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Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, Massachusetts
Address reprint requests to: Dr. Jeffrey Blumberg, Antioxidants Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111. E-mail: jeffrey.Blumberg{at}tufts.edu
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ABSTRACT |
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 TOPFOOTNOTES ABSTRACT INTRODUCTIONDISEASES OF THE EYECANCERCORONARY HEART DISEASE AND...CONCLUSIONSREFERENCES |
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Key words: lutein, zeaxanthin, xanthophylls, carotenoids, age-related macular degeneration, cataract, cancer, heart disease, stroke
Key teaching points:
• Rich dietary sources of lutein and zeaxanthin are dark green leafy vegetables and egg yolks.
• Many epidemiologic studies indicate an inverse relationship between xanthophyll intake and/or status and both cataract and age-related macular degeneration.
• Observational studies and animal model data suggest a potential protective role for xanthophylls against certain kinds of cancers, with promising albeit inconsistent results for breast and lung cancers, and largely a null outcome for bladder cancer.
• A limited body of experimental and epidemiological evidence suggests a potential role for lutein and zeaxanthin in reducing the risk for coronary heart disease and stroke.
• Dietary guidelines for promoting health are consistent with generous intakes of foods rich in lutein and zeaxanthin.
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INTRODUCTION |
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TOPFOOTNOTESABSTRACTINTRODUCTIONDISEASES OF THE EYECANCERCORONARY HEART DISEASE AND...CONCLUSIONSREFERENCES |
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- and ß-carotene and lycopene, and the monohydroxyl carotenoid, ß-cryptoxanthin (Fig. 1). The hydrophilic properties of lutein and zeaxanthin allow them to react with singlet oxygen generated in water phase more efficiently than nonpolar carotenoids [7]. Unlike - and ß-carotene and ß-cryptoxanthin, lutein and zeaxanthin are not precursors of vitamin A.
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DISEASES OF THE EYE |
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TOPFOOTNOTESABSTRACTINTRODUCTIONDISEASES OF THE EYECANCERCORONARY HEART DISEASE AND...CONCLUSIONSREFERENCES |
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Increased ingestion of foods rich in lutein and zeaxanthin [25,26] or ingestion of lutein supplements [27–29] or zeaxanthin supplements [29] have been reported to increase macular pigment density in healthy adults. In patients with inherited retinal degeneration, lutein supplementation augmented the macular pigment in many but not all patients, though central vision was unchanged after the supplementation [30]. The preservation of visual sensitivity in older people has been associated with macular pigment density [31]. Positive associations have been reported between dietary intakes of lutein plus zeaxanthin vs. macular pigment density [32] and between serum concentrations of these carotenoids vs. macular pigment density [32–34]. In contrast, Beatty et al. [35] found no relationship between intakes of lutein and/or zeaxanthin and macular pigment density.
A. Age-related Macular Degeneration
AMD is the most common cause of visual impairment and irreversible blindness among elderly Americans [36] and a number of investigations have examined the relationship between lutein and zeaxanthin and AMD. In a case-control study, Bone et al. [37] examined human autopsy retinas from 56 donors with AMD and from 56 controls without the disease. They found that lutein and zeaxanthin concentrations in three concentric regions centered on the fovea were lower, on average, in AMD donors than controls. Those in the highest quartile of lutein and zeaxanthin content in peripheral retina had an 82% lower odds ratio (OR) for AMD than those in the lowest quartile (OR: 0.18; 95% CI: 0.05–0.64). Bernstein et al. [38] reported that compared to non-AMD controls, the average macular pigment levels were 32% lower in AMD patients who did not consume lutein supplements. AMD patients who consumed lutein supplements (
4 mg/d) after their initial diagnosis had macular pigment levels that were in the normal range.
Data from the Eye Disease Case-Control Study [39] involving 391 cases and 577 controls are consistent with the hypotheses that a reduced risk of neovascular (exudative or wet) AMD is inversely associated with xanthophyll status. Neovascular AMD is less common than atrophic (dry) AMD, but is much more likely to result in severe vision loss [40]. Persons with serum lutein and zeaxanthin concentrations 0.668 µmol/L were 70% less likely to have neovascular AMD than those with serum concentrations 
0.247 µmol/L (OR: 0.3; 95% CI: 0.2–0.6; P-trend = 0.0001). Seddon et al. [41] reported that the Eye Disease Case-Control Study also revealed that higher dietary intakes of lutein plus zeaxanthin are strongly associated with a reduced risk for neovascular AMD with an odds ratio of 0.43 for those in the highest quintile of intake compared to those in the lowest quintile (95% CI: 0.2–0.7; P-trend, <0.001). A higher frequency of intake of spinach or collard greens, vegetables that are rich in lutein, was associated with a substantially lower risk for neovascular AMD with an odds ratio of 0.14 for those who ingested these vegetables 5 times/wk compared to those who ingested them <1 time/mo (95% CI: 0.01–1.2; P-trend, <0.001) [41].
In a cross-sectional study of 380 elderly men and women in Sheffield, UK, Gale et al.. [42] found that plasma zeaxanthin was significantly associated with risk of AMD. Those with plasma zeaxanthin in the lowest third of the distribution had an odds ratio for risk of AMD of 2.0 when compared to those in the highest third (95% CI: 1.0–4.1; P-trend = 0.046). Risk of AMD was also increased in people with lowest plasma lutein and lowest plasma lutein plus zeaxanthin, however, these associations were not statistically significant.
Mares-Perlman et al. [43] examined the relationship between dietary and serum status of lutein plus zeaxanthin to photographic evidence of age-related maculopathy among persons >40 y old (n = 8,222) in the third National Health and Nutrition Examination Survey (NHANES III) and found no inverse correlations. However, when analysis was limited to those in the youngest age groups, higher levels of dietary lutein plus zeaxanthin were related to lower odds for developing pigment abnormalities, an early sign of age-related maculopathy (people in highest vs. lowest quintiles of intake OR: 0.1; 95% CI: 0.1–0.3), and lower odds for developing AMD (OR: 0.1; 95% CI: 0.0–0.9). In a study in the Netherlands involving 72 cases and 66 controls, Snellen et al. [44] found that the prevalence rate of AMD in subjects with low lutein intake was more than twice that in subjects with high intake (OR: 2.4; 95% CI: 1.1–5.1).
The above studies lend support to the hypothesis that low levels of xanthophylls in the diet, plasma, or macula could represent a risk factor for the development of AMD. However, the clinical implications of low lutein and zeaxanthin status have yet to be clarified. Richter et al. [45] reported that among atrophic AMD patients in the Veterans Lutein Antioxidant Supplementation Trial (LAST), ingestion of lutein supplements alone or together with other nutrients, increased macular pigment density and improved visual function (visual acuity, contrast sensitivity, Amsler grid) as compared to ingestion of placebo. Schupp et al. [46] reported that in adults with cystic fibrosis, the concentrations of lutein and zeaxanthin in serum and macula are 54–64% lower than those in sex-matched healthy control subjects, and yet there were no significant differences between the 2 groups in visual performance (contrast sensitivity, color discrimination, and retinal function) under conditions of daylight illumination.
