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Lycopene and beta carotene protect in vivo iron-induced oxidative stress damage in rat prostate

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It has been suggested that iron overload may be carcinogenic. In the present study, we evaluated the effect of plasma and prostate caro- tenoid concentration on oxidative DNA damage in 12-week-old Wistar rats treated with intraperitoneal (ip) ferric nitrilotriacetate (Fe-NTA) (10 mg Fe/kg). Plasma ß-carotene and lycopene concentrations were measured as a function of time after ip injection of carotenoids (10 mg kg -1 day -1 ß-carotene or lycopene) in rats. The highest total plasma concentration was reached 3 and 6 h after ip injection of lycopene or ß-carotene, respectively. After 5 days of carotenoid treatment, lyco- pene and ß-carotene were present in the 0.10-0.51 nmol/g wet tissue range in the prostate. Using a sensitive method to detected 8-oxo-7,8- dihydro-2'-deoxyguanosine (8-oxodGuo) by HPLC/EC, the level of 8-oxodGuo in rat prostate DNA was significantly higher (6.3 ± 0.6 residues/10 6 dGuo) 3 h after Fe-NTA injection compared with control rats (1.7 ± 0.3 residues/10 6 dGuo). Rats supplemented with lycopene or ß-carotene for 5 days prior to Fe-NTA treatment showed a reduction of about 70% in 8-oxodGuo levels to almost control levels. Compared with control rats, the prostate of Fe-NTA-treated animals showed a 78% increase in malondialdehyde accumulation. Lycopene or ß- carotene pre-treatment almost completely prevented lipid damage. Epidemiological studies have suggested a lower risk of prostate cancer in men reporting a higher consumption of tomato products. However, before associating this effect with tomato sauce constitu- ents, more information is required. The results described here may contribute to the understanding of the protective effects of carotenoids against iron-induced oxidative stress.
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Brazilian Journal of Medical and Biological Research (2006) 39: 203-210
Prostate, DNA oxidation, and carotenoids
203
ISSN 0100-879X
Lycopene and ß-carotene protect in vivo
iron-induced oxidative stress damage in
rat prostate

1
H.R. Matos3, S.A. Marques1,
Departamento de Bioquímica, Instituto de Química,
2
O.F. Gomes1, A.A. Silva2,
Departamento de Clínica Médica-Nefrologia, Faculdade de Medicina,
J.C. Heimann2,
Universidade de São Paulo, São Paulo, SP, Brasil
3
P. Di Mascio1
Departamento de Fisiologia, Universidade Federal de Sergipe, São Cristóvão,
and M.H.G. Medeiros1
SE, Brasil
Abstract
Correspondence
It has been suggested that iron overload may be carcinogenic. In the
Key words
M.H.G. Medeiros
present study, we evaluated the effect of plasma and prostate caro-
• Lycopene
Departamento de Bioquímica
tenoid concentration on oxidative DNA damage in 12-week-old Wistar
• ß-carotene
Instituto de Química, USP
rats treated with intraperitoneal (ip) ferric nitrilotriacetate (Fe-NTA)
• DNA damage
Av. Prof. Lineu Prestes, 748
(10 mg Fe/kg). Plasma ß-carotene and lycopene concentrations were
• 8-oxo-7,8-dihydro-
05508-900 São Paulo, SP
measured as a function of time after ip injection of carotenoids (10 mg
2'-deoxyguanosine
Brasil
• Ferric nitrilotriacetate
kg-1 day-1 ß-carotene or lycopene) in rats. The highest total plasma
Fax: +55-11-3815-5579
• Prostate cancer
E-mail: mhgdmede@iq.usp.br
concentration was reached 3 and 6 h after ip injection of lycopene or
ß-carotene, respectively. After 5 days of carotenoid treatment, lyco-
Research supported by FAPESP,
pene and ß-carotene were present in the 0.10-0.51 nmol/g wet tissue
CNPq, and PRONEX/FINEP.
range in the prostate. Using a sensitive method to detected 8-oxo-7,8-
P. Di Mascio is the recipient of a
dihydro-2'-deoxyguanosine (8-oxodGuo) by HPLC/EC, the level of
fellowship from the John Simon
8-oxodGuo in rat prostate DNA was significantly higher (6.3 ± 0.6
Memorial Guggenheim Foundation.
residues/106 dGuo) 3 h after Fe-NTA injection compared with control
rats (1.7 ± 0.3 residues/106 dGuo). Rats supplemented with lycopene
or ß-carotene for 5 days prior to Fe-NTA treatment showed a reduction
Received January 31, 2005
of about 70% in 8-oxodGuo levels to almost control levels. Compared
Accepted October 27, 2005
with control rats, the prostate of Fe-NTA-treated animals showed a
78% increase in malondialdehyde accumulation. Lycopene or ß-
carotene pre-treatment almost completely prevented lipid damage.
