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ß-Carotene and Other Carotenoids as Antioxidants

Jean Mayer United States Department of Agriculture, Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts (R.M.R.)
Faculdade de Medicina de Botucatu, Universidade Estadual Paulista (UNESP), São Paulo, BRAZIL (S.A.R.P.)

Address reprint requests to: Sudhir K. Dutta, M.D., Sinai Hospital of Baltimore, 2435 W. Belvedere Avenue, Baltimore, MD 21215.

	ABSTRACT

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Carotenoids are natural pigments which are synthesized by plants and are responsible for the bright colors of various fruits and vegetables. There are several dozen carotenoids in the foods that we eat, and most of these carotenoids have antioxidant activity. ß-carotene has been best studied since, in most countries it is the most common carotenoid in fruits and vegetables. However, in the U.S., lycopene from tomatoes now is consumed in approximately the same amount as ß-carotene. Antioxidants (including carotenoids) have been studied for their ability to prevent chronic disease. ß-carotene and others carotenoids have antioxidant properties in vitro and in animal models. Mixtures of carotenoids or associations with others antioxidants (e.g. vitamin E) can increase their activity against free radicals. The use of animals models for studying carotenoids is limited since most of the animals do not absorb or metabolize carotenoids similarly to humans.

Epidemiologic studies have shown an inverse relationship between presence of various cancers and dietary carotenoids or blood carotenoid levels. However, three out of four intervention trials using high dose ß-carotene supplements did not show protective effects against cancer or cardiovascular disease. Rather, the high risk population (smokers and asbestos workers) in these intervention trials showed an increase in cancer and angina cases. It appears that carotenoids (including ß-carotene) can promote health when taken at dietary levels, but may have adverse effects when taken in high dose by subjects who smoke or who have been exposed to asbestos. It will be the task of ongoing and future studies to define the populations that can benefit from carotenoids and to define the proper doses, lengths of treatment, and whether mixtures, rather than single carotenoids (e.g. ß-carotene) are more advantageous.

Key words: carotenoids, ß-carotene, antioxidants, oxidative stress, retinol

Key teaching points:

• Many different types of carotenoids, including Lycopene and Xanthophylls, are synthesized by plants and microorganisms.

• The biological mechanism of action of carotenoids remains uncertain, but possibilities include:

1. Provitamin A activity,
   
2. Modulation of Lipoxygenase activity
   
3. Antioxidant property
   
4. Activation of certain gene responsible cell to cell communication.
   

• Antioxidant activity of carotenoids is based on their singlet oxygen quenching properties.

• Bioavailability of carotenoids is dependent on food source, dietary factors, food particle size and the location of the carotenoid in chloroplast.

• A large body of epidemiological studies consistently reveal an inverse relationship between high dietary intake of carotenoids and cancer of upper gastrointestinal tract as well as pulmonary system.

	BIOCHEMISTRY AND PHYSIOLOGY

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Carotenoids are natural pigments synthesized by plants and microorganisms, but not by animals. Carotenoids are classified as follows: 1) Carotenoid hydrocarbons are known as carotenes and contain specific end groups. Lycopenes have two acyclic end groups. ß-Carotene has two cyclohexene type end groups. 2) Oxygenated carotenoids are known as xanthophyls. Examples of these compounds are a zeaxanthin and lutein (hydroxy), b) spirilloxanthin (methoxy), c) echinenone (oxo), and d) antheraxanthin (epoxy) [1].

The biosynthetic sequence of the carotenoids in plants is as follows: phytoenephytofluene-caroteneneurosporene lycopene-carotene and ß-carotene. Each enzymatic step from phytoene to lycopene adds one double bound to the molecule, resulting in lycopene, which is a symmetrical molecule containing 13 double bonds. The biosynthetic step after lycopene involves enzymatic cyclization of the end groups, which results in -carotene (one beta ring) and ß-carotene (two beta rings). The addition of oxygen to the molecule leads to the formation of xanthophylls [1].

The concentration of each carotenoid in a fruit or vegetable suggests which enzyme or enzymes may be rate-limiting in the biosynthetic cascade. For example a very high concentration of lycopene in red tomatoes suggests a lack of sufficient enzyme activity to convert lycopene to -carotene (i.e. insufficient cyclase activity) [2].

