Carotenoids are natural pigments found in plants, including fruit and vegetables, giving them their bright colour. About 600 carotenoids have been identified, of which about six appear to be used in significant ways by the blood or other tissues. About 50 have pro-vitamin A activity, and of these, all-trans beta-carotene is the most active on a weight basis and makes the most important quantitative contribution to human nutrition. Beta-carotene is fat soluble. Apart from beta-carotene, other significant carotenoids (according to research conducted so far) are alpha-carotene, astaxanthin, cryptoxanthin, lycopene, lutein and zeaxanthin.
The bioavailability of those carotenoids with pro-vitamin A activity (e.g. alpha-carotene, beta-carotene, cryptoxanthin) is less than that of retinol (preformed vitamin A).
The absorption and utilisation of carotenoids varies, but the generally accepted relationship in the UK is that 1 µg retinol is equivalent to 6 µg beta-carotene or 12 µg of other pro-vitamin A carotenoids. (Other carotenoids with pro-vitamin A activity are not converted to vitamin to the same extent as is beta-carotene.) However, the bioactivity of carotenoids in foods is now known to be less than was previously thought and there is much debate about the conversion factors. The US Food and Nutrition Board revised its conversion factors in 2001 such that 1 µg retinol is equivalent to 12 µg beta-carotene or 24 µg of other provitamin A carotenoids.
The amount of beta-carotene in dietary supplements may be expressed in terms of micrograms or International Units. One unit of beta-carotene is defined as the activity of 0.6 µg beta-carotene. Thus:
1 unit beta-carotene = 0.6 µg beta-carotene; and
1 µg beta-carotene = 1.67 units beta-carotene.
There is currently no UK Dietary Reference Value for beta-carotene (or any other carotenoids). This is because, until recently, its only role has been considered to be as a precursor of vitamin A. Some authorities are starting to make recommendations for beta-carotene, e.g. 6 mg daily (Finland); 4 mg daily (France); 2 mg daily (Germany).
In the UK, the average adult diet provides 2.28 mg (beta-carotene) daily.
Carotenoids have the following functions. They:
quench singlet oxygen and prevent the formation of free radicals. Note: natural beta-carotene (cis form) acts as an antioxidant, while the synthetic (trans) form has been suggested to be pro-oxidant;
react with or scavenge free radicals directly and thus act as an antioxidant;
enhance some aspects of immune function; and act as precursors for vitamin A (e.g. alpha-carotene, beta-carotene, cryptoxanthin).
Carotenoids are found in a wide variety of fruits and vegetables, although they may not be the ones commonly consumed. Alpha-carotene is found in palm oil, maize, carrots and pumpkin. Lycopene is concentrated in red fruits, such as tomatoes (particularly cooked and pureed tomatoes), guava, watermelon, apricots, peaches and red grapefruit. Lutein and zeaxanthin are found in dark green vegetables, red pepper and pumpkin. Cryptoxanthin is present in mangoes, oranges and peaches.
Although there are a huge number of carotenoids, most research has been conducted on beta-carotene, and less is known about the others, particularly in terms of metabolism. Hence, only the metabolism of beta-carotene is described here.
Beta-carotene consists of two molecules of vitamin A, which are hydrolysed in the gastrointestinal tract. It is absorbed into the mucosal cells of the small intestine and converted to retinol. The efficiency of absorption is usually 20–50%, but can be as low as 10% when intake is high. The conversion of beta-carotene to retinol is regulated by the vitamin A stores of the individual and by the amount ingested; conversion efficiency varies from 2:1 at low intakes to 12:1 at higher intakes. On average, 25% of absorbed beta-carotene appears to remain intact and 75% is converted to retinol.
Intact beta-carotene is transported in very-low-density lipoprotein (VLDL) or low-density lipoprotein (LDL) cholesterol. Blood levels, unlike those of retinol, are not maintained constant but vary roughly in proportion to the amounts ingested. Increased blood levels (hyper-carotenaemia) are sometimes associated (as a secondary condition) with hypothyroidism, diabetes mellitus, and hepatic and renal disease. Hypercarotenaemia can also be caused by a rare genetic inability to convert beta-carotene to vitamin A.