Associations between lutein and/or zeaxanthin and AMD were not observed in other studies. For example, the Beaver Dam Eye Study in Wisconsin failed to show any significant association of lutein and zeaxanthin with the development of AMD [47–49]. Retrospective analyses found no statistically significant correlations between dietary intakes of lutein and zeaxanthin 10 y before study enrollment vs. early- or late-stage age-related maculopathy [48]. In a prospective 5-y follow-up of participants, lutein and zeaxanthin intakes at baseline and 10 y prior to study enrollment were not significantly associated with the development of early signs of maculopathy [49]. No significant difference in non-fasting serum concentrations of lutein and zeaxanthin was observed between a subsample of 167 case-control pairs [47].
Similarly, in northern London, UK, Sanders et al. [50] found no significant difference in mean plasma lutein concentrations of 65 elderly patients with age-related maculopathy and 65 controls. In a study in Italy, Simonelli et al. [51] also found no significant difference in serum lutein plus zeaxanthin in 48 AMD patients and 46 subjects without AMD. In the Blue Mountains Eye Study in Australia, Flood et al. [52] observed no association between baseline intakes of lutein and zeaxanthin and the 5 y incidence of early age-related maculopathy. A recent report of a prospective follow-up study of women in the Nurses’ Health Study (n = 77,562 for up to 18 y) and men in the Health Professionals Follow-up Study (n = 40,866 for up to 12 y) by Cho et al. [53] showed that fruit intake, but not intakes of vegetables, vitamins A, C, and E, lutein plus zeaxanthin, as well as total carotenoids, were not related to either early or neovascular AMD.
B. Cataract
Oxidative damage to lens cell membranes is considered an important factor in the initiation and progression of age-related cataract [54] and increased lipid peroxidation products have been detected in lens and aqueous humor of patients with cataracts [55,56].
The Nurses’ Health Study included an examination of the relation of dietary intake with risk of cataract extraction [57], early age-related nuclear cataract [58], and early age-related cortical and subcapsular cataract [59]. Chasan-Taber et al. [57] reported that in a prospective study of this cohort (n = 77,466) with repeated administration of a food-frequency questionnaire during 12 y follow-up, 1,471 cataracts were extracted. Women with the highest intakes of lutein plus zeaxanthin (top 10%) had a 22% reduction in relative risk (RR) of cataract severe enough to require extraction as compared to those with poorest intakes (bottom 20%) (RR: 0.78; 95% CI: 0.63–0.95; P-trend = 0.04). Other carotenoids (ß-carotene, -carotene, lycopene, and ß-cryptoxanthin) were not associated with cataract extraction. Increased frequency of intakes of lutein-rich spinach and kale was associated with a moderate decreased risk of cataract extraction. In a sub-sample of nurses without previously diagnosed cataracts and who completed 5 food frequency questionnaires during a 13–15 y period before cataract diagnosis (n = 478), Jacques et al. [58] reported that the prevalence of early age-related nuclear lens opacities was significantly lower in those in the highest compared to lowest quintile category of lutein plus zeaxanthin intake (P = 0.03); however, after adjustment for other nutrients, the inverse association was no longer significant (P = 0.08). Taylor et al. [59] analyzed data from this same subcohort and reported no significant trends in association between lutein plus zeaxanthin intake and odds of early age-related cortical and posterior subcapsular lens opacities.
In a prospective cohort study of US male health professionals (n = 36,644), Brown et al. [60] reported that during 8 years of follow-up, 840 cases of senile cataract extraction were documented. Men with the highest intakes of lutein plus zeaxanthin, but not other carotenoids, had a 19% lower risk of cataract extraction compared to those in the lowest quintile (RR: 0.81; 95% CI: 0.65–1.01; P-trend = 0.03). Among specific foods, broccoli and spinach were consistently associated with decreased risk of cataract.
Associations of lutein and age-related cataract in the Beaver Dam Study were inconsistent. An inverse association between dietary lutein and cataract was seen, but not between serum lutein and cataract. A retrospective study by Mares-Perlman et al. [61] in 1,919 subjects showed that women in the highest quintile of lutein intake (median: 949 µg/d) 10 y before dietary interview had a 27% lower prevalence of severe nuclear sclerosis (OR: 0.73; 95% CI: 0.50–1.06; P-trend = 0.02) compared to women in the lowest quintile of lutein intake (median: 179 µg/d). In men, an inverse association was observed between lutein intake and risk of severe nuclear sclerosis but the relationship did not reach statistical significance. Among the foods evaluated, spinach was significantly associated with decreased risk in women, but not in men.
In a prospective 5 y follow-up of 1,354 persons enrolled in the Beaver Dam Eye Study, Lyle et al. [62] reported those in the highest quintile of lutein intake 10 y prior to study enrollment were 50% less likely to have an incident nuclear cataract (OR: 0.5; 95% CI: 0.3–0.8; P-trend = 0.002) as those in the lowest quintile of intake. Similar results were obtained using lutein intake during the year preceding study enrollment (baseline) but only in subjects <65 y old (OR: 0.4; 95% CI: 0.2–0.8; P-trend = 0.06). Thus, longer-term intake of lutein was more strongly associated with nuclear cataract than short-term intake. The stronger association of distant past diet (10 y earlier) with incident cataract as compared with recent past diet (year before baseline) may reflect dietary influences on early biochemical events preceding lens opacification. Intakes of spinach in the highest compared to lowest quintile during the year preceding baseline was related to lower risk for nuclear cataract (OR: 0.6; 95% CI: 0.4–0.9; P-trend = 0.02). Interestingly, in persons <65 y old, intake of eggs in the highest compared to lowest quintile was markedly related to lower risk for nuclear cataract (OR: 0.4; 95% CI: 0.2–0.9; P-trend = 0.004).
In contrast to the findings of an inverse association of dietary lutein and cataract risk, non-fasting lutein in serum obtained at baseline was not significantly associated with the 5 y incidence of severe nuclear cataract in a random subsample of 400 subjects from the Beaver Dam Eye Study cohort [63]. As suggested by the investigators, the lack of an association may have been due to inadequate sample size. A total of 252 persons were eligible for incident cataract, of who only 57 developed nuclear cataract in at least one eye during the 5 y period. The finding of a lack of association between nuclear cataract and serum lutein in this prospective study is in contrast with an earlier report from the Beaver Dam Eye Study in which more severe cataracts were found, particularly in women, with high serum concentrations of lutein when associations were examined cross-sectionally at baseline [64]. The authors speculated that temporal confounding may have influenced the direct associations observed in the cross-sectional study. A cross-sectional study done in Spain among 138 patients with senile cataract and 110 control subjects also reported that higher serum levels of lutein and zeaxanthin were associated with greater risk for cataract [65].
In a cross-sectional study of 372 older adults in England, Gale et al. [66] found that the risk of posterior subcapsular cataract (but not nuclear or cortical cataract) was lowest in those with higher concentrations of plasma lutein. The OR of those in the highest tertile of plasma lutein concentration compared to those in the lowest tertile was 0.5 (95% CI: 0.2–1.0; P-trend = 0.012). No association of plasma zeaxanthin and any type of cataract was seen. Interestingly, in a small trial of people with cataract, lutein supplementation (15 mg administered 3 times/wk for 2 y) has been shown to improve visual acuity and glare sensitivity [67].