Of the over 600 carotenoids found in nature, about 40 are present in a typical human diet. Of these carotenoids, only 14 and some of their metabolites have been identified in blood and tissues [3]. Many epidemiologic studies have associated high carotenoid intake with a decrease in the incidence of chronic disease. However, the biological mechanisms for such protection are currently unclear. Multiple possibilities exist: certain carotenoids 1) can be converted to retinoids (i.e. have provitamin A activity), 2) can modulate the enzymatic activities of lipoxygenases (proinflammatory and immunomodulatory molecules), 3) can have antioxidants properties which are well above what is seen with vitamin A, 4) can activate the expression of genes which encode the message for production of a protein, connexin 43, which is an integral component of the gap junctions required for cell to cell communication. Such gene activation is not associated with antioxidant capacity and is independent of pro-vitamin A activity [4]. On the other hand, it should be recognized that carotenoids in the epidemiologic studies might have been serving as markers for other protective factors in fruits and vegetables, but were not acting as effective agents themselves.

Stimulation of gap junctional communication has beensuggested as a possible biochemical mechanism underlying the cancer-preventive activity of carotenoids. It appears that the presence of a six-membered ring substituent at the end of the conjugated system of double bonds is required for the stimulatory effect; five-membered ring carotenoids are less active. However, there is increasing evidence that oxidation products of carotenoids, especially retinoic acid analogs, significantly contribute to this biological property [5].

The antioxidant actions of carotenoids are based on their singlet oxygen quenching properties and their ability to trap peroxyl radicals [6]. The best documented antioxidant action of carotenoids is their ability to quench singlet oxygen. This results in an excited carotenoid, which has the ability to dissipate newly acquired energy through a series of rotational and vibrational interactions with the solvent, thus regenerating the original unexcited carotenoid, which can be reused for further cycles of singlet oxygen quenching. The quenching activity of a carotenoid mainly depends on the number of conjugated double bonds of the molecule and is influenced to a lesser extent by carotenoid end groups (cyclic or acyclic) or the nature of substituents in carotenoids containing cyclic end groups. Lycopene (eleven conjugated and two nonconjugated double bonds) is among the most efficient singlet oxygen quenchers of the natural carotenoids [7]. The prevention of lipid peroxidation by carotenoids has been suggested to be mainly via singlet oxygen quenching [6].

ß-Carotene is also scavenger of peroxyl radicals, especially at low oxygen tension [8]. This activity may be also exhibited by others carotenoids. The interaction of carotenoids with peroxyl radicals may proceed via an unstable ß-carotene radical adduct [8,9]. Carotenoid adduct radicals have been shown to be highly resonance stabilized and are predicted to be relatively unreactive. They may further undergo decay to generate non-radical products and may terminate radical reactions by binding to the attacking free radicals [9]. Carotenoids act as antioxidants by reacting more rapidly with peroxyl radicals than do unsatured acyl chains. In this process, carotenoids are destroyed [10].

	AVAILABILITY IN DIFFERENTFOOD PRODUCTS

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Carotenoids are found in colored fruits and vegetables. Apricots, cantaloupe, carrots, pumpkin and sweet potato are sources of -carotene and ß-carotene; pink grapefruit, tomatoes and watermelon are sources of lycopene, -carotene, ß-carotene, phytofluene and phytoene. Mango, papaya, peaches, prunes, squash and oranges are sources of lutein, zeaxanthin, - and ß-cryptoxanthin, -, ß- and -carotene, phytofluene and phytoene, whereas green fruits and vegetables such as green beans, broccoli, brussel sprouts, cabbage, kale, kiwi, lettuce, peas and spinach are sources of lutein, zeaxanthin, - and ß-carotene. Carotenoid concentrations in fruits and vegetables vary with plant variety, degree of ripeness, time of harvest, and growing and storage conditions [11].