All carotenoids are deposited in the liver to a less extent than is vitamin A. Most are stored in the adipose tissue, epidermal and dermal layers of the skin and the adrenals; there are high levels in the corpus luteum and in colostrum.
Beta-carotene is eliminated mainly in the faeces.
Beta-carotene is not very stable, and potency is lost if it is exposed to oxygen. Mild cook-ing processes can improve bioavailability, e.g. absorption from raw carrot can be as low as 1%, but this figure increases dramatically when carrots are subject to short periods of boiling. However, overcooking reduces bioavailability. Significant losses can also occur during frying, freezing and canning.
No specific symptoms have been defined.
Carotenoids are being investigated in a variety of conditions, particularly cancer, CVD and cataract.
More than 50 epidemiological studies have demonstrated that a high intake of foods rich in carotenoids (i.e. fruit and vegetables) and high serum levels of beta-carotene are associated with reduced risk of certain cancers, especially lung cancer, but also cancers of the cervix, endometrium, breast, oesophagus, mouth and stomach.
Fruit and vegetables contain several types of carotenoids in addition to beta-carotene, and it is incorrect to assume that beta-carotene is responsible for all the preventive effects of fruit and vegetables. For example, increased alpha-carotene intakes from diet have been associated with a reduced risk of lung cancer, with suggestive inverse associations for other carotenoids also.
However, serum analysis has also shown an association between low serum beta-carotene levels and increased cancer risk, possibly indicating a more specific link. Intervention studies published so far have provided very little evidence for a beneficial effect of beta-carotene supplementation on cancer risk; indeed, some have indicated that there may be an increased risk.
Intervention trials A 12-year US study involving 22 071 male physicians randomly allocated to 50 mg beta-carotene every other day or placebo did not demonstrate any statistically significant benefit or harm from supplementation. In the beta-carotene group, 1273 subjects developed malignant neoplasms compared with 1293 in the placebo group. No serious adverse effects were noted in the study.
In a double-blind, placebo-controlled Finnish intervention trial, known as the Alpha-Tocopherol, Beta-Carotene Prevention (ATBC) Study, 29 000 male smokers were randomised to receive beta-carotene 20 mg daily, alpha-tocopherol 50 mg daily, both beta-carotene and alpha-tocopherol, or placebo. Lung cancer incidence increased in all the groups receiving beta-carotene, but the effect was stronger in those who smoked heavily, a finding consistent with the CARET study (see below). However, lung cancer incidence was not correlated with serum beta-carotene, suggesting that this was not a direct effect of beta-carotene. There was also no significant effect on incidence or mortality of cancer of the pancreas, nor on the incidence of colorectal adenomas.
Another US study (the beta-carotene and retinol efficacy trial – CARET) in 4060 subjects with substantial work-related exposure to asbestos and also 14,254 heavy smokers, showed that beta-carotene 30 mg with vitamin A 25,000 units increased the risk of lung cancer compared with placebo. Mortality was also 17% higher. As a consequence, this trial was stopped prematurely.
These unexpected results were reviewed extensively and numerous possible explanations were proposed. One possible explanation for the negative results of the human beta-carotene intervention trials is that the positive effects of beta-carotene shown in case-control studies were instead the results of other nutrients that co-vary with carotenoids and carotenoids are only one of several factors in fruits and vegetables that must be consumed together to be effective. Carotenoids could also be a marker for a generally healthy lifestyle that includes a diet low in fat and high in fruits and vegetables.
