Food selection based on total antioxidant capacity can modify
antioxidant intake, systemic inflammation, and liver function without
altering markers of oxidative stress1–3
Silvia Valtueña, Nicoletta Pellegrini, Laura Franzini, Marta A Bianchi, Diego Ardigò, Daniele Del Rio, PierMarco
Piatti, Francesca Scazzina, Ivana Zavaroni, and Furio Brighenti
ABSTRACT
Background: It is unknown whether diets with a high dietary total
antioxidant capacity (TAC) can modify oxidative stress, low-grade
inflammation, or liver dysfunction, all of which are risk factors for
type 2 diabetes and cardiovascular disease.
Objective: We studied the effect of high- and low-TAC (HT and LT,
respectively) diets on markers of antioxidant status, systemic in-
flammation, and liver dysfunction.
Design: In a crossover intervention, 33 healthy adults (19 men, 14
women) received the HT and LT diets for 2 wk each. Dietary habits
were checked with a 3-d food record during both diet periods and the
washout period.
Results: Fruit and vegetable, macronutrient, dietary fiber, and al-
cohol intakes did not differ significantly between the 2 diets, whereas
dietary TAC, ␣-tocopherol, and ascorbic acid were significantly (P
쏝 0.001) higher during the HT diet. Plasma ␣-tocopherol rose during
the HT and decreased during the LT diet (P 쏝 0.02 for difference)
without changes in markers of oxidative stress except plasma mal-
ondialdehyde, which decreased unexpectedly during the LT diet (P
쏝 0.05). Plasma high-sensitivity C-reactive protein, alanine amino-
transferase, gamma-glutamyltranspeptidase, and alkaline phospha-
tase concentrations decreased during the HT compared with the LT
diet (mean 앐 SEM for pre-post changes: Ҁ0.72 앐 0.37 compared
with 1.05 앐 0.60 mg/L, P 쏝 0.01; Ҁ1.73 앐 1.02 compared with 2.33
앐 2.58 U/L, P 쏝 0.01; Ҁ2.12 앐 1.45 compared with 5.15 앐 2.98
U/L, P 쏝 0.05; and 1.36 앐 1.34 compared with 5.06 앐 2.00 U/L, P
쏝 0.01, respectively).
Conclusion: Selecting foods according to their TAC markedly af-
fects antioxidant intake and modulates hepatic contribution to sys-
temic inflammation without affecting traditional markers of antiox-
idant status. Am J Clin Nutr 2008;87:1290 –7.
INTRODUCTION
Systemic inflammation and oxidative stress appear to be in-
volved in the pathogenesis of type 2 diabetes and cardiovascular
disease (CVD) in the context of the metabolic syndrome. On one
hand, obesity, hypertension, insulin resistance, and nonalcoholic
fatty liver disease are all conditions associated with higher levels
of inflammatory proteins, increased markers of oxidative stress,
and lower plasma concentrations of antioxidants (1– 4). On the
other hand, prospective cohort studies have linked the consump-
tion of fruit and vegetables to a decreased risk of cardiovascular
events (5) and the intake of green leafy or dark-yellow vegetables
1290 Am J Clin Nutr 2008;87:1290 –7. Printed in USA. © 2008 American Society for Nutrition
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and coffee to a reduced risk of type 2 diabetes (6 – 8), which
suggests a protective effect of dietary antioxidants (9).
Indeed, public campaigns have been launched in several coun-
tries to increase the amount of fruit and vegetables consumed by
the general population (10 –12) as a tool for the primary preven-
tion of chronic disease, partly because of the contribution of fruit
and vegetables to overall antioxidant intake. Fruit and vegetables
are the main dietary sources of ascorbic acid and carotenoids and
contain a large number of phenolic antioxidants (which are more
ubiquitous in foods such as coffee, chocolate, tea, red wine,
whole-grain cereals, pulses, and nuts) (13, 14). However, even if
antioxidant compounds, including the scarce bioavailable phe-
nolics, are thought to play a role in disease prevention, the results
of intervention studies with single antioxidants administered as
supplements have been poor so far (15, 16).
Recently, the total antioxidant capacity (TAC) of foods, which
describes the ability of food antioxidants to scavenge preformed
free radicals, has been suggested as a tool for investigating the
health effects of antioxidants present in mixed diets (17). We
reported an inverse and independent cross-sectional relation be-
tween dietary TAC and markers of systemic inflammation
[C-reactive protein (CRP) and leukocytes], particularly in sub-
jects with hypertension (17). This suggests that dietary antioxi-
dants could protect against CVD by decreasing CRP concentra-
tions, primarily in subjects at risk. Because CRP is primarily
synthesized in the liver, and increasingly so in subjects with intra-
hepatic fat accumulation, oxidative stress, and liver dysfunc-
tion, we hypothesize that dietary antioxidants could modulate
low-grade systemic inflammation by counteracting hepatic
inflammation and liver dysfunction (18, 19). An additional
observation in the above-mentioned study was that almost
1
From the Department of Internal Medicine and Biomedical Sciences
(SV, LF, DA, and IZ) and the Department of Public Health (NP, MAB, DDR,
FS, and FB), University of Parma, Parma, Italy, and the Medicine Division,
Diabetology, Endocrinology and Metabolic Disease Unit, Scientific Institute
San Raffaele, Milano, Italy (PP).
2
Supported by the COFIN 2004 project from the Italian Ministry of Uni-
versity and Research and by the EC project “PIPS—Personalised Informa-
tion Platform for Life & Health Services” (IST-2004-507019).
3
Address reprint requests to F Brighenti, Human Nutrition Unit, Depart-
ment of Public Health, University of Parma, Via Volturno 39, 43100 Parma,
Italy. E-mail: furio.brighenti@unipr.it.
Received May 23, 2007.
Accepted for publication December 20, 2007.
 EFFECT OF DIETARY TAC ON ANTIOXIDANT STATUS AND INFLAMMATION 1291
TABLE 1
Dietary instructions for subjects during the high total antioxidant capacity (HT) and low total antioxidant capacity (LT) diets

