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Journal of the American College of Nutrition, Vol. 20, No. 3, 232-238 (2001)
Published by the American College of Nutrition

Original Research

No Significant Effects of Lutein, Lycopene or ß-Carotene Supplementation on Biological Markers of Oxidative Stress and LDL Oxidizability in Healthy Adult Subjects

Isabelle A. Hininger, PhD, Anita Meyer-Wenger, PhD, Ulrich Moser, PhD, Anthony Wright, PhD, Susan Southon, PhD, David Thurnham, PhD, Mridula Chopra, PhD, Henk Van Den Berg, PhD, Begona Olmedilla, PhD, Alain E. Favier, PhD, FACN and Anne-Marie Roussel, PhD, FACN

Laboratoire de Biologie du Stress Oxydant, Faculté de Pharmacie, Université Joseph Fourier de Pharmacie, La Tronche, FRANCE (I.A.H., A.E.F., A.-M.R.)
Hoffmann La Roche, Bale, SWITZERLAND (A.M.-W., U.M.)
Institute of Food Research, Norwich, UNITED KINGDOM(A.W., S.S.)
University of Ulster, Coleraine, NORTHERN IRELAND (D.T.,M.C.)
TNO-CIVO Institute, Zeist, THE NETHERLANDS (H.V.D.B.)
Clinica Puerta de Hierro, Madrid, SPAIN (B.O.)

Address reprint requests to: Pr. Anne-Marie Roussel, Laboratoire de Biologie du Stress Oxydant (LBSO), Faculté de Pharmacie, UJF, Domaine de la Merci, 38700 La Tronche, FRANCE. E-mail: Anne-Marie.Roussel{at}ujf-grenoble.fr


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objective: The objective of this study was to determine the effect of individual carotenoid supplementation on biochemical indices of oxidative status in apparently healthy adult males.

Methods:The study was a placebo controlled single blind study. Healthy male volunteers (n=175) were assigned to four groups. They received daily supplements of ß-carotene (15 mg), lutein (15 mg), lycopene (15 mg) and placebo for three months. The effects of the supplementation on antioxidant status were monitored by plasma carotenoid, vitamin C and A levels, glutathione (GSH and GSSG) concentrations, protein SH groups, erythrocyte antioxidant enzyme activities (Cu-Zn SOD, Se-GSH-Px) and susceptibility of LDL to copper-induced oxidation.

Results:ß-carotene, lycopene and lutein supplementation led to significant plasma and LDL increases in each of these carotenoids, without modifications of other carotenoid levels in plasma or in LDL. The supplementation failed to enhance the resistance of LDL to oxidation or to modify the LDL polyunsaturated/saturated fatty acid ratio. Vitamin C, GSH, protein SH groups and antioxidant metalloenzyme activities were also unchanged.

Conclusion: We did not observe beneficial or adverse effects of lutein, lycopene or ß-carotene supplementation on biomarkers of oxidative stress. In apparently healthy subjects, carotenoid supplementation does not lead to significantly measurable improvement in antioxidant defenses.

Key words: lutein, lycopene, ß-carotene, LDL oxidizability, oxidative stress, carotenoid supplementation


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
An increased oxidative stress has been implicated in the incidence of diseases such as cardiovascular disease and cancer [1,2]. It has been proposed that dietary antioxidants, providing protection against free radical attack, could reduce the risk of these diseases [3]. A high consumption of fruits and vegetables could decrease the risk of cancers [4] or CVD [5], whereas low intakes of fruits and vegetables increased this risk [6]. Epidemiological data show that carotenoid intakes and status are inversely related to the incidence of cancer [7] and cardiovascular diseases [8]. However, recent interventional trials did not show such a protective effect [9,10]. Most of the reports focused on ß-carotene nutriture, but a possible link between lycopene intakes and a lower risk of prostate [11], stomach and pancreatic cancer [12] and myocardial infarction [13] has been also reported. The mechanism of these effects is still not totally explored since carotenoids have multiple biological functions. The protective effect against cardiovascular disease could be related to decreased susceptibility of LDL to oxidation, since the relationship between LDL oxidation and atherogenesis has been well documented [14]. Enrichment of LDL with ß-carotene has been shown to protect LDL against copper-induced oxidation in vitro [15]. In a previous study [16], we reported the beneficial effects of a carotenoid-rich diet on LDL oxidizability in smokers. Other mechanisms of action, such as a sparing effect on antioxidant circulating systems (vitamin C, glutathione or antioxidant enzymes) cannot be totally ruled out [8].