Epidemiological studies have suggested a lower risk of prostate
cancer in men reporting a higher consumption of tomato products.
However, before associating this effect with tomato sauce constitu-
ents, more information is required. The results described here may
contribute to the understanding of the protective effects of carotenoids
against iron-induced oxidative stress.
Introduction
be attributed to a variety of compounds, such
as dietary fiber, folic acid, vitamin A, and
Epidemiological studies have suggested
other antioxidants (vitamin C, vitamin E,
that consumption of fruits and vegetables
carotenoids, selenium) (1,2). Because caro-
can help cancer prevention. This effect can
tenoids are widely distributed in these foods,
Braz J Med Biol Res 39(2) 2006

204
H.R. Matos et al.
much interest has been focused on elucidat-
prostate cancer (2). Recently, Boileau et al.
ing the molecular mechanisms responsible
(26) investigated the effect of tomato prod-
for their biological effects. In addition to the
ucts or lycopene in a rat model of prostate
well-known pro-vitamin A activity of some
carcinogenesis. They observed that tomato
carotenoids, part of their beneficial effects
powder but not lycopene inhibited prostate
has been attributed to their antioxidant prop-
carcinogenesis, suggesting that tomato prod-
erties (3,4). Their ability to scavenge free
ucts contain compounds in addition to lyco-
radicals (5-7) and to physically quench sin-
pene that reduce the risk of prostate cancer.
glet molecular oxygen (8) has been well
In contrast, a stimulatory effect of a lyco-
described. Carotenoids have also been asso-
pene oxidation product on gap junctional
ciated with other biological mechanisms such
communication between cells was observed
as modulation of intercellular gap junctional
in rat liver epithelial WB-F344 cells, indi-
communication, immune system and meta-
cating a potential role of lycopene degrada-
bolic pathways (9,10).
tion products in cell signaling (27). There-
On the other hand, iron has been exten-
fore, more information is required to eluci-
sively reported to mediate oxidative stress
date the biochemical mechanisms respon-
(11-14). In fact, a high production of free
sible for the protective effects of lycopene.
radicals occurs in animal models of iron
The purpose of the present study was to
overload (15). Liver iron deposits are fre-
determine if lycopene or ß-carotene or both
quent in cirrhotic patients with hepatitis C
can protect against iron-induced oxidative
and seem to contribute to the development
DNA damage in the rat prostate.
of hepatocellular carcinoma (16). It has been
demonstrated that the iron chelate, ferric
Material and Methods
nitrilotriacetate (Fe-NTA), is a potent in-
ducer of lipid peroxidation in cells and in
Chemicals
animal models (17). It has also been reported
that rats intraperitoneally (ip) injected with
Nitrilotriacetic acid (NTA), tetrahydro-
Fe-NTA show an increase in the level of
furan (THF), nuclease P1, alkaline phos-
thiobarbituric acid-reactive substances in
phatase, ribonuclease A and T1, proteinase
liver and an elevation of the plasma levels of
K, acetonitrile, ß-carotene, methanol, and
aspartate aminotransferase and alanine ami-
isopropyl alcohol were from Sigma (St.
notransferase indicative of hepatic injury
Louis, MO, USA). All other solvents and
(18). Fe-NTA causes renal carcinomas in
chemicals used were of analytical grade and
rats (19) and induces the formation of 8-oxo-
were supplied by Merck (Darmstadt, Ger-
7,8-dihydro-2'-deoxyguanosine (8-oxodGuo)
many). Water was purified with a Milli-Q
in DNA from isolated rat kidney cells (20-
system (Millipore, Bedford, MA, USA).