Bioavailability of carotenoids (bioavailability, as used here, relates to the intestinal uptake and passage of a compound into the systemic circulation) is influenced by several factors such as characteristics of the food source, interactions with other dietary factors and various subject characteristics. Small particle size (e.g. pureeing), the location of the carotenoid in the plant (chloroplasts or chromoplasts) and the presence of factors that interfere with the proper micelle formation (e.g. pectin) are among some factors that can alter carotenoid uptake and absorption [12,13]. For example, Giovannucci et al. found consumption of tomato sauce, but not of fresh tomatoes or tomato juice, to be the strongest predictor for high serum lycopene concentration [14]. The uptake of lycopene was found to be greater from heated tomato juice than from unprocessed tomato juice, perhaps due to thermal rupture of cell walls and by the enhancement of the extraction of lycopene into the oily medium by heat. Cooking, chopping and pureeing vegetables can result in smaller partical size and plant cell disruption, so that the carotenoids become more available in the intestinal lumen for absorption [15]. Little or no degradation of carotenoids occurs during thermal processing, except for epoxy carotenoids, which are somewhat sensitive to heat treatment [16].

In nature, carotenoids are predominantly present in the all-trans configuration. However, processing fruits and vegetables produces a 10% to 39% increase in cis-isomers [11]. The degree of isomerization is directly correlated with the intensity and duration of the heating process [13]. However, when Rock et al. [13] fed processed vegetables to subjects, no increase in 9-cis-ß-carotene plasma concentrations was observed. Rather, the plasma response was characterized by an increase of all-trans-ß-carotene, due to isomerization of cis isomers to all-trans-ß-carotene or a rapid tissue uptake.

	CELLULAR AND MOLECULAR STUDIES ON THE POTENTIAL PREVENTIVE ACTION IN HEART DISEASE AND CARCINOGENESIS

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A number of studies have shown that ß-carotene and others carotenoids have lipid-soluble antioxidant activity. In homogeneous lipid solutions, in membrane models and also in intact cells, ß-carotene has been studied mostly, and it is a less effective antioxidant than -tocopherol [10]. Other carotenoids have different reactivity to oxygen species. However, carotenoids that show a similar protective ability and reactivity in solution (e.g. ß-carotene and zeaxanthin) differ in their ability to protect liposomes against lipid peroxidation [10]. These findings suggest that the position and orientation of the carotenoids in the membrane are important factors in determining their relative effectiveness in protecting against free radicals.

Carotenoids partially or completely protect intact cells (e.g. human liver cell line HepG2) against oxidant-induced lipid peroxidation, and the protective effect is independent of provitamin A activity [17]. Further, in both normal and transformed thymocytes, ß-carotene acted as an antioxidant at 150 mm Hg pO₂, inhibiting radical-induced lipid peroxidation. However, upon increasing the pO₂ to 760 mmHg, ß-carotene lost its antioxidant activity in normal thymocytes and actually exhibited a dose-dependent prooxidant effect in the tumor thymocytes [18]. These data point out a key role of the oxygen tension on the antioxidant/prooxidant effects of ß-carotene [8]. High carotenoid concentrations may also result in a prooxidative effect, which may be modified by interactions with other nutrients [19]. Palozza et al. [20], using in vitro studies, showed that the prooxidant effect of ß-carotene was completely prevented by the addition of -tocopherol.

Oxidative modification of low density lipoprotein (LDL), which is thought to be a key step in early atherosclerosis, is protected by the lipoprotein-associated antioxidants. LDL contains 1 carotenoid and 12 -tocopherol molecules per LDL particle, a relatively small number compared with 2300 molecules of oxidizable lipid in each LDL particle [21]. Some antioxidant supplements, such as -tocopherol consistently appear to enhance the ability of LDL to resist oxidative stress [22,23], whereas ß-carotene shows less consistent protective ability [19,24]. For example, Gaziano et al. observed that high dose ß-carotene supplementation in vivo resulted in an increased susceptibility of LDL to oxidation [19]. In contrast, Lin et al. showed that depletion of ß-carotene in healthy women increased the susceptibility of LDL to oxidation, whereas a normal intake provided protection to LDL [25]. Moreover, upon supplementing LDL particles with several carotenoids in vitro, Romanchick et al. observed that ß-carotene was unique among the carotenoids studied in having a small, but significant effect on protecting LDL against oxidation [26]. Mixtures of carotenoids have been found to be more effective than any one single carotenoid in protecting liposomes against lipid peroxidation, and this synergistic effect is most pronounced if lycopene or lutein is present in the mixture [27]. It is possible that ß-carotene and -tocopherol act cooperatively as antioxidants in membranes and lipoproteins.