Another hypothesis is that a large dose of beta-carotene, such as was used in these trials, is metabolised differently than a smaller dietary dose, resulting in adverse effects. The idea was tested experimentally in a model of smoke-exposed, beta-carotene-treated ferrets. In the lungs of these animals, retinoid oxidative en-ymes were elevated and retinoid levels were reduced.12 This was found, in part, to be the result of enhanced oxidative excentric cleaving of beta-carotene to produce various beta-carotene metabolites (e.g. beta-apo-carotenals). How-ever, when alpha-tocopherol and ascorbic acid were added to beta-carotene in ferrets exposed to cigarette smoke, the production of beta-apo-carotenals was inhibited, while the production of retinoids was increased. When either alpha-tocopherol or vitamin C alone was added, the production of retinoids was not affected, suggesting that alpha-tocopherol and ascorbic acid may act synergistically in preventing the enhanced oxidative cleavage of beta-carotene induced by smoking exposure. A more recent study in a ferret lung cancer model indicates that combined antioxidative supplementation could be a useful chemopreventive strategy against lung carcinogenesis through maintaining tissue retinoid levels and inhibiting cell proliferation and other potentially carcinogenesis pathways in the lung.
In patients with documented cervical dysplasia given either beta-carotene 30 mg or placebo for 9 months, complete remission occurred in 23% of the supplemented group and 47% of the placebo group, showing that beta-carotene had no beneficial effect on resolution of cervical dysplasia. However, in another study there was an inverse relationship between breast cancer and beta-carotene intake in pre-menopausal women.
In a further study, beta-carotene was neither beneficial nor harmful in reducing the risk of developing skin cancer. A total of 1621 subjects aged 20 to 69 were randomised into four groups – beta-carotene and sunscreen, sunscreen and placebo, beta-carotene and no sunscreen, and no sunscreen and placebo. Sunscreen was applied daily to all exposed areas of the head, neck, arms and hands, with re-application after swimming or increased perspiration. No dosing details were given for beta-carotene. At the end of the study, there were no statistically significant differences in development of basal or squamous cell carcinoma between the beta-carotene and placebo groups. A lack of effect of beta-carotene supplementation in non-melanoma skin cancer was observed among men with low baseline plasma beta-carotene.
More recent trials continue to show mixed results with beta-carotene alone. One RCT in 264 patients who had been treated for a recent early-stage squamous cell carcinoma of the oral cavity, pharynx or larynx found that beta-carotene 50 mg daily had no significant effect on second cancers of the head and neck (RR 0.69; 5% CI, 0.39 to 1.25) or lung cancer (RR 1.44; 5% CI, 0.62 to 3.39) and total mortality was not affected. However, in this study the point estimates suggested a possible decrease in second head and neck cancer risk but a possible increase in lung cancer risk. In a further trial involving patients treated for head and neck cancer, beta-carotene (75 mg daily) had no significant effect on the incidence of second primary tumours, but there was a statistically non-significant 40% reduction in the risk of death among subjects assigned to beta-carotene and no increase in death from CVD.20 In patients with early-stage head and neck cancer, supplemental beta-carotene did not have pro-oxidant effects in either smokers or non-smokers.
Beta-carotene has been shown in one RCT to be protective of colorectal adenoma recurrence among subjects who neither smoked cigarettes nor drank alcohol. A total of 864 subjects who had had an adenoma removed and were polyp-free were randomised to receive beta-carotene (25 mg) and/or vitamins C and E in combination (1000 mg and 400 mg, respectively) or placebo. They were followed at 1 and 4 years for adenoma recurrence. Among subjects who did not smoke or drink, beta-carotene was associated with a marked decrease in risk of one or more recurrent adenomas (RR 0.56, 95% CI, 0.35 to 0.89), but beta-carotene supplementation conferred a modest increase in the risk of recurrence in those who smoked or drank. For people who smoked and drank more than one alcoholic drink a day, beta-carotene doubled the risk of adenoma recurrence, suggesting that both alcohol and smoking modify the effect of beta-carotene supplementation on the risk of colorectal adenoma recurrence. Vitamin A and alpha-carotene have also been found to protect against recurrence of adenomatous polyps in non-smokers and non-drinkers.
Diets rich in fruit and vegetables are generally associated with a lower risk of CVD, but evidence for a direct protective effect of beta-carotene was reported from the US Physicians’ Health Study.23 In an analysis of a subgroup of volunteers who had previously had stable angina or coronary revascularisation, 50 mg beta-carotene on alternate days reduced subsequent coronary events by 50% compared with placebo.