23). In previous studies, we have shown that
Lycopene was donated by Dr. Zohar Nir,
lycopene can protect cultured mammalian
LycoRed Natural Products Industries Ltd.
cells against damage to biomolecules in-
(Beer-Sheva, Israel). Fresh stock solutions
duced by Fe-NTA/ascorbate treatment (24).
of lycopene were kept in the dark and used
Furthermore, we showed a significant pro-
immediately. The Fe-NTA solution was pre-
tective effect of lycopene against DNA oxi-
pared just before use as described by Bates
dation, membrane damage and histopatho-
and Schlabach (28). Briefly, aqueous solu-
logic changes observed in the liver of Fe-
tions of FeCl3 and NTA were mixed at a
NTA-treated rats (25).
molar ratio of 1:4 FeCl3/NTA. The pH of
One of the cancers which benefit from a
these solutions was adjusted to values rang-
diet rich in tomatoes and tomato products is
ing from 6.5 to 7.4 before use.
Braz J Med Biol Res 39(2) 2006

Prostate, DNA oxidation, and carotenoids
205
Lycopene or ß-carotene stock solutions
Plasma (100 µL) was extracted with 100 µL
ethanol and 200 µL hexane and samples
Lycopene or ß-carotene (100 mg) was
were vortexed for 1 min and centrifuged for
mixed in 2 mL Tween-80 at room tempera-
5 min at 2500 rpm and 4ºC. The upper
ture until a homogenous paste was obtained.
organic phase was removed and dried in the
Physiologic saline at room temperature was
dark under a stream of nitrogen at 30ºC.
added dropwise and with vigorous stirring to
Samples were redissolved in HPLC solvent,
a final concentration of 10 mg lycopene or ß-
after which 10 µL of a 5-mM solution of ß-
carotene per mL of suspension (29).
ionone was added as internal standard. The
amounts of lycopene and ß-carotene were
Animal treatments
measured by HPLC using a Shimadzu HPLC
system (Kyoto, Japan) equipped with two
Male Wistar rats (12 weeks old) were
LC-10AD pumps, a Rheodyne injector and
taken from the colony of the Instituto de
an SPD-M10AV photodiode array detector,
Química, Universidade de São Paulo. All
controlled by a CBM-10A communication
animals were allowed one week of in-house
bus module and the CLASS LC-10AWS
acclimatization with ad libitum access to
software. The following conditions were
standard laboratory food and water. The ani-
employed for HPLC: a reverse phase C-18
mals were divided into six groups of five or
column (Spherex, 250 x 4.6 mm, 5 µm)
10 individuals each: a) control with animals
eluted with an isocratic solvent system con-
receiving ip Tween-80 in saline (vehicle); b)
sisting of acetonitrile:THF:methanol (68:22:
animals receiving ip lycopene (10 mg kg-1
10, v/v/v), with 0.025% (w/v) ammonium
day-1) in vehicle, for 5 days; c) animals
acetate at 1 mL/min. Lycopene and ß-caro-
receiving ip ß-carotene in vehicle (10 mg kg-1
tene were detected at 445 nm. The detection
day-1) for 5 days; d) animals receiving ip
limit of the assay was 5 pmol/injection, based
lycopene in vehicle (10 mg kg-1 day-1) for 5
on a signal-to-noise ratio of 3:1. The quanti-
days, and after an ip Fe-NTA injection (10
fication limit of the assay was determined as
mg Fe/kg); e) animals receiving ip ß-caro-
the concentration equal to six times the value
tene in vehicle (10 mg kg-1 day-1 for 5 days)
of the signal-to-noise ratio and was 7.5 pmol/
and after an ip Fe-NTA injection (10 mg Fe/
injection.
kg). Animals were sacrificed 3 h after Fe-
NTA administration and the prostate was
Lycopene and ß-carotene determination in
removed, snap frozen in liquid nitrogen and
the prostate
stored at -80ºC.