HT instructions HT food list LT instructions LT food list

Five medium-sized Fruit: red berries, oranges, grapefruit, plums Five medium-sized Fruit: apple, pear, banana, grape (white), melon
portions a day (red), grapes (black), pineapple portions a day
Vegetable: spinach, beet, Swiss chard, Vegetable: aubergine, leek, potatoes,
pepper (red bell), Brussels sprouts, courgettes, French beans, carrots, celery,
broccoli, rocket, radicchio, olive (black), lettuce, cucumber, radish, beans
mushrooms, broad beans
At least 2 cups of Coffee (espresso, cappuccino, American No hot beverages —
hot beverages a coffee, barley coffee), tea (black and allowed
day green), hot chocolate
At least 200 mL of Fresh-squeezed orange juice, fresh- No restrictions of the Apple juice, cola,1 soda2
drink squeezed grapefruit juice, blueberry juice, following drinks
mixed juice (orange, carrot, and lemon),
orange juice
Fats allowed Extra-virgin olive oil Fats allowed Refined olive oil
Alcoholic beverages Red wine Alcoholic beverages White wine, beer
allowed (if used) allowed (if used)
Sweets allowed Black chocolate bars, red berries ice cream Sweets allowed White chocolate bars, vanilla ice cream
Other items allowed Walnuts, red vinegar Other items allowed Peanuts, white vinegar
1
Coca-cola; Coca-Cola HBC, Italy.
2
Sprite; Coca-Cola HBC.