In summary, ß-carotene and other carotenoids have antioxidant properties, which are variable depending on the system being used to study them. The antioxidant activity of these compounds can shift into a prooxidant activity depending on such factors as oxygen tension or carotenoid concentrations. Mixtures of carotenoids or associations with others antioxidants (e.g. vitamin E) can increase their ability to protect against lipid peroxidation.

	RELEVANT ANIMAL DATA ONTHE POTENTIAL PREVENTIVE ACTION IN HEART DISEASEAND CARCINOGENESIS

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That carotenoids can function as antioxidants in vivo has been reported in animal models in which the pigments have been injected or added directly to the diet [28]. Like humans, ferrets, Mongolian gerbils and preruminant calves absorb intact ß-carotene [29]. Rodents, generally, have poor carotenoid absorption (their intestines efficiently convert some carotenoids to retinol) [30]. Rodents only accumulate carotenoids in tissues when they are provided in the diet at supraphysiological levels.

Ultraviolet A irradiation, injection of carbon tetrachloride or consumption of an oxidized oil have been used to promote lipid peroxidation in vivo in mice and rats. In these studies, ß-carotene suppressed lipid peroxidation in mouse and rat tissues [31–33]. Recently, Levin et al. showed that 9-cis-ß-carotene is a more efficient antioxidant than the all-trans form in weanling female rats [33].

However, many questions remain. For example, Shaish et al. showed that probucol (a strong antioxidant) protected LDL from oxidation in vitro and inhibited atherosclerotic lesion formation in the aortas of hypercholesterolemic rabbits. In contrast, tocopherol modestly inhibited LDL oxidation, but did not prevent atherosclerosis. While ß-carotene had no effect on LDL oxidation ex vivo, the all-trans isomer inhibited atherosclerotic lesion formation to the same degree as probucol. These results suggest that metabolites derived from all-trans-ß-carotene can inhibit atherosclerosis in rabbits on high cholesterol diets [34], but the mechanism may not be by antioxidation.

Animal models have also been used to study the effect of carotenoids in cancer prevention. For example, Conaway et al. showed that ß-carotene treatment did not inhibit a total tumor formation in the lungs of female A/J mice treated with the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [35]. However, high doses of ß-carotene significantly retarded the malignant progression. Lycopene exerted a chemopreventive effect in lung carcinogenesis when given in the post-initiation stage to B6C3F1 mice treated with diethylnitrosamine, N-methyl-N-nitrosourea and 1,2-dimethylhydrazine [36]. Also, the initiation and progression of 7,12-dimethyl-benz[a]anthracene-induced rat mammary tumors were suppressed by lycopene-enriched tomato oleoresin, but not with ß-carotene [37]. In another study, lycopene was shown to protect efficiently against mammary tumorigenesis in a strain of mice that has a high predisposition for developing mammary tumors [38].

However, some studies failed to demonstrate any carotenoid protective effect against tumorigenesis. For example, supplementation the diet with ß-carotene did not protect Sencar mice from 7,12-dimethylbenz[a]anthracene-initiated, 12-O-tetradecanoylphorbol-13-acetate-promoted, two-stage skin induced tumors [39]. In another report, hamsters with benzo[a]pyrene-induced tumors fed a high ß-carotene diet did not show a decrease in the incidence of preneoplastic changes or tumors of the respiratory tract; on the contrary, the tumors of the respiratory epithelium were almost twice as frequent in hamsters fed the high ß-carotene diet than in hamsters fed a low ß-carotene diet [40].

In summary, carotenoids may act as antioxidants and may exhibit chemopreventive anti-atherosclerotic effects and anticancer effects in some specific animal models, using specific carcinogens. However, most animals which have been used in these studies do not absorb or metabolize carotenoids similarly to humans. Thus, the results of animal studies are equivocal.

	IMPORTANT CLINICAL STUDIES

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Research emphasizing the biology of carotenoids was initiated after Peto et al. suggested that ß-carotene might be the primary anticancer agent in fruits and vegetables [41]. In the literature, clinical studies using carotenoids may be divided into a) studies that make associations between the antioxidant capacity of blood or tissue with carotenoid levels in the diet or blood, b) observational and prospective epidemiologic studies and c) intervention trials.