Carotenoids were measured in the pros-
Plasma concentration of lycopene and
tate according to the method described by
ß-carotene
Zhao et al. (32). THF was added to tissue
slices and the mixture was sonicated. After
All rats, except the control groups, re-
five extractions the extracts were dried un-
ceived a 1-mL ip injection of a 10-mg/mL
der N2 and the residue was treated with
solution containing ß-carotene or lycopene.
methanolic KOH (10%) under N
2 for 1 h at
Blood was collected from the rat tail 3, 6, 9,
room temperature to remove lipid. The caro-
and 24 h after the injection and centrifuged
tenoids were extracted with 1.5 mL NaCl
to obtain plasma. Lycopene and ß-carotene
(10%)/methanol and 1.5 mL dichlorometh-
were analyzed by HPLC. Lycopene and ß-
ane. The upper organic phase was removed
carotene in plasma were measured accord-
and dried in the dark under a stream of
ing to a previously described method (30,31).
nitrogen at 30ºC, after which the amounts of
Braz J Med Biol Res 39(2) 2006

206
H.R. Matos et al.
lycopene and ß-carotene were measured by
Analysis of 8-oxo-7,8-dihydro-2'-
HPLC as described above.
deoxyguanosine by HPLC-electrochemical
detection

DNA extraction and enzymatic hydrolysis
Samples (100 µg) of digested DNA were
DNA was isolated by the chaotropic NaI
injected into the HPLC/electrochemical de-
method (33). Tissue (300 mg) was suspended
tection system consisting of a Shimadzu
in 2 mL of a lysis solution (1% (w/v) Triton
model LC-10AD pump connected to a Luna
X-100, 0.32 M sucrose, 5 mM EDTA, 10
C18 (Phenomenex, Torrance, CA, USA) re-
mM Tris-HCl, pH 7.5). After centrifugation
verse-phase column (250 x 4.6 mm ID, par-
at 1500 g for 10 min, the pellets were sus-
ticle size 5 µm). The flow rate of the isocratic
pended in 600 µL 10 mM Tris-HCl buffer,
eluent (50 mM potassium phosphate buffer,
pH 8.0, containing 5 mM EDTA, 10% SDS
pH 5.5, and 8% methanol) was 1 mL/min.
and 0.15 mM desferrioxamine. The enzymes
Coulometric detection was obtained with a
RNase A (30 µL, 1 mg/mL) and RNase T1 (8
Coulochem II detector (ESA, Chemsford,
µL, 1000 U/mL) in 10 mM Tris-HCl buffer,
MA, USA). The potentials of the two elec-
pH 7.4, containing 1 mM EDTA and 2.5 mM
trodes were set at 120 and 280 mV. Elution
desferrioxamine, were added and the reac-
of unmodified nucleosides was monitored
tion mixture was incubated at 50oC. After 15
simultaneously with a Shimadzu SPD-10A
min, 30 µL proteinase K (20 mg/mL) was
UV detector set at 254 nm. A Shimadzu
added followed by additional incubation at
Class-LC10 1.6 software was used to calcu-
37oC for 1 h. After centrifugation at 5000 g
late the peak areas. The molar ratio of 8-
for 15 min, the liquid phase was collected
oxodGuo to dGuo in each DNA sample was
and 1.2 mL 7.6 M NaI was added to it,
determined based on coulometric detection
followed by the addition of 1 mL isopro-
at 280 mV for 8-oxodGuo and on absorb-
panol. The content in the tube was mixed
ance at 254 nm for dGuo in each injection.
well by inversion until a whitish precipitate
appeared. The precipitate was collected by
Malondialdehyde determination
centrifugation at 5000 g for 15 min and
washed with 1 mL 40% isopropanol (w/v),
Malondialdehyde (MDA) was measured
followed by 1 mL 70% ethanol (w/v). After
as described (34). Briefly, an aqueous sample
additional centrifugation at 5000 g for 15
containing MDA at pH 6.5-8.0 was separated
min, the DNA pellet was suspended in 100
by HPLC using an aminophase column (S-5
µL 0.1 mM desferrioxamine. The DNA con-
Spherisorb-NH2) with acetonitrile 30 mM Tris
centration was measured spectrophotometri-
buffer, pH 7.4 (1:9, v/v), as the mobile phase at
cally at 260 nm and was considered to be
1 mL/min. The effluent was monitored at 267
homogeneous, A260/A280 >1.75. DNA (100
nm, the molar absorptivity (?) of the enolate
µg) was diluted in 200 µL of deionized wa-
anion form of free MDA, was taken to be
ter, followed by the addition of 4 µL 1 M
31,500 at pH 7.4. To deproteinize the sample,
sodium acetate buffer, pH 5.0, containing 5
300 mg of the tissue was mixed with an equal
units of nuclease P1 and incubated at 37ºC for
volume of acetonitrile followed by centrifuga-
30 min. Twelve microliters of 1 M Tris-HCl
tion. A 20-µL aliquot of the supernatant was
buffer, pH 7.4, 12 µL phosphatase buffer, and
injected into the HPLC apparatus.