Considering that supplementation trials with lutein and lycopene are scarce, we investigated the effects of lutein and lycopene supplementation on oxidative stress variables. We measured in healthy male adults, receiving individually lutein, lycopene or ß-carotene, blood biomarkers of oxidative stress (Vitamin C, Cu-Zn SOD, SeGPx, protein SH groups and GSH/GSSG) and copper-induced LDL oxidizability, in relation to carotenoid status.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Subjects
This study was a part of a large interventional European trial (AAIR), aimed at investigating the beneficial effects of fruit and vegetable consumption on health. The procedures used were in accordance to the declaration of Helsinki. The protocol was approved by all relevant Ethical Committees, and all the subjects gave their written informed consent. Adult males 25 to 45 years old were recruited in five European centers: Grenoble, France; Coleraine, Northern Ireland; Cork, Ireland; Zeist, Netherlands; Madrid, Spain. The volunteers were enrolled all at once and randomly assigned to four treatment groups at each center. They had a stable lifestyle, were apparently healthy, non-smoking and did not take any medications or nutritional supplements. Exclusion criteria included smoking, serum retinol below 1 µmol/L and BMI>28 kg/m2. Only volunteers exhibiting normal lipidemic and normal hematological values were included. The final number of volunteers at the completion of the study was 175.

Groups and Supplementation
All the subjects completed a food-frequency questionnaire to assess their carotenoid intakes before starting the trial. Subjects were assigned to four groups receiving 15 mg/day of ß-carotene (Group 1), lutein (Group 2), lycopene (Group 3) or placebo (Group 4) for 12 weeks. ß-carotene and lutein capsules were a gift from Quest International (Cork, Ireland). Palm oil carotene ({alpha}-carotene [31%], ß-carotene [69%]) and marigold extract were respectively used as the source of ß-carotene and lutein. Lycopene was a gift from Makhtesim Chemical Wirks Ltd (Beer-Sheva, Israel) obtained from natural tomato extract (90% lycopene and 10% ß-carotene).

Analysis
Blood was taken from fasting subjects by venipuncture on day 0 and after three months of daily supplementation. Plasma was separated from cells immediately after collection by centrifugation at 3,000xg and stored at -80°C prior to analysis. Plasma carotenoid and retinol levels were measured as described [17]. Plasma ascorbic acid was stabilized and quantified by HPLC [18] in addition to the concurrent quantification of uric acid which appeared in the same HPLC run. The quality control was assessed through the Fat-Soluble Vitamin QA Program (NIST, USA), and the performance of analysis during the study was rated by NIST. The concentration of plasma SH protein groups was determined in 100 µL plasma samples [19]. Erythrocyte Cu-Zn SOD activity was measured after hemoglobin precipitation by monitoring the autoxidation of pyrogallol [20]. Erythrocyte Se-GPx activity was evaluated by the method of Gunzler [21] using tert-butyl hydroperoxide (Sigma Chemical Co, via Coger, Paris, France) as substrate instead of hydroperoxide. Results were expressed as nanomoles of NADPH oxidized per minute per liter. Total glutathione was determined by the modified method of Akerboom [22]. Whole blood (400 µL) was added to 3600 µL aqueous of metaphosphoric acid (6% w/v). The mixture was centrifuged for 10 minutes at 4°C. The acidic, protein-free supernatants were stored at -80°C until analysis. Measurement of copper-induced LDL susceptibility to oxidation was performed as described in De Waart [23], after incubation of LDL isolated from 1 mL of plasma with a freshly prepared 2.5 mol/L CuCl2 solution in phosphate buffered saline (PBS), Ph7.4 at 20° for five hours [24], with modification in the isolation step according to Himber [25]. Formation of conjugated dienes was measured every 15 minutes for five hours by monitoring the increase of the 234 nm absorbance following the Cu-induced oxidation of LDL. The length of the lag phase (in minutes) was determined as described by Frei and Gaziano [26]. Serum cholesterol and triglycerides were determined by enzymatic methods. Lipids were extracted with chloroform/methanol, dried under nitrogen, transmethylated with methalonic-hydrochloric and separated by gas chromatography (HP5890A; Hewlett-Packard, Palto Alto CA) as detailed previously [27]. Briefly, a fused silica capillary column (50 mm length, 0.25mm inner diameter, 0.1 mm layer thickness) was used under the following conditions: injection at 55°C, 10°C/min from 55–177°C, 1°C/min from 177–218°C, 4°/min from 218–270°C. C-17 methyl ester was used as internal standard, and fatty acids were quantified by using commercial methyl ester standards.