In a study by Omaye et al., a diet low in carotenoids but adequate in all other nutrients resulted in diminished markers of antioxidant capacity of the blood [42], whereas supplementation of the usual daily diet with 90 mg of ß-carotene was shown to increase the plasma antioxidant capacity [43]. However, Cao et al. [44], using a relatively simple but sensitive and accurate method for quantifying the oxygen radical absorbance capacity (ORAC) of total antioxidants in biological tissues, failed to demonstrate that carotenoids make a significant contribution to the antioxidant capacity of the blood. In another report, carotenoids had no effect on the total antioxidant capacity of the plasma and oxidative stress status measured by breath pentane measurements [45]. Nevertheless, a large body of observational and prospective epidemiologic studies has consistently shown an inverse relationship between various cancers (predominantly of the aero-digestive tract) and with higher dietary intakes or blood levels of ß-carotene (reviewed by [46]). For coronary heart disease similar positive associations were found [47–50].

Four large interventional trials were designed to test the hypothesis that ß-carotene protects against cancer and/or cardiovascular disease development in humans. These studies used a ß-carotene supplement with or without other nutrients. 1) Specifically, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study in Finland [51], commonly referred to as the ATBC study, was designed to examine the effect of ß-carotene and vitamin E on lung cancer incidence. The ATBC study was a placebo-controlled trial that assigned male, heavy smokers to receive 20 mg ß-carotene and/or 50 mg of -tocopherol/day. There was an 8% increment of relative risk of death among smokers who received ß-carotene supplements for five to eight years. Also, among the ATBC participants, supplementation with ß-carotene was associated with a slight increase in angina [52]. In a substudy of 1862 men enrolled in the ATBC study, who had a previous myocardial infarction, it was observed that the number of major coronary events in men with a previous myocardial infarction who smoked was not decreased with ß-carotene supplements vs. placebo. In fact, the risk of fatal coronary heart disease was increased in the groups that received either ß-carotene or the combination of -tocopherol and ß-carotene [53]. 2) The Beta Carotene and Retinol Efficacy Trial (CARET) in United States [54] was also designed to examine the effect of ß-carotene and retinyl palmitate (vitamin A) on lung cancer incidence. The CARET enrolled men and women at high risk for lung cancer because of histories of cigarette smoking or occupational exposure to asbestos. In this trial a combined treatment with 30 mg of ß-carotene and 25,000 IU of retinyl palmitate vs. placebo was used. The relative risk of death by lung cancer also increased by 17% in the ß-carotene supplemented heavy smokers vs. placebo group. 3) The Physicians Health study (PHS) was designed to test whether ß-carotene would lower the risk of cancer and cardiovascular disease [55]. The PHS enrolled male physicians to receive 50 mg of ß-carotene on alternate days or placebo and 11% were current smokers. The supplementation was done during a twelve-year period and was neither beneficial nor harmful in terms of the incidence of malignant neoplasms, cardiovascular disease or death from all causes. In all of these studies, much higher doses of ß-carotene were used than could be obtained from the diet, and the blood levels attained were two to six times higher than the 95^th percentile level of ß-carotene in the Health and Nutrition Examination Survey of the United States [55–58].

On the other hand, a fourth study, the Linxian trial, conducted in China, was designed to assess the effect of nutrients on upper gastrointestinal cancer. The Linxian population was selected for the study because of its extraordinarily high rates of upper gastrointestinal cancers, such as esophagus and stomach, and its high prevalence of marginal micronutrient status, such as ß-carotene, retinol, riboflavin, vitamins C and E [59]. Subjects were supplemented with a combination of nutrients (15 mg of ß-carotene, 30 mg of -tocopherol and 50 µg of selenium) and showed a 9% reduction in cancer mortality and in 21% in stomach cancer mortality over a five-year period [59].

The negative results in three of the four intervention trials could have been from using the wrong dose of carotene or wrong duration of treatment, or perhaps the intervention was started too late when cancers were already present due to the heavy smoking histories of the participants. From the combined epidemiologic and intervention trial data, it could be hypothesized that beneficial effects of ß-carotene occur at physiologic or dietary levels of intake, whereas harmful effects in some subpopulations can be seen if pharmacologic levels are given. At high levels of ß-carotene supplementation, there can be an accumulation, not only of ß-carotene, but of its many metabolic products in lung tissues, which, in conjunction with cigarette smoke and/or asbestos exposure, might have a pro- rather than an anti-cancer effect. The beneficial effects observed in the Linxian trial could be due to the environmental conditions, the poorer nutritional status and lower dose of ß-carotene used—in combination with vitamin E and selenium in the Chinese population.