6 units of alkaline phosphatase were then
added for an additional 1-h incubation at 37°C.
Statistical analysis
The sample was centrifuged and the aqueous
layer was collected and analyzed by HPLC.
Data are reported as means ± SEM and
Braz J Med Biol Res 39(2) 2006

Prostate, DNA oxidation, and carotenoids
207
were analyzed by two-way ANOVA fol-
centration protects in vivo against oxidative
lowed by the post hoc Bonferroni test per-
damage, membrane and DNA damage was
formed using GraphPad Prism version 4.02
evaluated in prostate tissue. Carotenoid lev-
for Windows (GraphPad Software, San Di-
els in the prostate of rats treated for 5 con-
ego, CA, USA) to compare groups or by the
secutive days with ip injections of 10 mg/kg
Student t-test when two groups were com-
body weight lycopene or ß-carotene were:
pared. Differences were considered signifi-
0.51 ± 0.04 nmol lycopene/g wet tissue and
cant at P < 0.05.
0.13 ± 0.01 nmol ß-carotene/g wet tissue for
the lycopene and ß-carotene treatments, re-
Results and Discussion
Oxidative damage to biomolecules has
been postulated to be involved in several
chronic diseases (35). Iron is a well-known
inducer of oxidative stress. The administra-
tion of Fe-NTA to rats and mice causes in
vivo
oxidative DNA damage. It has been
reported that all four DNA bases are modi-
fied in the renal chromatin of rats within 24
h of Fe-NTA administration (22). Prostate
tissue is vulnerable to oxidative stress (36)
and whether carotenoids can protect against
DNA damage and lipoperoxidation associ-
ated with this process is of particular inter-
est.
Plasma ß-carotene and lycopene concen-
trations, measured as a function of time after
10 mg of ip injection of the carotenoid in
rats, are shown in Figure 1. The highest
concentration of ß-carotene in plasma, 4.05
± 0.84 nmol/mL, was reached after 6 h,
remaining at this level for another 3 h (Fig-
ure 1A). Rats injected with the same amount
of lycopene displayed a four-fold lower
plasma carotenoid concentration peak (0.97
± 0.16 nmol/mL blood) than those injected
with ß-carotene (Figure 1B). The maximum
plasma lycopene level was observed 3 h
after administration. The control animals,
which did not receive carotenoid treatment,
displayed no detectable plasma lycopene or
ß-carotene. Therefore, the carotenoid con-
centration used in this study for the treat-
ment of rats effectively raised plasma con-
centrations.
Figure 1. Plasma carotenoid concentration as a function of time. Data are reported as
means ± SEM for 5 rats in each group. A, ß-carotene levels. B, Lycopene levels. Blood was
To provide additional support for the
collected from rats supplemented with ß-carotene or lycopene (1-mL ip injection of a 10-mg/
hypothesis that increased carotenoid con-
mL solution) and analyzed by HPLC-electrochemical detection.
Braz J Med Biol Res 39(2) 2006

208
H.R. Matos et al.
spectively. Lycopene or ß-carotene were not
h after Fe-NTA treatment for rats pre-treated
detected in prostate tissue of control rats
with lycopene and with ß-carotene (377 ± 36
(data not shown).
nmol/g). ß-Carotene pre-treatment almost
Treatment with Fe-NTA caused substan-
completely prevented Fe-NTA-induced
tial lipid peroxidation in rat prostate tissue as
membrane damage, as indicated by MDA
indicated by MDA formation (Table 1). MDA
formation.
levels were 817 ± 122 nmol/g tissue 3 h after
The steady state level of 8-oxodGuo was
Fe-NTA administration. Carotenoid-supple-
quantified using a sensitive HPLC-electro-
mented rats showed inhibition of MDA for-
chemical detection method. The level of 8-
mation to control levels (364 ± 17 nmol/g) 3
oxodGuo in rat prostate DNA was signifi-
cantly higher (6.3 ± 0.6 residues/106 dGuo)
3 h after Fe-NTA administration compared
Table 1. Lycopene and ß-carotene supplementa-
with control rats (1.7 ± 0.3 residues/106
tion block the increase of MDA content of rat
prostate tissue after Fe-NTA treatment.