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CANCER |
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TOPFOOTNOTESABSTRACTINTRODUCTIONDISEASES OF THE EYECANCERCORONARY HEART DISEASE AND...CONCLUSIONSREFERENCES |
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The mechanisms for a potential protective role of xanthophylls against carcinogenesis may include selective modulation of apoptosis [74,77,78], inhibition of angiogenesis [74], enhancement of gap junctional intercellular communication [79], induction of cell differentiation [80], prevention of oxidative damage [81], and modulation of the immune system [82–87].
Oxidative metabolites of lutein, thought to arise from lutein’s antioxidant mechanism of action, have been isolated and characterized from extracts of human serum and plasma [88]. Haegele et al. [81] observed that plasma lutein in women was inversely correlated with indices of oxidative DNA damage [8-hydroxy-2`-deoxyguanosine (8-OHdG) in DNA isolated from peripheral lymphocytes and 8-OHdG excreted in urine] and lipid peroxidation (8-epiprostaglandin F2 in urine). During the course of a dietary intervention with increased fruit and vegetable intakes, they found an inverse correlation between the change in plasma lutein and change in lymphocyte 8-OHdG concentration. However, Collins et al. [89] reported that although the basal lutein concentration in serum correlate inversely with oxidized pyrimidines in the DNA of lymphocytes from human volunteers, supplementation with 15 mg lutein/d for 12 wk did not have a significant effect on endogenous oxidative DNA damage in lymphocytes. Similarly, Torbergsen and Collins [90] found that lutein supplementation in healthy volunteers produced 2-fold increases in mean plasma lutein but had no effect on rejoining of DNA strand breaks in isolated lymphocytes treated with hydrogen peroxide. In a human lymphocyte cell line, there was no evidence that lutein protected cellular DNA from oxidation under basal conditions or after oxidative challenge with hydrogen peroxide; however, lutein enhanced the recovery of cells from oxidative challenge by stimulating DNA strand break repair [91].
The action of carotenoids on the immune system has recently been reviewed by Chew and Park [92]. Protecting the immune system could enhance cell-mediated immune responses and consequently, resistance to tumor formation. The immuno-modulatory action of dietary lutein has been demonstrated in domestic cats [86] and dogs [87]. In mice fed lutein-containing diets, lutein uptake by the spleen suggests a role for lutein in modulating immunity [93]. Lutein has been shown to enhance antibody production in response to T-dependent antigens in spleen cells in vitro, as well as in mice in vivo [82]. The numbers of immunoglobulin M- and G-secreting cells increased in vivo with lutein administration when mice were primed with T-dependent antigens [82]. In cultures of murine T-helper cells and unprimed spleen cells, zeaxanthin augmented the number of immunoglobulin M antibody-secreting cells [83]. Dose-related increases in the expression of the pim-1 gene, which is involved in early activation of T cells, has been observed in splenic lymphocytes of mice fed lutein, but not ß-carotene or astaxanthin [84]. However, in healthy male nonsmokers, lutein supplementation, unlike ß-carotene supplementation, had no effect on the percentage of monocytes expressing major histocompatibility complex class II molecules [94], cell surface molecules responsible for presenting antigen to T-helper cells. Further, cell-to-cell adhesion appears to be critical for the initiation of a primary immune response and lutein supplementation, unlike ß-carotene supplementation, also had no effect on the expression of intercellular adhesion molecules by monocytes [94].
A. Breast Cancer
The associations of xanthophyll intake or serum levels with breast cancer risk in humans have been investigated in many epidemiologic studies and the results have been inconsistent. Zhang et al. [95] reported that during 14 y follow-up (1980–1994) of a large prospective study of 83,234 female nurses who were 34–59 y of age at baseline (Nurses’ Health Study), 2,697 developed invasive breast cancer. Prediagnostic intake of lutein plus zeaxanthin was inversely associated with breast cancer risk in premenopausal (n = 784) but not in postmenopausal women (n = 1,913). Among premenopausal women, the RR of those in the highest compared to those in the lowest quintile of intake was 0.79 (95% CI: 0.63–0.99; P-trend = 0.04). The inverse association for increasing quintiles of intake and breast cancer risk was stronger among premenopausal women with a positive family history of breast cancer. The RR of those in the highest compared to those in the lowest quintile of intake was 0.38 (95% CI: 0.18–0.81; P-trend = 0.004). In contrast to this, Cho et al. [96] found no association of lutein plus zeaxanthin intakes and breast cancer risk in a prospective cohort of 90,655 female nurses who were 25–42 y of age at baseline (Nurses’ Health Study II); during 8 y of follow-up (1991–1999), 714 incident cases of invasive breast cancer were documented.
Freudenheim et al. [97] conducted a case-control study (297 cases, 311 control subjects) of premenopausal breast cancer risk and intake of nutrients in western New York. A reduction in premenopausal breast cancer risk was associated with a high intake of lutein plus zeaxanthin during the 2 y prior to dietary interview. The OR of those in the highest quartile compared to those in the lowest quartile of intake was 0.47 (95% CI: 0.28–0.77; P-trend, <0.001).
In a case-control study in northern Sweden (201 cases, 290 controls) from 3 population-based cohorts, Hulten et al. [98] found that overall, plasma lutein at baseline was not related to the risk of developing breast cancer. However, results from stratified analysis showed a significant trend of an inverse association between plasma lutein and incident breast cancer risk in premenopausal women from 2 combined cohorts. Ito et al. [99] examined 206 breast cancer patients, 150 hospital controls, and 61 healthy controls in India and found that serum xanthophyll levels were significantly lower among cases than controls in post-menopausal but not in premenopausal women.
In a study involving 270 case-control pairs nested within a prospective cohort study in New York with up to 9 y follow-up, Toniolo et al. [100] found that the risk of breast cancer was doubled among subjects with prediagnostic serum lutein at the lowest quartile, as compared with those at the highest quartile (OR: 2.08; 95% CI: 1.11–3.90; P-trend = 0.01). No association of serum zeaxanthin with breast cancer risk was observed.
In a case control study (105 cases, 209 controls) nested within a prospective cohort study in Columbia, Missouri, Dorgan et al. [101] found no significant protective effect against breast cancer with increased serum lutein plus zeaxanthin overall during up to 9.5 y (median: 2.7 y) follow-up. However, in women that donated blood at least 2 y before diagnosis (60 cases) and 120 matched controls, a marginally significant gradient of decreasing breast cancer risk with increasing serum lutein plus zeaxanthin was observed. Those in the highest quartile had a RR of 0.6 (95% CI: 0.2–1.7; P-trend = 0.08) compared to those in the lowest quartile category. It is thought that the use of blood collected prior to diagnosis may generally be more informative than blood collected after diagnosis, since the disease process could alter the levels of blood constituents.
Rock et al. [102] reported that in women newly diagnosed with breast cancer, higher plasma concentration of lutein was associated with an increased likelihood of having estrogen receptor-positive status, a condition that has been linked to improved response to hormone therapy and survival [103]. Kim et al. [104] reported the serum concentration of zeaxanthin plus lutein was inversely associated with the risk of breast cancer, and that the relationship did not differ according to the presence or absence of a p53 mutation.
In a prospective, nested case-control study in Washington Country, Maryland of women who participated in a blood collection campaign in 1974 or/and 1989, Sato et al. [105] reported that serum lutein was significantly lower (P = 0.02) in 115 subjects from the 1989 cohort (but not the 1974 cohort) who subsequently developed breast cancer compared to their matched controls. However, although an inverse association of serum lutein with breast cancer risk was observed, no significant dose-response association was seen (P-trend = 0.11).