However, in a large placebo-controlled trial involving men between 50 and 69 who smoked five or more cigarettes a day, supplementation with beta-carotene was not helpful in angina pectoris and may have slightly increased the incidence of the condition. In this study, 5602 patients received beta-carotene 20 mg daily, 5570 patients received alpha-tocopherol 50 mg daily, 5548 patients received alpha-tocopherol 50 mg and beta-carotene 20 mg daily, and 5549 received placebo. Follow-up continued for a maximum of 7 years. Patients taking vitamin E alone or in combination with beta-carotene showed a minor decrease in angina pectoris, but beta-carotene alone was associated with a slight increase in angina incidence.
Incidence of myocardial infarction was not reduced by beta-carotene supplementation (50 mg daily) in US male physicians. Beta-carotene was not effective in the treatment of increased serum triglycerides or cholesterol levels, and was not shown to reduce the risk of stroke.
A meta-analysis that looked at the effect of antioxidant vitamins on long-term cardiovascular outcomes included 12 RCTs, of which eight involved beta-carotene.28 Beta-carotene was associated with a slight statistically significant increase in all-cause mortality and cardiovascular death compared with the control. The authors concluded that the use of supplements containing beta-carotene should be actively discouraged.
Beta-carotene may protect against cataract formation. In a retrospective study,29 the group with the lowest serum beta-carotene levels had over five times the risk of developing cataract as the group with the highest serum levels. Two RCTs have evaluated the influence of beta-carotene supplements in age-related cataract. In the US Physicians’ Health Study, 22 071 men aged 40–84 were randomly assigned to receive either beta-carotene 50 mg on alternate days or placebo for 12 years. There was no difference between the beta-carotene and placebo groups in the overall incidence of cataract, relative risk or cataract extraction. In smokers, however, beta-carotene appeared to attenuate excess risk of cataract by about 25%.30 In the Women’s Health Study, 39 867 female health professionals aged 45 or older were randomised to receive beta-carotene 50 mg on alternate days, vitamin E and aspirin for the prevention of cancer and CVD. The beta-carotene arm was terminated early and the main outcome measures were visually significant cataract and cataract extraction. However, 2 years of beta-carotene treatment had no large beneficial (or harmful) effect on the development of cataract.
Serum beta-carotene levels may be reduced in diabetic patients, and one case-control study has shown a negative correlation between beta-carotene and glycaemic control.32 However, in the US Physicians’ Health Study, beta-carotene supplementation (50 mg daily) was ineffective in reducing the risk of developing type 2 diabetes.
Data on beta-carotene’s influence on the immune system are conflicting. One study showed that supplementation (beta-carotene 15 mg daily for 26 days) resulted in a significant increase in the proportion of monocytes involved in initiating immune responses.How-ever, in other studies, T-cell immunity was un-affected by beta-carotene supplementation.
Lutein is a carotenoid found in high concentrations in the eye, where it filters out blue light, and it may have a protective role in the visual apparatus and its vascular supply. There is evidence that lutein may help to prevent ARMD and cataracts. Supplements may also help to improve visual function in patients with retinal degeneration.
A study in Miami tested the effects of 30 mg of lutein on eye pigment in two people for a period of 140 days. The results showed that 20–40 days after starting the lutein supplement, the density of the pigment in the subject’s eyes started to increase. The amount of blue light reaching the photoreceptors, Bruch’s membrane and the retinal pigment epithelium (vulnerable eye tissues affected in macular degeneration) was reduced by 30–40%. Another carotenoid, lycopene, appears to confer protection against oxidative changes in the epithelial cells of the lens.
Dietary intake of lutein and its isomer zeaxanthin may reduce the risk of developing both cataract and macular degeneration. In the US Nurses’ Health Study, those in the highest quintile for consumption of lutein and zeaxanthin had a 22% reduced risk of cataract extraction compared with those in the lowest quintile. In the US Physicians’ Health Study, those in the highest quintile for lutein and zeaxanthin intake had a 19% reduction in risk for cataract extraction when smoking, age, and other risk factors were controlled for. Other carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene) were not associated with a reduced risk of cataract.