one-half of the variability in habitual TAC intake was ex-
plained by differences in antioxidant content among single
food items within any given food group, leading to the hy-
pothesis that fruit, vegetables, grains, and drinks could have
different effects on health depending on the antioxidant con-
tent of the single items actually consumed (17).
To test the above hypotheses, we conducted a crossover inter-
vention study to investigate the effects of a diet naturally rich in
antioxidants compared with a diet low in antioxidants, both con-
taining the same amount of fruit, vegetables, alcoholic bever-
ages, and fiber, on markers of antioxidant status, systemic in-
flammation, and liver dysfunction. Secondary endpoints were
traditional risk factors for CVD (namely insulin resistance, blood
pressure, and the lipid profile) and adipokines.
SUBJECTS AND METHODS
Subjects
Nineteen men and 15 postmenopausal women from a cohort of
apparently healthy workers and exworkers of a local food com-
pany who were enrolled in a follow-up survey on diabetes and
CVD (20) volunteered to participate in the present intervention
study. Exclusion criteria were diabetes mellitus, cardiovascular
events, evidence of hepatitis B virus or hepatitis C virus infec-
tion, chronic liver diseases or nephropathies, cancer, organ fail-
ure, smoking, last menses within the past 12 mo, taking
cholesterol-lowering or anti-inflammatory medications, and
having taken hormone replacement therapy for the past 12 mo.
The protocol was approved by the Ethics Committee for Human
Research of the University of Parma.
Study design
Subjects consumed a diet with high TAC (HT) and a diet with
low TAC (LT) for 2 wk each, with a 2-wk washout (WO) period
in between. The order of diets was randomly assigned. The sub-
jects were also instructed to maintain their usual level of physical
activity and to not consume supplements of any type during the
study. In the last week of the HT, LT, and WO periods, the
subjects completed a 3-d food record to assess dietary habits and
compliance. At the beginning and the end of each diet, a medical
history to check health status and medication use, a brief physical
examination including anthropometric variables and blood pres-
sure, and a blood draw for biochemical analyses after the subjects
had fasted overnight for 12 h were taken. Liver steatosis was
assessed by echography, but the subjects were not recruited on
the basis of that characteristic.
Description of diets
Two dietary interventions (HT and LT) were designed to be
comparable for energy, macronutrient, fiber, and alcohol intakes
but to differ substantially in TAC. To achieve this objective, the
subjects were asked to consume a minimum of 5 medium-sized
portions of fruit and vegetables daily in both diets, but choices of
only high-TAC items were permitted during the HT diet and
choices of only low-TAC foods were allowed during the LT diet
(21, 22). Similar changes were introduced regarding beverages,
sweets, and dressings (Table 1). To control for dietary sources of
TAC and to enhance compliance, a wide choice of food items
permitted during each dietary period was delivered biweekly to
the volunteers at home free of charge and in sufficient amounts
to cover the intended consumption of each volunteer and his or
her household. Volunteers were also instructed to follow sug-
gestions regarding the consumption of first courses, with partic-
ular attention to seasoning (ie, use of tomato sauce, olive oil,
vinegar, and spices). Finally, the subjects were asked to consume
their usual diet during the WO period and to maintain their usual
dietary habits relative to the consumption of meat, fish, milk and
dairy products, eggs, cereal products, sweets, cakes, and alcohol
throughout the whole 6-wk study period.
Data collection
Anthropometric variables (height, weight, and waist circumfer-
ence) were collected as previously described (17). Blood pressure
was measured twice in a standard manner (17). Hypertension was