In a large case-cohort analysis (1,452 cases, 5,239 controls) of women enrolled in the Canadian National Breast Screening Study who completed a self-administered dietary questionnaire, Terry et al. [106] found no association between dietary intakes of lutein plus zeaxanthin at baseline and breast cancer risk during 11 y follow-up in the overall study population, nor in subgroups defined by menopausal status, family history of breast cancer, smoking status, relative body weight as assessed by body mass index, and intakes of total fat, energy, alcohol, or folic acid. In a population-based case-control study involving 414 incident cases and 429 controls in French Canadians in Montreal, Nkondjock and Ghadirian [107] found that dietary intakes of lutein or zeaxanthin were not associated with breast cancer risk.
In a study of early-onset breast cancer among 568 cases with in situ and localized disease and 1,451 population-based controls conducted in 3 centers in the US, Potischman et al. [108] reported that dietary intake of lutein during the year before study enrollment was not associated with risk of early-stage breast cancer.
Ronco et al. [109] studied 400 women in Uruguay with newly diagnosed breast cancer and 405 controls and found dietary intake of lutein plus zeaxanthin was unrelated to breast cancer risk. Similarly, in a cohort of Finnish women (n = 4697), Jarvinen et al. [110] found 88 breast cancer cases diagnosed during 25 y of follow-up, but no significant relationship between lutein intake at baseline and the occurrence of the disease.
In a small case-control study in 46 women whose biopsies revealed invasive or in situ breast cancer (cases) and 63 women whose biopsies revealed benign disease (controls), Zhang et al. [111] observed an inverse but non-significant association between breast adipose tissue levels of lutein plus zeaxanthin and risk of breast cancer. Yeum et al. [112] did not observe any significant differences in the concentrations of lutein and of zeaxanthin in serum and in normal breast adipose tissue of breast cancer patients (n = 44) and benign breast tumor patients (n = 46).
According to Czeczuga-Semeniuk et al. [113], the predominant carotenoids in the surrounding fatty tissue in both malignant and benign breast tumor are xanthophyll epoxides, i.e., lutein epoxide (taraxanthin) and zeaxanthin 5,6,5`6`-diepoxide (violaxanthin); and that in neoplastic material, the predominant carotenoids are epoxide carotenoids, as well as other carotenoids including zeaxanthin and lutein. No relationship was found between the severity of neoplasm or lesion diameter and specific carotenoids. The physiological significance of xanthophyll epoxides in breast tissue of patients with malignant or benign breast tumors is not known, but previous studies have shown that ß-carotene epoxides were much more active than ß-carotene in inducing the differentiation of the leukemic cell line NB4 in vitro [114]. However, neither taraxanthin nor violaxanthin were detected in human plasma after the oral ingestion of chemically prepared compounds by 3 volunteers [115]. Xanthophyll epoxides are abundant in green vegetables [116].
Although human studies regarding the relationship of lutein and zeaxanthin with breast cancer risk have been inconclusive, studies in human mammary cells and in animal models support a protective role of xanthophylls. Lutein has been shown to selectively induce apoptosis in transformed cells, but not normal human mammary cells, and protect normal cells, but not transformed cells, from apoptosis induced by the chemotherapy agents etoposide and cisplatin [77]. Low levels of dietary lutein from marigold extract enhanced lymphocyte proliferation, lowered lipid peroxidation, lowered mammary tumor incidence, increased tumor latency, and suppressed tumor growth in susceptible mice [74,75,85] by selectively modulating apoptosis and inhibiting angiogenesis [74], although higher lutein levels were less effective [75].
B. Lung Cancer
The association of xanthophylls and risk of lung cancer was investigated in a large prospective study of male smokers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study conducted in Finland. Holick et al. [117] reported that of 27,084 male smokers who completed a dietary questionnaire at baseline, 1,644 developed lung cancer during 14 y follow-up. Men in the highest quintile of lutein plus zeaxanthin intake at baseline (median: 2,106 µg/d) had a 17% lower risk of lung cancer (OR: 0.83; 95% CI: 0.71–0.99; P-trend = 0.006) compared to men in the lowest quintile of lutein plus zeaxanthin intake (median: 853 µg/d).
De Stefani et al. [118] reported that in a case-control study in Uruguay involving 541 cases of lung cancer and 540 hospitalized controls, retrospective dietary information obtained for the year before onset of symptoms (for cases) or the year before study enrollment (for controls) showed that those in the highest quartile of lutein intake had a 43% lower risk of lung cancer (OR: 0.57; 95% CI: 0.39–0.85; P-trend = 0.004) compared to those in the lowest quartile of lutein intake.
In a population based case-control study conducted in Hawaii involving 332 lung cancer cases and 865 controls, Le Marchand et al. [119] reported a significant dose-dependent inverse association for dietary lutein and risk of lung cancer. Subjects with a high combined intake of lutein, ß-carotene, and -carotene had the lowest risk of lung cancer suggesting that a greater protection was afforded by consuming a variety of vegetables as compared to only foods rich in a particular carotenoid.
Goodman et al. [120] reported that in a prospective nested study of 276 lung cancer case-control pairs from the Beta-Carotene and Retinol Efficacy Trial high-risk cohort of asbestos-exposed workers and heavy smokers (n = 18,314), the mean serum concentration of lutein was lower for lung cancer cases (121 ng/mL) than controls (137 ng/mL) (P = 0.0008); similarly, the mean serum concentration of zeaxanthin was lower for lung cancer cases (24.1 ng/mL) than controls (27.1 ng/mL) (P = 0.004). Statistically significant trends across quartiles were observed for an inverse association of serum lutein or zeaxanthin with lung cancer risk. The OR for persons in the highest compared to lowest quartile of serum lutein was 0.55 (95% CI: 0.33–0.93; P-trend = 0.02); for serum zeaxanthin, it was 0.56 (95% CI: 0.33–0.95; P-trend = 0.02). The inverse relations were more marked among women than men.
In Washington County, Maryland, Comstock et al. [121] found, among subjects who had donated blood for a serum bank in 1989, 258 lung cancer cases through 1993 and matched them with 515 controls; serum/plasma concentrations of lutein plus zeaxanthin were significantly lower by 10.1% among cases than controls. In an ecological study among 20 ethnic groups in several island nations of the South Pacific (Cook Islands, Fiji, Tahiti, and New Caledonia), Le Marchand et al. [122] reported that smoking, as expected, explained the majority of the variability (61%) in incidence of lung cancer among the ethnic groups; lutein intake explained 14%, whereas other factors explained only 5–7% each of the remaining variance in incidence. The association of lutein intake with lung cancer was inverse and statistically significant (P = 0.01).
In contrast, examining 2 large cohorts (46,924 men in the Health Professionals Follow-up Study and 77,283 women in the Nurses’ Health Study), Michaud et al. [123] observed no statistically significant relation between lung cancer risk and intake of lutein. Dietary assessments were derived using food-frequency questionnaires at baseline and during follow-up. Among men, 275 new cases of lung cancer were diagnosed during 10 y follow-up; among women, 519 new cases were diagnosed during 12 y follow-up. In the analyses of individual or pooled cohorts, although those in the highest compared to lowest quintile of intake had lower multivariate relative risks, no significant linear trends were observed across the quintile categories of lutein intake, but the association was stronger and of borderline significance in women (P = 0.09) than in men (P = 0.39).