There is increasing interest in lycopene in the literature. There have been reports of protective effects of raw tomato intake with respect to cancers of the oral cavity, pharynx, esophagus, stomach, colon and rectum, with the most potent effects seen with stomach neoplasia [60]. Inverse relationships have been reported also between lycopene intake or serum lycopene values and the risk of cancer of the prostate, pancreas and the stomach. In the Health Professional Follow-up study [14] and the Seventh-Day Adventist study [61] tomato-based products were associated with a lower prostate cancer risk.

In a multicenter case-control study (EURAMIC Study) conducted to evaluate the relations between antioxidant status, assessed by levels of carotenoids and tocopherols in adipose tissue, and acute myocardial infarction, each of the carotenoids studied appeared to be protective. However, using conditional logistic regression models that controlled for age, body mass index, socioeconomic status, smoking, hypertension, and maternal and paternal history of disease, lycopene remained independently protective and the associations for - and ß-carotene were largely eliminated [62]. The authors concluded that lycopene, or some substance highly correlated which is in a common food source, may contribute to the protective effect of vegetable consumption on myocardial infarction risk [62].

	A SUMMARY OF THE AVAILABLE INFORMATION BASE WHICH SUPPORTS PREVENTIVE ROLE OF THE NUTRIENT IN HEART DISEASE AND CANCER

TOP ABSTRACT BIOCHEMISTRY AND PHYSIOLOGY AVAILABILITY IN DIFFERENTFOOD... CELLULAR AND MOLECULAR STUDIES... RELEVANT ANIMAL DATA ONTHE... IMPORTANT CLINICAL STUDIES A SUMMARY OF THE... REFERENCES

 
There are several dozen carotenoids in the foods that we eat, and most of these carotenoids have antioxidant activity. ß-carotene has been best characterized with regard to its singlet oxidant quenching and antioxidant capabilities, since in most countries it is the most prevalent carotenoid in fruits and vegetables. However, in the U.S., lycopene from tomatoes now is consumed in approximately the same amount as ß-carotene, and this compound has been far less well characterized. Antioxidants (including carotenoids) have been studied for their ability to prevent chronic disease, since the free radical theory of aging in chronic disease etiology remains pre-eminent.

ß-carotene and others carotenoids have antioxidant properties, but the antioxidant capability is variable depending on the in vitro system used. The antioxidant activity of these compounds can shift into a prooxidant effect, depending on such factors as oxygen tension or carotenoid concentration. Mixtures of carotenoids alone or in association with others antioxidants can increase their activity against lipid peroxidation.

In certain animal models, carotenoid compounds can act as antioxidants, cancer chemopreventive agents and anti-atherosclerotic agents. However, animal models are limited in their usefulness, since most laboratory animals do not absorb or metabolize carotenoids in a fashion similar to humans.

Observational and prospective epidemiologic studies have shown an inverse relationship between various cancers and carotenoid intake and/or blood levels. A similar inverse relationship has been seen with cardiovascular disease. However, three out of four intervention trials using high doses of ß-carotene supplements did not show protective effects against cancer or cardiovascular disease.

Thus, carotenoids and ß-carotene seem to be health promoting when taken at physiologic levels, but may take on circumstantially adverse properties when given in high dose and in the presence of highly oxidative conditions. There remains a great interest in the possible health promoting effects of carotenoids, but the mechanism by which these compounds are acting (antioxidant or other properties) is in need of further study.

	FOOTNOTES

 
Supported in part by Federal funds from U.S. Department of Agriculture, Agriculture Research Service under contract number 53-3K06-5-10. SARP was supported by a grant from the "Fundação de Amparo à Pesquisa do Estado de São Paulo"—FAPESP, São Paulo, BRAZIL.

The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture nor does mention of trade names, commercial products, or organizations imply endorsement by U.S. Government.

Received March 1, 1999.

	REFERENCES

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