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 1292 VALTUEÑA ET AL
defined as active treatment with blood pressure–lowering medica-
tions or systolic blood pressure 욷140 mm Hg or diastolic blood
pressure 욷 90 mm Hg on at least 2 occasions out of the 4 d in which
blood pressure was measured. A liver ultrasonography was per-
formed to assess the degree of liver steatosis (0, absent; 1, mild; 2,
moderate; 3, severe) as defined by Saverymuttu et al (23). All ul-
trasonographies were performed by the same operator, who was
blinded to dietary assignment and laboratory values, using a Hitachi
AU 600 echographer equipped with a convex 3.5 MHz transducer
(Hitachi Ltd, Tokyo, Japan).
Dietary data
At baseline, the subjects completed a food-frequency question-
naire specially designed to retrieve information on usual antioxidant
intake (24). In addition, a certified dietitian trained the subjects to fill
in a 3-d weighed-food record that included all foods, beverages, and
supplements consumed during 2 nonconsecutive working days plus
a weekend day the last week of the LT, HT, and WO periods. The
food record relative to the WO period was considered to be repre-
sentative of the subject’s usual diet. The record was checked for
completeness and portion sizes within 48 h of compilation by using
a book of photographs and standard household measures. Nutrient
intakes and TAC were calculated by using an in-house Microsoft
ACCESS application (Microsoft Corp, Redmond, WA) linked to
the food database of the European Institute of Oncology, which
covered 쏜700 Italian foods (25) integrated with the TAC values of
쏜150 raw foods, measured as ferric-reducing antioxidant power
(26). Moreover, compliance during the HT and LT periods was
assessed by means of a food chart specifically designed to track the
number of portions consumed daily of each food item permitted.
Biochemical analyses
High-sensitivity CRP (hs-CRP) was measured by using an
ELISA kit (ICN Pharmaceuticals, New York, NY) with a mini-
mum detectable concentration of 0.004 mg/L. Intra- and inter-
assay CVs were 2.3% and 2.5%, respectively. Serum insulin
concentrations were measured by microparticle enzyme immu-
noassay (IMX; Abbott Laboratories, Abbott Park, IL), with
intra- and interassay CVs of 3.0% and 5.3%, respectively. For
human leptin, adiponectin, and tumor necrosis factor-␣, see the
supplemental online material. Fasting plasma glucose, total cho-
lesterol, HDL cholesterol, triacylglycerols, uric acid, aspartate
aminotransferase, alanine aminotransferase (ALT), gamma-
glutamyltranspeptidase (GGT), and alkaline phosphatase were
assessed by a central laboratory using standard methods. LDL
cholesterol was calculated by using the Friedewald formula. A
complete blood cell count was performed at the Laboratory of
Hematology by using a Beckman-Coulter Hmx analyzer
(Beckman-Coulter, Miami, FL).
The TAC of plasma was estimated from its ability to reduce a
Fe(III)-2,4,6-tri(2-pyridyl)-s-triazine complex to Fe(II)-2,4,6-
tri(2-pyridyl)-s-triazine (26) by using a multiplate reader (Tecan,
Maennedorf, Switzerland). Each determination was performed in
triplicate on plasma obtained from EDTA-collected blood and was
analyzed within 4 h of collection. Plasma ␣-tocopherol was quan-
tified by reversed-phase HPLC with diode array detection according
to the method of Gimeno et al (27), with slight modifications.
Plasma malondialdehyde was detected by the method of Del
Rio et al (28). Oxidized LDLs were detected in plasma by a
solid-phase two-site enzyme immunoassay (DRG International
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Inc, Mountainside, NJ), with 2 monoclonal antibodies directed
against separate antigenic determinants on the oxidized apoli-
poprotein B molecule. Finally, protein carbonyls were quantified
by the Protein Carbonyl Diagnostic kit (Biocell Corporation
Limited, Papatoetoe, Auckland, New Zealand).
Statistical analyses
Statistical analyses were performed by using SPSS (version
14.0; SPSS Inc, Chicago, IL). Preliminary data (17) were used for
statistical power calculations (80% power and ␣ of 5%), showing
that 24 subjects had to complete both dietary treatments to detect
a change of 2.5 mg/L in hs-CRP concentrations with an SD of 2.9
mg/L. A total of 34 subjects were recruited to allow for dropouts
and for nonparametric statistical analysis (15% additional sub-
jects required), because we anticipated that not all clinical and
biochemical data would be normally distributed at all time
points. This actually applied to certain variables (notably hs-
CRP, tumor necrosis factor-␣, and liver enzymes), and given that
not all of them could be normalized, we preferred the more
conservative approach of using nonparametric tests in all occa-
sions. Clinical and biochemical variables at any given time point
(pre- and postdietary variables) were expressed as means 앐 SDs
when the data were normally distributed and as medians (inter-
quartile range) when the data did not follow a normal distribu-
tion. Differences in clinical and biochemical variables between
pre- and postintervention periods, being normally distributed,
were all expressed as means 앐 SEMs. The homeostasis model
assessment was used as surrogate of insulin resistance (29). For
comparisons between sexes, the Mann-Whitney U test or chi-
square statistics were used as appropriate. Comparisons between
pre- and postdiet values and between the LT and HT periods were
performed by using Wilcoxon’s test for paired samples. All di-
etary variables were normally distributed. Comparisons among
the HT, LT, and WO diets were performed by repeated-measures
general linear models and Bonferroni post-hoc tests, with diet as
a within-subject factor and the order of intervention as a between-
subject factor.
Repeated-measures general linear models were also applied to
investigate the interaction between treatment and presence of
liver steatosis, after data transformation into rank proportion
estimates according to Tukey’s formula. All tests were two-
sided, and significance was set at P 쏝 0.05.
RESULTS
Immediately after the first visit, a woman randomly assigned
to receive the HT diet as the first intervention dropped out for
personal reasons. The characteristics at admission of the 33 sub-
jects who completed the protocol are shown in Table 2. Five (4
male and 1 female) volunteers were taking antihypertensive
medications, and 11 (9 male and 2 female) subjects fulfilled the
criteria for having hypertension during the study. The prevalence
of hypertension and plasma TAC were significantly higher, and
plasma concentrations of HDL cholesterol, leptin, and adiponec-
tin were significantly lower, in men than in women. No other
significant difference between the sexes was observed at baseline
for the variables studied. Liver steatosis was absent in 14 subjects
(8 female), mild in 13 (1 female), moderate in 5 (3 female), and
severe in 1 (female).
 EFFECT OF DIETARY TAC ON ANTIOXIDANT STATUS AND INFLAMMATION 1293
TABLE 2
Demographic, clinical, and dietary characteristics of the volunteers at admission1