In a study of 763 lung cancer cases and 564 controls in New Jersey among white male current and recent cigarette smokers, Ziegler et al. [124] found that lung cancer risk was increased 62% in those in the lowest quartile (1,727 µg/d) compared to those in the highest quartile (4,196 µg/d) of lutein plus zeaxanthin intake 4 y before diagnosis or study enrollment; the linear trend was borderline but not statistically significant (P-trend = 0.07). In the Netherlands Cohort Study on Diet and Cancer, Voorrips et al. [125] reported that in a cohort of 58,279 men, 939 lung cancer cases were registered after 6.3 y follow-up; inverse non-significant association with lutein plus zeaxanthin intake at baseline was limited to small cell and squamous cell carcinomas. In a population-based, case-control study of women in the Missouri Women’s Health Study, Wright et al. [126] reported that data from 587 incident primary lung cancer cases and 624 controls showed an inverse relation between lung cancer risk and intake of lutein plus zeaxanthin 2 to 3 y prior to interview, but the relation was no longer statistically significant in models adjusted for total vegetable intake.
Yuan et al. [127] reported that in a large prospective study of diet and lung cancer in Chinese men and women residing in Singapore (n = 63,257), 482 lung cancer cases occurred during 8 y follow-up; baseline intake of lutein plus zeaxanthin was not associated significantly with lung cancer risk. In the Canadian National Breast Screening Study, Rohan et al. [128] reported that a case-cohort study, based on a randomly selected subcohort with 155 incident lung cancer cases and 5,361 non-cases after 8 to 13 y follow-up, showed no association between baseline lutein intake and subsequent lung cancer risk. Kneckt et al. [129] reported that during a 25 y follow-up of 4,545 men in the Finnish Mobile Clinic Health Examination Survey, the association of lung cancer incidence (n = 138) with intake of lutein plus zeaxanthin at baseline was not statistically significant. Garcia-Closas et al. [130] reported that a study in women in Barcelona, Spain among 103 lung cancer cases and 206 hospital controls showed no association of lutein intake with lung cancer risk.
In a case-control study (209 cases, 622 controls) nested in a large, prospective cohort study among men in Shanghai, China, Yuan et al. [131] reported that prediagnostic serum levels of lutein plus zeaxanthin were inversely associated with risk of lung cancer during 12 y follow-up; however, the association was not statistically significant after adjustment for smoking. Ito et al. [132] reported that a prospective case-control study (147 cases of lung cancer deaths, 311 controls) nested in the large Japan Collaborative Cohort Study showed an inverse association of serum lutein and zeaxanthin at baseline with risk of lung cancer death among Japanese during 8 y follow-up; however, the risk for those in the highest vs. lowest quartile of serum xanthophyll levels were not significantly different.
One prospective study conducted in China in a cohort of tin miners found a positive association of serum lutein plus zeaxanthin with lung cancer risk among alcohol drinkers, but not among non-drinkers [133]. During 6 y follow-up, this case-control study (108 incident lung cancer cases, 216 controls) showed that high serum level of lutein plus zeaxanthin at 2.5 y prior to diagnosis was significantly associated with increased lung cancer risk among alcohol drinkers; the OR of those in the highest compared to lowest tertile of serum xanthophyll level was 2.3 (95% CI: 1.2–6.6; P-trend = 0.04). Conversely, a high serum level of lutein plus zeaxanthin was associated with decreased lung cancer risk among non-drinkers of alcohol; the OR of those in the highest compared to lowest tertile of serum xanthophyll level was 0.4 (95% CI: 0.2–1.1; P-trend = 0.04).
C. Colorectal Cancer
In a large case-control study, Slattery et al. [134] investigated associations of dietary lutein and the risk of colon cancer in 1,993 subjects with first primary incident adenocarcinoma of the colon and 2,410 population-based control subjects in an 8-county area in Utah and in the metropolitan Twin Cities area of Minnesota. An inverse association between dietary lutein intake during the 2 y prior to diagnosis or study admission vs. colon cancer risk was detected. The OR for the highest quintile of intake relative to the lowest quintile of intake was 0.83 (95% CI: 0.66–1.04; P-trend = 0.04). A stronger inverse association was observed in persons in whom cancer was diagnosed before they were 67 y of age (OR: 0.66; 95% CI: 0.48–0.92; P-trend = 0.02) and among those with tumors located in the proximal segment of the colon (OR: 0.65; 95% CI: 0.51–0.91; P-trend, <0.01). In this study, lutein intake was the only carotenoid intake that appeared to be inversely associated with colon cancer.
Levi et al. [135] reported that in a case-control study in Vaud, Switzerland, involving 223 patients with incident colon or rectal cancer and 491 patients with acute non-neoplastic conditions, inverse associations were observed between lutein plus zeaxanthin intake during the 2 y prior to diagnosis or study admission and risk of colorectal cancer. The OR for persons in highest vs. lowest tertile of intake was 0.41 (95% CI: 0.2–0.7). In a study in Washington County, Maryland, in bloods obtained before diagnosis, the median chromatographic peak height for serum lutein was 11% lower for subjects who subsequently developed rectal cancer than for those who did not [136].
McMillan et al. [137] reported that in a small study conducted in Glasgow, UK, involving patients with gastrointestinal cancer (10 patients with colon cancer, 2 with liver cancer) and 12 healthy controls, plasma lutein was significantly lower in the cancer group (median: 0.06 µmol/L) than in the control group (median: 0.24 µmol/L) (P < 0.001). The cancer patients had an inflammatory response as reflected by an elevated plasma C-reactive protein and anti-inflammatory treatment with ibuprofen resulted in small but significant increases in plasma carotenoid concentrations. These results indicate that in these cancer patients, inflammation plays an important role in the regulation of plasma lutein and other carotenoids, a finding with important implications regarding the use and interpretation of plasma carotenoid levels in gastrointestinal cancer when blood is collected after disease diagnosis. A similar inverse correlation between plasma concentrations of lutein and other carotenoids vs. C-reactive protein has been reported in lung cancer patients within 1 mo of diagnosis [138].
Other studies have found inverse associations of the xanthophyll carotenoids with precancerous lesions in colon and rectum. Rumi et al. [139] showed that in 59 patients with adenomatous colorectal polyp, the concentration of serum zeaxanthin but not of lutein or other carotenoids was lower than that in a healthy control group. Muhlhofer et al. [140] reported that in patients with colorectal adenoma, the concentrations of all carotenoids, including zeaxanthin and lutein, in biopsies of adenomatous tissue were significantly reduced as compared to non-involved mucosa. Nair et al. [141] reported that patients with adenomatous polyps have lower levels of lutein in their colon mucosa, but not serum, as compared to control gastrointestinal patients with normal colonic mucosa.
No potential protective effect of lutein against colorectal cancer was observed in some large, prospective cohort studies. Terry et al. [142] reported that data from a subcohort (295 cases and 5,334 noncases) of the Canadian National Breast Screening Study with 11 y follow-up did not show any association between dietary intakes of lutein (or other carotenoids) and colorectal cancer risk, either overall or for cancers of the colon or rectum when examined separately. Malila et al. [143] reported that in middle-aged male smokers who were participants of the ATBC Study and who had complete dietary data and serum samples available from baseline (n = 26,951), 184 colorectal cancer cases were diagnosed during 8 y follow-up; no association was seen between lutein plus zeaxanthin intake or serum levels and risk for colorectal cancer. Similarly, in a case-control study in North Carolina involving 613 colon cancer cases and 996 matched controls, Satia-Abouta et al. [144] reported that lutein intake during the year prior to diagnosis or interview was not significantly associated with colon cancer risk in either African-American or white study participants. These null results are consistent with reports from 2 case-control studies which found no association of lutein plus zeaxanthin intake [145] or plasma concentrations [146] with prevalence of colorectal adenomatous polyps.