Similarly, in the US Beaver Dam Eye Study, lutein and zeaxanthin were the only carotenoids of those examined associated with reduction in cataracts – in this case, nuclear cataracts. People in the highest quintile of lutein intake in the distant past were half as likely to have an incidence of cataract as those in the lowest quintile. As part of the same study, 252 subjects were followed over a 5-year period. Only a trend towards an inverse relationship between serum lutein and cryptoxanthin and risk of cataract development was noted.
In a UK cross-sectional survey, the risk of posterior subscapular cataract was lowest in those with higher plasma concentrations of lutein and the risk of cortical cataract was lowest in people with the highest plasma concentrations of lycopene. However, the risk of nuclear cataract was lowest in people with the highest plasma concentrations of alpha- or beta-carotene.
In the first published intervention trial involving lutein, 17 patients with age-related cataracts were randomised in a double-blind study involving dietary supplementation with lutein 15 mg, alpha-tocopherol 100 mg or placebo three times a week for up to 2 years. Visual performance (visual acuity and glare sensitivity) improved in the lutein group but not with alpha-tocopherol or placebo.
The second trial was a 21-month randomised, double-masked, placebo-controlled trial that involved 90 patients with atrophic ARMD. One group of patients received lutein 10 mg daily, another group received lutein 10 mg with antioxidants and vitamins and min-erals while the third group received a placebo. Visual function (as measured by macular pigment optical density, Snellen equivalent visual acuity and contrast sensitivity) improved with both lutein alone and lutein together with the other nutrients compared with placebo.47 The authors concluded that lutein or lutein together with antioxidant vitamins was not a cure for ARMD but could reverse various symptoms of the condition and improve visual function.
Lycopene is a carotenoid pigment that functions as a free radical scavenger and antioxidant. Supplementation has been reported to protect against macular degeneration, athero-sclerosis, and cancer, especially prostate cancer.
Intervention trials have begun to evaluate the effects of lycopene supplements in prostate cancer. In a pilot trial, 26 men with newly diagnosed, clinically localised prostate cancer were randomised to receive 15 mg of lycopene twice daily or no supplementation for 3 weeks before radical prostatectomy. The results suggested that lycopene supplementation may reduce the growth of prostate cancer, but the authors emphasised that no firm conclusions could be reached because of the small sample size.
The same research group conducted a further pilot trial involving the use of a tomato extract containing 30 mg lycopene each day in 26 men – again for 3 weeks before radical prostatectomy. After intervention, subjects in the intervention group had smaller tumours, less involvement of extra-prostatic tissue with cancer and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia. Mean prostate-specific antigen (PSA) was lower in the intervention group than the placebo group. The authors concluded that this pilot study suggests that lycopene may have beneficial effects in prostate cancer, although large trials are warranted to investigate the potential preventive and/or therapeutic role of lycopene in the disease.
In another trial, 54 men with prostate cancer were assigned to receive orchidectomy alone or orchidectomy plus lycopene (2 mg twice daily). At 6 months there was a significant reduction in PSA in both treatment arms, but this was more marked in the lycopene group. This change was more consistent after 2 years. Adding lycopene to orchidectomy produced a more reliable and consistent reduction in PSA, shrinking the primary tumour, diminishing secondary tumours, providing better relief from bone pain and lower urinary tract symptoms and improving survival compared with orchidectomy alone. A further trial using a supplement containing lycopene, isoflavones, silymarin and antioxidants found that this supplement delayed PSA progression after potentially curative treatment (radical prostatectomy).
A meta-analysis of 11 case-control studies and 10 cohort studies or nested case-control studies involving tomato, tomato products or lycopene concluded that tomato products may play a role in the prevention of prostate cancer, but the effect is small.
No serious problems have been reported. Supplements should be avoided by people with known hypersensitivity to carotenoids.
Pregnancy and breast-feeding
No problems have been reported.
Unlike retinol, carotenoids are generally non-toxic. Even when ingested in large amounts, they are not known to cause birth defects or to cause hypervitaminosis A, primarily because efficiency of absorption decreases rapidly as the dose increases and because conversion to vitamin A is not sufficiently rapid to induce toxicity.