Statistical analysis
Values are means ±SEM. Values (Week 0 and Week 12) were compared among groups by analysis of variance (ANOVA), with p<0.05 regarded as significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
At the beginning of the study, the characteristics of volunteers in the groups were not statistically different for age, BMI and lipid profile (Table 1).


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  		Table 1. Characteristics of the Subjects at Baseline1

 
Effect of the Supplementation on Carotenoid Status
At the onset of the study, ß-carotene, lycopene and lutein intakes, estimated by food questionnaire, were respectively 5.30±0.35 mg/day, 4.84±0.39 mg/day and 2.53±0.19 mg/day. These intakes were in the normal range according to dietary recommended intakes for carotenoids. Plasma carotenoid levels in the three groups were also in the physiological range [16] and not statistically different from those measured in the placebo group. After 12 weeks of supplementation (W12), plasma carotenoid levels increased in each supplemented group, in relation to the nature of the carotenoid supplementation (Table 2). In the ß-carotene group, supplementation resulted in an increase of 326% in ß-carotene and 887% in {alpha}-carotene, while plasma retinol remained constant. In the lutein group, plasma lutein and zeaxanthine were enhanced by 327% and 117%, respectively. In the lycopene group, plasma lycopene increased 86%. In each group, plasma levels of other carotenoids were not altered by the supplementation. On the contrary, we observed a 35% increase in serum ß-carotene following lycopene supplementation. Plasma ascorbic acid, retinol and acid uric were not modified by the supplementation (Table 3).


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  		Table 2. Effects of Supplementation on Plasma Carotenoid Levels1

 

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  		Table 3. Effect of Supplementation on Plasma Acid Uric, Retinol and Ascorbic Acid1

 
Effect of the Supplementation on the Biomarkers of Oxidative Stress
Oxidative stress parameters were not different among the groups at W0, and they remained unchanged after 12 weeks (Table 4). As shown in Table 5, for each group there was a significant LDL enrichment following carotenoid supplementation. LDL susceptibility to oxidation, assessed by lag time after copper-induced oxidation, was not modified by the supplementation (Table 5). Moreover, in the four groups, the P/S ratio, as a potential marker of LDL fatty acid oxidation, remained unchanged.


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  		Table 4. Effects of Supplementation on Plasma and RBC Antioxidant Defenses1

 

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  		Table 5. Effect of Supplementation on LDL Oxidizability (min), LDL carotenoid content (ng/mg LDL Cholesterol) and Polyunsaturated on Saturated Fatty Acid Ratio (P/S)1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
Several studies reported the beneficial effect of ß-carotene intakes in decreasing oxidative stress and protecting LDL against oxidation. However, to our knowledge, no studies have focused on the effects of lycopene. Our objective was to compare the effects of supplemental intakes of lutein or lycopene to those of ß-carotene on oxidative stress and especially on LDL oxidizability. Carotenoids were given at 15 mg/day, which represents relatively high doses, given the nutritional recommendations. In all of the supplemented groups, we observed a response to the supplementation leading to a rise in the supplementing carotenoid. These data corroborate other results using chemical forms of carotenoids [28–30], but differ from trials using a carotenoid-rich fruit and vegetable diet [16], which led to moderate increases of carotenoid plasma levels. The discrepancy could be due to a higher bioavailability of chemical forms than those of natural sources [31–33]. In this study, we did not observe adverse interactions between carotenoids. These data suggest that the respective absorptions were not modified by a competitive mechanism. In the ß-carotene group, the increase in {alpha}-carotene could be expected since {alpha}-carotene and ß-carotene were combined in the capsules. Serum {alpha}-carotene enhancement was higher than that measured for ß-carotene, in relation to the given doses. We reported a similar effect [16], possibly related to a deficient {alpha}-carotene status of the subjects at inclusion. In the lutein group (Group 2), we also noted a rise of zeaxanthin, as described by others [7]. Lycopene supplementation in Group 3 resulted in an increase in serum lycopene and ß-carotene, in relation to the combined composition of the capsule, containing 10% ß-carotene. The question of possible adverse effects of carotenoid supplementation on other carotenoid metabolism is a matter of debate. Indeed, some studies, using individual or combined doses, have reported adverse effects of supplemental ß-carotene on plasma levels of other carotenoids [34–36] or no effect [29]. In males, ß-carotene given for six weeks lowered serum lutein levels [31]. In the Polyp Prevention Study, the supplementation of 25 mg/day of ß-carotene for four years did not lead to significant changes in serum levels of lycopene, {alpha}-carotene, cryptoxanthin or lutein. In contrast, in the ATBC trial, 20 mg/day of ß-carotene resulted in increases of {alpha}-carotene, ß-cryptoxanthin and lutein [10]. Carotenoids are present in low-density lipoprotein and they could prevent LDL oxidation [37,38]. After 12 weeks of supplementation, there was an enrichment of LDL in ß-carotene, lycopene and lutein, but no modification of oxidizability, assessed by lag time and polyunsaturated/saturated fatty acid ratio. Regarding ß-carotene, these data confirm the lack of protective effects on LDL observed by others [39,40] using higher doses, but do not corroborate the data observed in our previous report in smokers [16]. These discrepancies could be due to a better efficiency of the combined carotenoids present in food compared to those of an isolated chemical supplement. The complementary effects of all the other antioxidant components of the foods cannot be ruled out. Similar to ß-carotene, lutein and lycopene did not exhibit properties in enhancing LDL resistance to oxidation. In this study, we enrolled healthy adults exhibiting an adequate carotenoid status. Our data, failing to observe a protective effect of supplemental carotenoids on LDL oxidation, suggest that such a supplementation in healthy subjects cannot be recommended as useful. However, they cannot exclude a potential beneficial effect of this supplementation in protecting LDL from oxidation in deficient subjects.