Animal studies lend support for a chemopreventive role of lutein against colon carcinogenesis. The formation of colonic aberrant crypt foci in rats that received intrarectal doses of N-methylnitrosourea was inhibited by a daily gavage of lutein [72]. A similar protective effect of lutein has been reported against the development of preneoplastic aberrant crypt foci in colons of mice initiated with 1,2-dimethylhydrazine [73].
D. Prostate Cancer
Although lycopene and all-trans-ß-carotene are the predominant carotenoids in human prostate with mean concentrations of 0.80 and 0.54 nmol/g, respectively, lutein and zeaxanthin are consistently detectable at about half their level, 0.30 and 0.24 nmol/g, respectively, in this tissue [147].
Several large prospective studies have reported that dietary intake [148,149] or circulating levels [120,150–152] of the xanthophylls are unrelated to risk of prostate cancer; however, other studies have reported a reduction in risk associated with xanthophylls [153,154]. In a population-based case-control study of men <65 y of age in the Seattle area, Cohen et al. [153] reported that in 628 men newly diagnosed with prostate cancer and 602 matched controls, lutein plus zeaxanthin intake over the 3 to 5 y period before diagnosis or recruitment was inversely associated with prostate cancer risk. The OR for those with lutein plus zeaxanthin intake 2,000 µg/d compared to those with an intake of <800 µg/d was 0.68 (95% CI: 0.45–1.00). In a small hospital-based case-control study of 65 patients with prostate cancer and 132 cancer-free controls, Lu et al. [154] found significant inverse associations between prostate cancer risk and plasma concentrations of zeaxanthin and lutein when comparing highest with lowest quartiles. For zeaxanthin, the OR was 0.22 (95% CI: 0.06–0.83; P-trend = 0.003); for lutein, the OR was 0.30 (95% CI: 0.09–1.03; P-trend = 0.006).
In a large, prospective cohort study (Health Professionals Follow-up Study), dietary intakes of 47,894 eligible subjects were assessed at baseline and 3 more times during 6 y follow-up during which 812 new cases of prostate cancer were diagnosed; lutein intake was unrelated to subsequent development of prostate cancer [148]. In the Netherlands Cohort Study (n = 58,279), 642 incident prostate carcinoma cases were seen after 6.3 y follow-up; intake of lutein plus zeaxanthin had no effect on prostate cancer risk [149].
In a study which included 578 men from the Physicians’ Health Study cohort who developed prostate cancer within 13 y follow-up and 1,294 matched controls, plasma lutein levels were not associated with prostate cancer risk [150]. A study of 142 case-control pairs in a cohort of Japanese-American men in Hawaii showed that incident cases of prostate cancer over a follow-up period of 20 y was unrelated to prediagnostic serum levels of lutein or zeaxanthin [151]. In two nested case-control studies among men in Washington County, Maryland (with 182 and 142 cases, respectively, each case matched with 2 controls), prediagnostic levels of plasma lutein were unrelated to risk of developing prostate cancer during a median follow-up period of 17 y for the first study and 3.5 y for the second study [152]. Similarly, no statistically significant association between serum lutein or zeaxanthin and prostate cancer risk was found in a prospective nested case-control study of 205 case-control pairs from the Beta-Carotene and Retinol Efficacy Trial cohort [120].
It is worth noting that Hall et al. [155] found that lutein and zeaxanthin were less effective than ß-carotene, canthaxanthin or lycopene in inhibiting the growth of human DU145 prostate cancer cells.
E. Upper Aerodigestive Tract Cancers
A 5 y case-control study in northern Italy conducted by Franceschi et al. [156] involving 304 patients with a first incident squamous cell carcinoma of the esophagus and 743 control patients admitted to hospital for acute illnesses showed that lutein plus zeaxanthin intake was significantly inversely associated with risk of esophageal cancer. In another hospital-based case-control study, Zhang et al. [157] examined 95 incident cases of adenocarcinoma of the esophagus and gastric cardia (ACEGC) and 132 controls and found high dietary lutein associated with a decreased risk of ACEGC.
Olmedilla et al. [158] have reported that in men with recently diagnosed cancer of the larynx who had undergone total or partial laryngectomy (n = 51), serum concentration of lutein or zeaxanthin was significantly lower than those in a matched control group (n = 51).
In a nested case-control study conducted within a cohort of community volunteers in Washington Country, Maryland, Zheng et al. [159] reported that among 25,802 individuals who donated blood in 1974, 28 were diagnosed with primary oral and pharyngeal cancer during 1975 to 1990; 4 controls were selected for each case. Although serum lutein was lower in cases compared to controls (mean: 18.96 and 23.28 µg/dL, respectively) the difference was not statistically significant (P = 0.10). The OR of developing oral and pharyngeal cancer was 0.61 in persons in the highest compared to those in the lowest tertile of serum lutein, but the P-trend was not statistically significant, possibly due to the small sample size.
Nomura et al. [160] reported that in 69 cancer cases identified among 6,832 American men of Japanese ancestry during a surveillance period of 20 y and 138 matched controls, prediagnostic serum lutein or zeaxanthin concentrations were not significantly related to risk of subsequent cancer of the upper aerodigestive tract taken together or separated into esophageal, laryngeal, and oral-pharyngeal cancer. Further, in patients with upper aerodigestive tract cancer, lutein intake was not correlated with mutagen sensitivity as measured by an in vitro assay based on the quantification of bleomycin-induced chromatid breaks in cultured lymphocytes [161].
F. Ovarian Cancer
Dietary intake of lutein plus zeaxanthin has been inversely associated with ovarian cancer risk. A case-control study in 5 Italian areas conducted by Bidoli et al. [162] among 1,031 patients with confirmed incident epithelial ovarian cancer and 2,411 patients admitted to area hospitals for acute, non-neoplastic diseases (controls) showed that those in the highest quintile of lutein plus zeaxanthin intake had a 40% lower risk of developing ovarian cancer than those in the lowest quintile of intake (OR: 0.6; 95% CI: 0.5–0.8).
Similarly, Bertone et al. [163] reported that in a population-based, case-control study conducted in Massachusetts and Wisconsin, an inverse relationship between intake of lutein plus zeaxanthin and risk of ovarian cancer was observed. Incident cases were identified through statewide tumor registries (n = 327); controls were randomly selected from lists of licensed drivers and Medicare recipients (n = 3,129). Dietary intake data were collected by telephone interview. Participants with the highest dietary intake of lutein plus zeaxanthin at 5 y prior to diagnosis had a 40% lower RR of ovarian cancer (95% CI: 0.36–0.99) compared to those with lowest intakes.