Intake of >30 mg daily (either from commercial supplements or tomato or carrot juice) may lead to hypercarotenaemia, which is characterised by a yellowish coloration of the skin (including the palms of the hands and soles of the feet), and a very high concentration of carotenoids in the plasma. This is harmless and reversible and gradually disappears when excessive intake of carotenoids is corrected.
Hypercarotenaemia is clearly differentiated from jaundice by the appearance of the whites of the eyes (yellow in hypercarotenaemia but not in jaundice).
Diarrhoea, dizziness and arthralgia may occur occasionally with carotene supplements. Allergic reactions (hay fever and facial swelling), amenorrhoea and leucopenia have been reported rarely.
According to FAO/WHO, intakes up to 5 mg beta-carotene/kg body weight are acceptable.
The only serious toxic manifestation of carotenoid intake is canthaxanthin retinopathy, which can develop in patients with erythropoietic protoporphyria and related disorders who are treated with large daily doses (50–100 mg) of canthaxanthin (a derivative of beta-carotene) for long periods.
None specifically established (see also Vitamin A).
Beta-carotene, lutein, lycopene and mixed carotenoids are available in the form of tablets and capsules.
Beta-carotene as a single supplement should not be recommended.
Diets rich in carotenoids are protective against various conditions, particularly cancer and CVD. However, evidence that beta-carotene supplements are bene-icial for this purpose is lacking. Other carotenoids, such as lycopene and lutein, are now being studied. Preliminary evidence suggests that lutein may be protective in cataract and macular degeneration, while lycopene may be protective against macular degeneration and prostate cancer.
Levin G, Yeshurun M, Mockady S. In vitro antiper-oxidative effect of 9-cis beta-carotene compared with that of the all-trans isomer. J Nutr Cancer 1997; 27: 293–297.
Gaby SK, Singh VN. Betacarotene. In: Gaby SK, Bendich A, Singh VN, Machlin LJ, eds. Vitamin Intake and Health. A Scientific Review. New York: Marcel Dekker, 1991: 89–106.
Michaud DS, Feskanich D, Rimm EB, et al. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. Am J Clin Nutr 2000; 72: 990–997.
Knekt P, Jarvinen R, Tempo, et al. Role of various carotenoids in lung cancer prevention. J Natl Cancer Inst 1999; 91: 182–184.
Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long-term supplementation with beta-carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996; 334: 1145–1149.
The Alpha-Tocopherol, Beta-Carotene Cancer Pre-vention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer in male smokers. N Engl J Med 1994; 330: 1029–1035.
Albanes E, Heinonen OP, Taylor PR, et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996; 88: 1560–1570.
Rautalahti MT, Virtamo JRK, Taylor PR, et al. The effects of supplementation with alpha-tocopherol and beta-carotene on the incidence and mortality of carcinoma of the pancreas in a randomised, controlled trial. Cancer 1999; 86: 37–42.
Maliula N, Virtamo J, Virtanen M, et al. The effect of alpha-tocopherol and β-carotene supplementation on colorectal adenomas in middle-aged male smokers. Cancer Epidemiol Biomarkers Prev 1999; 8: 489–493.
Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of betacarotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996; 334: 1150–1155.
Mayne ST. Antioxidant nutrients and chronic dis-ease: use of biomarkers of exposure and oxidative stress status in epidemiologic research. J Nutr 2003; 33 (Suppl.): S933–940.
Liu C, Russell RM, Wang XD. Exposing ferrets to cigarette smoke and a pharmacological dose of β – carotene supplementation enhance in vitro retinoic acid catabolism in lungs via induction of cytochrome P450 enzymes. J Nutr 2003; 133: 173–179.
Liu C, Russell RM, Wang XD. Alpha-tocopherol and ascorbic acid decrease the production of beta-apo-carotenals and increase the formation of retinoids from β-carotene in the lung tissues of cigarette smoke-exposed ferrets in vitro. J Nutr 2004; 134: 426–430.