All Men Women

Variables (n ҃ 33) (n ҃ 19) (n ҃ 14)

Age (y) 61.1 앐 3.72 62.1 앐 3.6 59.8 앐 3.6

BMI (kg/m2) 27.3 앐 2.7 27.2 앐 1.6 27.4 앐 3.9
Waist girth (cm) 96.4 앐 7.7 96.2 앐 5.3 96.7 앐 10.3
Hypertension [n (%)] 16 (48) 13 (68) 3 (21)3
Liver steatosis [n (%)] 20 (61) 14 (74) 6 (43)
Fasting glucose (mg/dL) 95.1 앐 9.5 96.8 앐 8.0 92.8 앐 11.1
Fasting insulin (pmol/L) 60.0 앐 27.0 62.4 앐 28.2 56.9 앐 26.0
HOMA-IR 2.22 앐 1.11 2.47 앐 1.24 1.87 앐 0.82
Total cholesterol (mmol/L) 5.82 앐 0.94 5.71 앐 1.00 5.96 앐 0.88
HDL cholesterol (mmol/L) 1.47 앐 0.39 1.30 앐 0.33 1.70 앐 0.353
LDL cholesterol (mmol/L) 3.82 앐 0.74 3.85 앐 0.74 3.78 앐 0.76
Triacylglycerols (mmol/L) 1.15 앐 0.50 1.23 앐 0.55 1.06 앐 0.42
Uric acid (mg/dL) 4.87 앐 1.24 5.32 앐 1.40 4.26 앐 0.60
AST (U/L) 21.4 앐 5.8 22.3 앐 7.2 20.3 앐 2.7
ALT (U/L) 23.3 앐 8.0 24.9 앐 8.7 21.1 앐 6.7
GGT (U/L) 25.6 앐 17.1 28.8 앐 18.0 21.1 앐 15.4
Alk-P (U/L) 58.4 앐 14.6 55.1 앐 11.6 62.9 앐 17.3
hs-CRP (mg/L) 2.48 앐 2.06 2.09 앐 1.82 3.00 앐 2.31
Leucocytes (҂109/L) 5.5 앐 1.4 5.8 앐 1.6 5.1 앐 1.0
Leptin (ng/mL) 14.13 앐 12.16 7.03 앐 3.74 23.76 앐 13.074
Adiponectin (␮g/mL) 15.13 앐 7.23 11.48 앐 4.53 20.09 앐 7.383
TNF-␣ (pg/mL) 4.27 앐 4.93 4.10 앐 4.69 4.49 앐 5.42
␣-Tocopherol (␮mol/L) 34.77 앐 6.84 33.69 앐 6.63 36.25 앐 7.08
Plasma TAC [␮mol Fe(II)/L] 1019 앐 189 1096 앐 196 914 앐 1183
MDA (␮mol/L) 0.11 앐 0.03 0.12 앐 0.04 0.10 앐 0.03
Carbonyls (ng/mg protein) 0.13 앐 0.14 0.14 앐 0.17 0.11 앐 0.07
oxLDL (␮mol/L) 81.30 앐 34.44 82.15 앐 29.13 80.20 앐 41.42
Dietary TAC [mmol Fe(II)/d] 22.00 앐 5.91 23.01 앐 6.76 20.62 앐 4.39
1
HOMA-IR, homeostasis model assessment of insulin resistance; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, ␥-glutamyl-
transpeptidase; Alk-P, alkaline phosphatase; hs-CRP, high-sensitivity C-reactive protein; TNF-␣, tumor necrosis factor-␣; TAC, total antioxidant capacity;
MDA, malondialdehyde; oxLDL, oxidized LDL. The Mann-Whitney U test or chi-square statistics were used for comparisons between men and women as
appropriate.
2
x៮ 앐 SD (all such values).
3,4
Significantly different from men: 3 P 쏝 0.010, 4 P 쏝 0.001.