G. Endometrial Cancer
McCann et al. [164] reported that in women in the Western New York Diet Study, data collected from 232 endometrial cancer cases and 639 matched controls showed an inverse association of dietary lutein plus zeaxanthin intake during the 2 y prior to interview and risk of endometrial cancer (OR: 0.3; 95% CI: 0.2–0.5). In contrast, Jain et al. [165] reported no association between baseline lutein intake and subsequent risk of endometrial cancer in a randomly selected subcohort (n = 5,684) of the Canadian National Breast Screening Study of which 221 women developed endometrial cancer after 8 to 13 y follow-up.
It is interesting to note that Kucuk et al. [166] found that plasma cholesterol ß-epoxides, oxidation products of cholesterol, are elevated in endometrial cancer patients and are inversely related to plasma cis-lutein plus zeaxanthin, but not other carotenoids. This data suggests there may be a preferential depletion of xanthophylls under oxidant stress in these cancer patients.
H. Kidney Cancer
In a study conducted in Los Angeles involving 1,204 renal cell carcinoma patients matched to the same number of neighborhood controls, Yuan et al. [167] found strong inverse associations between the intake of cruciferous and dark green leafy vegetables and cancer risk; a significant inverse association of lutein intake with cancer risk was also observed. Of potential relevance to renal cancer, lutein was found to protect against ultraviolet A light-induced oxidative stress in cultured rat kidney fibroblasts by restoring the activities of the antioxidant enzymes catalase and superoxide dismutase and decreasing the production of lipid peroxidation products [168].
I. Bladder Cancer
A study of 111 case-control pairs in a cohort of Japanese-American men showed that prediagnostic serum levels of lutein or of zeaxanthin were inversely associated with risk of developing bladder cancer over 20 y follow-up; however after adjusting for cigarette smoking, the inverse relation was no longer statistically significant [169]. Similarly, other studies failed to show a significant association between lutein intake with risk of bladder cancer [170–173]. An investigation of the Health Professionals Follow-up Study found that high cruciferous vegetable consumption from 1 mo to 10 y before cancer diagnosis may reduce bladder cancer risk [170]. Among individual lutein-rich cruciferous vegetables, a significant inverse association with risk of bladder cancer was observed for broccoli, but not for kale nor Brussels sprouts. No association was observed between lutein intake and bladder cancer risk [170]. In another prospective cohort study among male smokers who were initially enrolled in the ATBC Study and followed over a median of 11 y, dietary intakes of lutein plus zeaxanthin were not related to bladder cancer risk [171]. The prospective Netherlands Cohort Study also showed that dietary lutein plus zeaxanthin intake are not associated with bladder cancer risk during 6.3 y follow-up [172]. Similarly, a case-control study in Spain did not support the hypothesis that lutein intake is protective against bladder cancer risk [173].
J. Gastric Cancer
In the Netherlands Cohort Study (n = 120,852), a prospective case-cohort study conducted by Botterweck et al. [174] showed that in 282 incident cases of gastric carcinoma during 6.3 y follow-up and 3,123 controls, intake of lutein plus zeaxanthin at baseline was not associated with the development of gastric carcinoma. Similarly, in a case-control study in Spain that included 354 gastric cancer cases and 354 controls, Garcia-Closas et al. [175] found no association between lutein intake and risk of gastric cancer. Also, an ecological study by Tsubono et al. [176] conducted in 5 regions of Japan with different mortality rates from gastric cancer failed to observe an association between mean plasma lutein and zeaxanthin concentrations in men who were sampled randomly from the general populations vs. the mortality rates from gastric cancer in the 5 regions.
Interestingly, one study suggests a potential adverse association between xanthophylls and gastric cancer. Abneth et al. [177], in a prospective case-cohort study in Linxian, China involving 590 esophageal, 395 gastric cardia, and 87 gastric non-cardia case subjects and 1,053 controls, found high baseline serum concentrations of lutein plus zeaxanthin were directly associated with incident gastric non-cardia adenocarcinoma.
K. Cervical Cancer
Batieha et al. [178] employed a population-based, nested case-control study of women in Washington County, Maryland to compare 50 cases who developed invasive cervical cancer or in situ carcinoma with 100 matched controls and found pre-diagnostic serum lutein was not related to subsequent risk of cervical cancer after 16 y follow-up. Similarly, in surveying 4 Latin American countries, Potischman et al. [179] found no association between mean serum lutein among 387 cases of invasive cervical cancer stages I and II and 670 controls.
In Hawaii, Goodman et al. [180] examined 147 multiethnic women with squamous intraepithelial lesions of the cervix and 191 clinic controls and plasma lutein was not significantly associated with risk of cervical dysplasia. In Japan, Nagata et al. [181] matched 156 women diagnosed with cervical dysplasia to women attending the same clinic but with normal cervical cytology and found a small but non-statistically significant inverse association between serum lutein plus zeaxanthin and risk of cervical dysplasia. In a case-control study in Chicago involving 102 women with cervical intraepithelial neoplasia and 102 women with normal Pap smears, VanEenwyk et al. [182] reported that cervical neoplasia was not associated with dietary lutein intakes or serum lutein concentrations.
In contrast to those investigations which showed no association of xanthophylls and cervical neoplasia and carcinoma, in a study of Southwestern American Indian women involving 81 cases with cervical intraepithelial neoplasia (CIN) stages II and III and 160 controls from the same clinics, Schiff et al. [183] found a higher status of serum lutein plus zeaxanthin was associated with a lower risk for CIN stages II and III with an OR for those in the highest vs. lowest tertile of 0.40 (95% CI: 0.17–0.95; P = 0.03). Peng et al. [184] measured the concentrations of lutein and zeaxanthin in paired plasma and cervical tissue of cervical cancer (n = 27), precancer (n = 33), and non-cancer (n = 27) patients in Arizona, and found that plasma zeaxanthin was lowest among cancer patients, and highest among precancer patients; similar results were obtained for plasma lutein. Zeaxanthin in cancerous tissue was higher than in precancerous or non-cancerous tissue. The relevance of this relationship to cervical carcinogenesis is not known.
The association between serum antioxidant nutrients and persistent human papillomavirus (HPV) infection, an established risk factor for cervical cancer, was studied by Giuliano et al. [185] in a group of 123 low-income Hispanic women. Individual serum carotenoids including lutein were about 24% lower among women found to be HPV positive at two time points 3 mo apart, as compared with women found to be HPV negative twice or HPV positive once. In another study, persistent HPV infection was found lower among women who reported intake of lutein plus zeaxanthin in the upper 2 quartiles compared with those in the lowest quartile [186].
L. Skin Cancer
Animal studies have shown that lutein may have a protective role against light-induced skin damage. For example, Gonzalez et al. [187] reported that in hairless mice, dietary lutein plus zeaxanthin supplementation diminished the effects of ultraviolet B irradiation by reducing acute inflammatory responses and epidermal hyperproliferation. However, in humans, no evidence has been found that xanthophylls play a protective role against incident squamous cell carcinoma of the skin. Fung et al. [188] reported that data from the Nurses’ Health Study and Health Professionals Follow-up Study showed no association between dietary lutein plus zeaxanthin intake measured every 2–4 y and risk of skin cancer during 14 and 10 y follow-up, respectively. It is worth noting that only very low amounts of xanthophyll esters are present in human skin compared to the concentrations of ß-carotene and lycopene in this tissue [189].