Kim Y, Chongviriyaphan N, Liu C, et al. Combined antioxidant (beta-carotene, alpha-tocopherol and ascorbic acid) supplementation increases the levels of lung retinoic acid and inhibits the activation of mitogen-activated protein kinase in the ferret lung cancer model. Carcinogenesis 2006; 27: 1410–1419.
Romney SL, Ho GYF, Palan PR, et al. Effects of betacarotene and other factors on outcome of cervical dysplasia and human papillomavirus infection. Gynecol Oncol 1997; 65: 483–492.
Bohlke K, Spiegelman D, Trichopoulou A, et al. Vitamins A, C and E and the risk of breast cancer: results from a case control study in Greece. Br J Cancer 1999; 79: 23–29.
Green A, Williams G, Neale R, et al. Daily sunscreen application and betacarotene supplementation in prevention of basal cell and squamous cell carcino-mas of the skin. Lancet 1999; 354: 723–729.
Schaumberg DA, Frieling UM, Rifai N, Cook N. No effect of beta-carotene supplementation on risk of nonmelanoma skin cancer among men with low baseline plasma beta-carotene. Cancer Epidemiol Biomarkers Prev 2004; 6: 1079–1080.
Mayne ST, Cartmel B, Baum M, et al. Randomized trial of supplemental beta-carotene to prevent second head and neck cancer. Cancer Res 2001; 61: 1457–1463.
Toma S, Bonelli L, Sartoris A, et al. Beta-carotene supplementation in patients radically treated for stage I–II head and neck cancer: results of a randomized trial. Oncol Rep 2003; 10: 1895–1901.
Mayne ST, Walter M, Cartmel B, et al. Supplemental bete-carotene, smoking, and urinary F2-isoprostane excretion in patients with prior early stage head and neck cancer. Nutr Cancer 2004; 49: 1–6.
Baron JA, Cole BF, Mott L, et al. Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma recurrence: results of a randomized trial. J Natl Cancer Inst 2003; 95: 717–722.
Steck-Stott S, Forman MR, Sowell A, et al. Carotenoids, vitamin A and risk of adenomatous polyp recurrence in the polyp prevention trial. Int J Cancer 2004; 112: 295–305.
Gaziano JM, Manson JE, Ridker PM, et al. Beta-carotene supplementation for chronic stable angina. Circulation 1990; 82 (Suppl. III): 201 (abstract 0796).
Rapola JM, Virtamo J, Haukka JK, et al. Effect of vitamin E and betacarotene on the incidence of angina pectoris: a randomized, double-blind, controlled trial. JAMA 1996; 275: 693–698.
Redlich C, Chung J, Cullen M, et al. Effect of long-term betacarotene and vitamin A on serum cholesterol and triglycerides among participants in the carotene and retinol efficacy trial (CARET). Atherosclerosis 1999; 145: 425–432.
Ascherio A, Rimm E, Hernan MA, et al. Rela-tion 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.
Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomized trials. Lancet 2003; 361: 2017–2023.
Jacques PF, Hartz SC, Chylack LT, et al. Nutritional status in persons with and without senile cataract: blood vitamin and mineral levels. Am J Clin Nutr 1988; 48: 152–158.
Christen WG, Manson JE, Glynn RJ, et al. A randomized trial of beta carotene and age-related cataract in US physicians. Arch Ophthalmol 2003; 121: 372–378.
Christen W, Glynn R, Sperduto R, et al. Age-related cataract in a randomized trial of beta-carotene in women. Ophthalmic Epidemiol 2004; 11: 401–412.
Abahusain MA, Wright J, Dickerson JWT, et al. Retinol, alpha-tocopherol and carotenoids in dia-betes. Eur J Clin Nutr 1999; 53: 630–635.
Liu S, Ajanu U, Chae C, et al. Long-term β-carotene supplementation and risk of type 2 diabetes mellitus. JAMA 1999; 282: 1073–1075.
Hughes DA, Wright AJA, Finglas PM, et al. The effect of beta-carotene supplementation on the im-mune function of blood monocytes from healthy male non-smokers. J Lab Clin Med 1997; 129: 309–317.
