Dark green leafy vegetables, a major food source of lutein and other important nutrients, are consumed on a limited basis in the western diet. While reduced consumption of lutein is specically associated epidemiologically with both cataract and ARMD, for perspective, there are more than a dozen nutrients associated with ocular health.7 ARMD is a complex disorder involving genetic, cardiovascular and environmental components. From a genetic standpoint, the disease is of multifactorial etiology with multiple genes modifying susceptibility to exogenous interrelated factors.8 In 1993, we hypothesized that ARMD might, in part, be a nutrition responsive disorder.9 In 1996 we demonstrated in a Department of Veterans Affairs double-blind, randomized, multicenter prospective clinical trial, that atrophic ARMD could be stabilized with nutritional intervention in the form of broad-spectrum antioxidants (sans lutein).10,11 Although vision stabilized, no study patients actually improved. The situation changed dramatically in early 1999 when we published preliminary pilot data demonstrating improvement in visual function in the majority of ARMD patients placed on either increased dark green leafy vegetables (lutein-rich spinach), or lutein supplements.12 Our unpublished case reports since 1999 have been equally striking. With a proper evaluation system, based upon both retinal physiology/pathophysiology and physiological optics,13 it now appears feasible to reverse or regenerate visual function in atrophic ARMD patients. Results of a 90-patient prospective, randomized, double-masked, placebo controlled lutein/lutein-antioxidantARMD study awaits peer review.14 It has been said that the eyes mirror health. In his excellent review, Dr. Shao raises the exciting prospect that macular pigment density may serve as an in vivo surrogate
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marker of systemic carotenoid status and ocular health. Of course, establishing a nutrient to be essential (i.e. a vitamin) requires proving causality in depletion/repletion experiments. Although, the Malinow et al. depletion studies were unable to assess visual acuity, the retinal appearance of monkeys deprived of lutein is identical in appearance to that of humans with atrophic ARMD, the most common ARMD subtype we see in the clinic.15 Add to this the epidemiological, biologic structure/function, and emerging prospective clinical repletion data, and it all suggests that lutein is positioned to have an important, if not essential role, in 21st century eye care. REFERENCES 1. Klein R, Klein B. Prevalence of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology. 1992;99:933-943. 2. Klein R, Klein B, Jensen S. The ve-year incidence and progression of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology. 1997;104:7-21. 3. Maruo T, Ikebukuro N, Kawanabe K, Kubota N. Changes in causes of visual handicaps in Tokyo. Jpn J Ophthalmol. 1991;35:268-272. 4. Evans J, Wormald R. Is the incidence of registrable agerelated macular degeneration increasing? Br J Ophthalmol. 1996;80:9-14. 5. VanNewkirk M, Nanjan M, Wang J, Mitchell P, Taylor H, McCarty C. The prevalence of age-related maculopathy: The visual impairment project. Ophthalmology. 2000;107:15931600. 6. Yuzawa M, Hagita K, Egawa I, Minato H, Matsui M. Macular lesions predisposing to senile disciform macular degeneration. Jpn J Ophthalmol. 1991;35:268-272. 7. Richer S. Antioxidants and the Eye. In: Friedlaender MH, ed. International Ophthalmology Clinics. Philadelphia: Lippincott Williams & Wilkins; 2000:1-16. 8. Ryan S. Retina. Chapters 67 & 68. St. Louis,MO: CV Mosby; 1994. 9. Richer SP. Is there a prevention and treatment strategy for macular degeneration? J Am Optom Assoc. 1993;64:1-13. 10. Richer S. ARMD Study Group -VA/PUCO Multicenter ophthalmic/nutritional ARMD Study - Part 1: Design, subjects & procedures. J Am Optom Assoc. 1996;67:12-29. 11. Richer S. ARMD Study Group: Multicenter ophthalmic and nutritional age-related macular degeneration studyPart 2: antioxidant intervention and conclusions. J Am Optom Assoc. 1996;67:30-49. 12. Richer S. Part II: ARMD Pilot (case series) environmental intervention data. J Am Optom Assoc. 1999;70:24-36.
13. Richer S. Part I: A protocol for the evaluation and treatment of atrophic age-related macular degeneration. J Am Optom Assoc. 1999;70:13-23. 14. Levy S. Researchers suggest new way to treat macular degeneration. Drug Topics. 1999:56. 15. Malinow M, Feeney-Burns L, Peterson L, Klein M, Neuringer M. Diet related macular anomalies in monkeys. Invest Ophthalmol Vis Sci. 1980;19:857-863.
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The Journal of the American Nutraceutical Association

Vol. 4, No. 2, Summer 2001

The Role of Lutein in Human Health

A Peer-Reviewed Journal on Nutraceuticals and Nutrition Mark Houston, MD Editor-in-Chief

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Dark Sunglasses Macular pigment (Lutein/zeaxanthin)

Antioxidants/Enzymes Carotenoids Lutein Glutathione Vitamins C & E

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Carotenoid intake Antioxidant intake Serum carotenoids

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Figure 10. Effect of carotenoid supplementation on UV-induced

Carotenoid Carotenoid Supplement Supplement

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