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CORONARY HEART DISEASE AND STROKE |
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A. Coronary Heart Disease
That lutein may have a protective effect against the progression of early atherosclerosis is supported by epidemiologic data from 2 studies which related circulating xanthophylls with carotid artery intima-media thickness (IMT). In a prospective study of a random sample of 480 participants from the Los Angeles Atherosclerosis Study cohort who had no history of heart attack, angina, revascularization or stroke, Dwyer et al. [190,194] found the progression of intima-media thickness of the common carotid arteries over a period of 18 mo was close to null (0.004 mm) among those in the highest quintile of plasma lutein and zeaxanthin concentrations at baseline, whereas it was increased by 0.021 mm among those in the lowest quintile (P = 0.01). On average, for every 1 µmol/L increase of plasma lutein or zeaxanthin, IMT progression was reduced by 3.2 or 4.7 µm/18 mo, respectively [194]. Significant inverse associations of IMT progression with plasma ß-cryptoxanthin or -carotene were also observed, but not with plasma lycopene or - or 
-tocopherols [194].
In a study of 231 asymptomatic case-control pairs selected from the Atherosclerosis Risk in Communities (ARIC) study cohort, Iribarren et al. [195] reported that mean serum lutein plus zeaxanthin concentrations were lower in cases than controls (mean: 0.35 and 0.37 IU, respectively; P = 0.05). A modest inverse association was also found between serum lutein plus zeaxanthin concentrations and carotid intima-media thickness, although ambiguity may have been introduced by measurement of the xanthophylls 3 y after carotid examination.
In a nested case-control study from the Washington County, Maryland cohort (n = 25,802) in 123 persons newly diagnosed with myocardial infarction and their matched controls, Street et al. [196] found a suggestive trend of an inverse association between first myocardial infarction and serum lutein (but not zeaxanthin) in bloods collected 7 to 14 y before the onset of the disease (P-trend = 0.09). When the results were stratified by smoking status, low serum levels of both xanthophylls were associated with an increased risk of subsequent myocardial infarction among smokers, but not non-smokers.
In contrast, Osganian et al. [197] examined 12 y follow-up data from the Nurses’ Health Study cohort (n = 73,286) and found intake of lutein plus zeaxanthin was not significantly associated with risk of development of incident coronary artery disease (both nonfatal myocardial infarction and fatal coronary artery disease), regardless of smoking status. Similarly, Hak et al. [198] found no relationship between any plasma carotenoids, including lutein, and risk of myocardial infarct in a nested case-control analysis of the Physicians’ Health Study with 13 y follow-up. Sesso et al. [199] also observed no relationship between quartiles of plasma lutein plus zeaxanthin and risk of cardiovascular disease (including cardiovascular disease death, nonfatal myocardial infarction, nonfatal stroke, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, and angina pectoris) in 483 case-control pairs of participants in the Women’s Health Study during 4.8 y follow-up.
From the Brubeck Study in northern Italy, D’Odorico et al. [200] found high plasma levels of - and ß-carotene, but not lutein, zeaxanthin, or other carotenoids, were inversely associated with the prevalence of atherosclerosis in the carotid and femoral arteries and with the 5 y incidence of atherosclerotic lesions in the carotid arteries. Similarly, in a case-control subsample from the elderly population of the Rotterdam Study, Klipstein-Grobusch et al. [201] found no association between aortic atherosclerosis and serum xanthophylls in samples collected at baseline and preserved for 5.8 y from 108 subjects with moderate/severe atherosclerosis and 109 controls. A case-control and follow-up study in Spain found no significant association of risk of myocardial infarction vs. plasma lutein plus zeaxanthin measured within the first 24 h after disease onset and 1 y later [202].
Another approach to determining the relationship between xanthophylls and risk for heart disease employs measures of oxidative stress as intermediary biomarkers. In the plasma of 30 patients with congestive heart failure, Polidori et al. [203] found lutein was significantly lower and malondialdehyde, a product of lipid peroxidation, was significantly higher as compared to 55 controls. Patients with more severe congestive heart failure had lower plasma lutein and higher malondialdehyde levels compared to patients with less severe disease condition. Further, ejection fraction, evaluated by echocardiography, was inversely correlated with malondialdehyde and directly correlated with lutein plasma levels in the patients [203]. In a comparative study of 5 European countries by Wright et al. [204], fasting LDL lutein concentration was found highest in France where cardiovascular disease death rate was lowest, but no relationship was observed between total antioxidant content of LDL and ex vivo resistance of LDL to Cu2+-induced oxidation in healthy subjects from the 5 sites with different cardiovascular mortality rates. Hininger et al. [205] supplemented healthy male volunteers daily with 15 mg lutein for 3 mo and found significant increases in plasma and LDL lutein content but no change in the resistance of LDL to Cu2+-induced oxidation or modification of the LDL polyunsaturated:saturated fatty acid ratio. Similarly, no changes were found in plasma reduced or oxidized glutathione, protein-SH groups or the activities of erythrocyte antioxidant enzymes glutathione peroxidase and superoxide dismutase.
B. Stroke
Investigating the Health Professionals Follow-up Study (n = 43,738), Ascherio et al. [206] found, among men who did not have cardiovascular disease or diabetes, an inverse relation of borderline statistical significance between lutein intake at baseline and incident stroke (210 ischemic, 70 hemorrhagic, and 48 unclassified stroke) after 8 y follow-up. The RR of those in the highest vs. lowest quintile of lutein intake was 0.70 after multivariate analysis (95% CI: 0.49–1.01; P-trend = 0.06). Similarly, among the ATBC cohort (n = 26,593) of male smokers without a history of stroke, Hirvonen et al. [207] observed a significant inverse relation between intake of lutein plus zeaxanthin and risk for subarachnoid hemorrhage after 6.1 y follow-up; however, after simultaneous modeling for other dietary antioxidants (vitamins C and E, ß-carotene, lycopene, and flavonoids), the association was no longer evident. In plasma, an inverse correlation between lutein and malondialdehyde in 28 ischemic stroke patients in comparison to matched controls was found by Polidori et al. [208]. Further, lower lutein and higher malondialdehyde concentrations in plasma were observed in patients with poor early phase recoveries relative to those who were functionally stable, suggesting lutein may modulate clinical outcomes following ischemic stroke.
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CONCLUSIONS |
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While consistency of results across studies is an important criterion for demonstrating a relationship between nutrients and chronic disease, so is biological plausibility. Thus, the evidence showing the xanthophylls possess antioxidant activity, filter blue light, stabilize membranes, and bind selectively to retinal transport proteins all support a distinct role for them in the eye. While there are a limited number of animal models for AMD, principally monkeys and quail, available to test some of these hypotheses, preliminary experimental studies are beginning to suggest an inverse relationship between xanthophylls and retinal disease. Similarly, mouse models of carcinogenesis indicate that lutein can inhibit tumor incidence, growth, and latency via effects on angiogenesis and apoptosis, though further research is clearly required. Experiments testing the mechanisms of lutein and zeaxanthin during the development of atherosclerosis are still very limited, but it is promising to note these carotenoids do increase the resistance of LDL to oxidation in vitro and reduce lipid peroxidation and aortic lesions in mice. Even as the evidence for a role of lutein and zeaxanthin in disease prevention continues to evolve from basic research as well as from human studies directed to their bioavailability, metabolism, and dose-response relationships with intermediary biomarkers and clinical outcomes, it is worth noting that recommendations to consume foods rich in xanthophylls are consistent with current dietary guidelines.
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