Santos MS, Leka LS, Ribaya-Mercado D, et al. Short and long-term beta-carotene supplementation do not influence T cell-mediated immunity in healthy elderly persons. Am J Clin Nutr 1997; 66: 917–924.
Hammond BR Jr, Johnson EJ, Russell RM, et al. Dietary modification of human macular pigment density. Invest Ophthalmol Vis Sci 1997; 38: 1795–1801.
Lyle BJ, Mares-Perlman JA, Klein BE, et al. Antioxidant intake and risk of incident age related nuclear cataracts in the Beaver Dam Eye Study. Am J Epidemiol 1999; 149: 801–809.
Dagnelie G, Zorge IS, McDonald TM. Lutein improves visual function in some patients with retinal degeneration: a pilot study via the Internet. Optometry 2000; 7: 147–164.
Landrum JT, Bone RA, Joa H, et al. A one year study of the macular pigment: the effect of 140 days of a lutein supplement. Exp Eye Res 1997; 65: 57–62.
Mohanty I, Joshi S, Trivedi D, et al. Lycopene prevents sugar-induced morphological changes and modulates antioxidant status of human lens epi-thelial cells. Br J Nutr 2002; 88: 347–354.
Mares-Perlman JA, Millen AE, Ficek TL, Hankinson SE. The body of evidence to support a protective role for lutein and zeaxanthin in delaying chronic disease. J Nutr 2002; 132 (Suppl.): S518–524.
Chasan-Taber L, Willett WC, Seddon JM, et al. A prospective study of carotenoid and vitamin A status and risk of cataract extraction in US women. Am J Clin Nutr 1999; 70: 509–516.
Brown L, Rimm EB, Seddon JM, et al. A prospective study of carotenoid extraction in US men. Am J Clin Nutr 1999; 70: 517–524.
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.
Gale CR, Hall NF, Phillips DIW, Martyn C. Plasma antioxidant vitamins and carotenoids and age-related cataract. Ophthalmology 2001; 108: 1992– 1998.
Olmedilla B, Granado F, Blanco I, Vaquero M. Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study. Nutrition 2003; 19: 21–4.
Richer S, Stiles W, Statuke L, et al. Double-masked, placebo-controlled, randomized trial of lutein anti-oxidant supplementation in the intervention of atrophic age-related macular degeneration: the Vet-erans LAST study (Lutein Antioxidant Supplemen-tation Trial). Optometry 2004; 75: 216–230.
Mares-Perlman JA, Brady WE, Klein R, et al. Serum antioxidants and age related macular degeneration in a population-based case-control study. Arch Oph-thalmol 1995; 113: 1518–1523.
Agarwal S, Rao AV. Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids 1998; 33: 981–984.
Giovanucci E. Tomatoes, tomato-based products, lycopene and cancer. Review of the epidemiologic literature. J Natl Cancer Inst 1999; 91: 317–331.
Gann PH, Ma J, Giovannucci E, et al. Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Cancer Res 1999; 59: 1225–1230.
Kucuk O, Sarkar FH, Sakr W, et al. Phase II randomized clinical trial of lycopene supplementa-tion before radical prostatectomy. Cancer Epidemiol Biomarkers Prev 2001; 8: 861–868.
Kucuk O, Sarkar FH, Djuric Z, et al. Effects of lycopene supplementation in patients with local-ized prostate cancer. Exp Biol Med 2002; 227: 881–885.
Ansari MS, Gupta NP. A comparison of lycopene and orchidectomy vs orchidectomy alone in the management of advanced prostate cancer. BJU Int 2003; 92: 375–378.
Schroder FH, Roobol MJ, Boeve ER, et al. Random-ized, double-blind, placebo-controlled crossover study in men with prostate cancer and rising PSA: effectiveness of a dietary supplement. Eur Urol 2005; 48: 922–930.
Etminan M, Takkouche B, Caamano-Isorna F. The role of tomato products and lycopene in the prevention of prostate cancer: a meta-analysis of observational studies. Cancer Epidemiol Biomarkers Prev 2004; 3: 340–345.