We investigated also the effects of supplementation on some circulating markers of oxidative stress. Antioxidant RBC enzyme activity (Cu-Zn SOD, Se GPx) remained unchanged. Consistent with previous studies using chemical forms of ß-carotene [41,42] or natural sources [16], we also observed no effect on antioxidant enzyme activities. A beneficial effect of ß-carotene on antioxidant enzyme activities has been reported after a carotenoid-depleted diet [43,44]. Protein SH group concentrations, blood vitamin C and GSH/GSSG were not modified and remained in the physiological ranges. These data did not agree with a possible sparing mechanism reporting interactions between ß-carotene and ascorbic acid in vitro [8]. In agreement with our study, a previous study [40] did not report any change in erythrocyte GSH. In contrast, others [41] observed a significant increase in GSH in HIV-infected patients receiving daily high doses of ß-carotene (60 mg/day) for one year. However, the low GSH level of the HIV-infected subjects in this study, the doses and the duration of the trial could explain the discrepancy.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
This study showed that in healthy subjects, lutein, lycopene and ß-carotene supplementation increases greatly the carotenoid status without adverse biological effects, but does not protect against oxidative stress. LDL oxidation, protein oxidation and antioxidant enzymatic activities were not modified. These data suggest that, when the diet provides adequate carotenoid intakes, the immediate effects of supplementation are limited. The consumption of carotenoid-rich foods should be encouraged.


   ACKNOWLEDGMENTS
 
This research has been supported by the European Union: AAIR project (AIR-CT93-0888, DG12SSMA).


   FOOTNOTES
 
Presented in part as an oral communication at the 38th American College of Nutrition Meeting, New York, October 1997.

Received March 1, 2000. Accepted March 27, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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J. D. Ribaya-Mercado and J. B. Blumberg
Lutein and Zeaxanthin and Their Potential Roles in Disease Prevention
J. Am. Coll. Nutr., December 1, 2004; 23(suppl_6): 567S - 587S.
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 J. Nutr.Home page
H. D. Sesso, S. Liu, J. M. Gaziano, and J. E. Buring
Dietary Lycopene, Tomato-Based Food Products and Cardiovascular Disease in Women
J. Nutr., July 1, 2003; 133(7): 2336 - 2341.
[Abstract] [Full Text] [PDF]

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 Cancer Res.Home page
C. Liu, F. Lian, D. E. Smith, R. M. Russell, and X.-D. Wang
Lycopene Supplementation Inhibits Lung Squamous Metaplasia and Induces Apoptosis via Up-Regulating Insulin-like Growth Factor-binding Protein 3 in Cigarette Smoke-exposed Ferrets
Cancer Res., June 15, 2003; 63(12): 3138 - 3144.
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