dGuo). Rats supplemented with lycopene or
ß-carotene for 5 days prior to Fe-NTA treat-
MDA (nmol/g protein)
ment showed a reduction of approximately
Control
359 ±
32b
70% in the 8-oxodGuo levels to almost con-
Lycopene (5 days)
363 ±
30
trol levels (Table 2). In fact, a large body of
ß-carotene (5 days)
367 ±
13
other evidence points to the role of oxidative
Fe-NTA (3 h)
817 ± 122a,b
Lycopene + Fe-NTA (3 h)
364 ±
17a
DNA damage in carcinogenesis (1). Induc-
ß-carotene + Fe-NTA (3 h)
377 ±
36a
tion of G:C to T:A transversion by 8-oxodGuo
can activate the ras oncogene by point muta-
Each value represents the mean ± SEM of 5 ani-
tion (37). The measurement of 8-oxodGuo
mals. Saline-treated animals served as control.
Lycopene or ß-carotene (10 mg/kg body weight)
in DNA has been indicated as a feasible
was administered for 5 consecutive days before
marker to investigate the antioxidant proper-
Fe-NTA (10 mg/kg body weight) treatment. MDA =
ties of food constituents in vivo (38).
malondialdehyde; Fe-NTA = ferric nitrilotriacetate.
aP < 0.001 compared to the Fe-NTA group; bP <
Using statistical analyses of Fourier trans-
0.005 compared to control (Student t-test).
form-IR spectra, Malins et al. (39) reported
that DNA of histologically normal human
prostates undergo structural changes in the
Table 2. Lycopene and ß-carotene supplementa-
bases and backbone with increasing age. Of
tion block the increase in 8-oxodGuo content of
prostate DNA of rats after Fe-NTA treatment.
the older men, 42% exhibited a DNA pheno-
type mimicking that of primary prostate tu-
8-oxodGuo
mors. Significantly higher levels of 8-
(residues/106 dGuo)
oxodGuo were found in prostate DNA of
Control
1.7 ± 0.3b
older men (ages 55-80 years) compared with
Lycopene
2.1 ± 0.4b
younger men (age 16-36 years). The authors
ß-carotene
2.3 ± 0.5
suggested that hydroxyl radicals contributed
Fe-NTA
6.3 ± 0.6a,b
Lycopene + Fe-NTA
1.8 ± 0.3a
to the structural changes that characterize
ß-carotene + Fe-NTA
1.9 ± 0.2a
the cancer-like phenotype (39).
The effect of consumption of tomato
Each value represents the mean ± SEM of 5 ani-
mals. Lycopene or ß-carotene (10 mg/kg body
sauce-based pasta dishes on lycopene up-
weight, ip) was administered for 5 days prior to
take, oxidative DNA damage, and prostate-
Fe-NTA (10 mg Fe/kg body weight, ip). 8-oxodGuo
specific antigen was reported by Chen et al.
= 8-oxo-7,8-dihydro-2'-deoxyguanosine; FE-NTA
(36) in patients diagnosed with prostate can-
= ferric nitrilotriacetate.
aP < 0.001 compared to the Fe-NTA group; bP <
cer. The levels of 8-oxodGuo were signifi-
0.005 compared to control (Student t-test).
cantly lower in the group consuming tomato
Braz J Med Biol Res 39(2) 2006

Prostate, DNA oxidation, and carotenoids
209
dishes for 3 weeks than in randomly selected
ported here, using iron as a model of oxida-
patients, and serum prostate-specific anti-
tive stress generation in vivo, indicate clearly
gen also decreased after this dietary inter-
that ß-carotene or lycopene provides strong
vention. These data indicate the possible
protection against membrane and DNA oxi-
application of tomato sauce constituent, pos-
dation in the prostate induced by iron treat-
sibly lycopene, in the treatment of prostate
ment. The present results support the in vivo
cancer.
antioxidant effect of carotenoids and pro-
Although epidemiological data show the
vide evidence to explain part of the benefi-
association between carotenoids and health
cial effects of tomato products reported in
protection, the antioxidant properties of these
epidemiological trials.
compounds are still debatable. The data re-
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