Dietary variables
Dietary data, as determined by the 3-d weighed-food record,
are reported in Table 3. Dietary intakes of energy, macronutri-
ents, and alcohol during the LT, HT, and WO periods were not
significantly different. As aimed for in the study design, dietary
fiber was not significantly different between the LT and HT
periods but was significantly lower during the WO period than
during the LT and HT periods (P 쏝 0.01).
As expected, intakes of single antioxidants and dietary TAC
was significantly higher during the HT than during the LT period

TABLE 3
Average daily dietary intake and total antioxidant capacity (TAC) during the high-TAC diet (HT), the low-TAC diet (LT), and the washout period (WO)1

HT LT WO P

TAC [mmol Fe(II)/d] 28.71 앐 8.05 a

5.62 앐 1.55b
19.09 앐 5.89c
쏝0.001
Energy (kcal/d) 2491 앐 429 2443 앐 447 2482 앐 453 0.624
Protein (g/d) 89.7 앐 23.2 86.0 앐 17.1 85.0 앐 17.4 0.494
Total fat (g/d) 87.8 앐 21.3 91.5 앐 18.1 92.7 앐 18.7 0.474
Saturated fat (g/d) 32.0 앐 4.4 34.7 앐 5.7 33.2 앐 4.9 0.095
Monounsaturated fat (g/d) 55.6 앐 5.0 53.5 앐 5.4 54.0 앐 4.3 0.130
Polyunsaturated fat (g/d) 12.4 앐 2.6 11.8 앐 2.0 12.9 앐 2.4 0.194
Total carbohydrate (g/d) 314.2 앐 65.6 295.7 앐 67.4 294.6 앐 72.4 0.255
Dietary fiber (g/d) 25.1 앐 6.3a 25.2 앐 5.9a 22.0 앐 5.5b 0.010
Alcohol (g/d) 22.7 앐 14.9 22.2 앐 13.6 27.8 앐 19.0 0.097
Vitamin C (mg/d) 423.0 앐 197.9a 91.7 앐 72.1b 168.0 앐 128.5c 쏝0.001
Vitamin E (mg/d) 16.2 앐 4.7a 7.5 앐 1.6b 14.5 앐 4.3a 쏝0.001
1
All values are x៮ 앐 SD. Comparisons were performed by repeated-measures GLM and Bonferroni post-hoc tests. Different letters correspond to
significantly different values.

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 1294 VALTUEÑA ET AL
30 The contribution of the antioxidant capacity of specific food
categories to daily TAC in the LT, HT, and WO periods is
25 reported in Figure 1. The major contributors to TAC during the
WO period were alcoholic beverages (28.1%, red wine being the
FRAP [mmol Fe(II)/d]

+8%
20
major contributor) and coffee and tea (34.2%, coffee being con-
Alcoholic
beverages
sumed overwhelmingly more than tea). During the LT diet, the
15 +21% reduction of daily TAC with respect to the WO period was mainly
-82%
Coffee & Tea
due to a reduced TAC intake from such beverages. Conversely,
10
-98% +123% the increase in daily TAC during the HT period was primarily due
5 -29%
Fruits & juices
+143%
to the highest TAC of fruit and vegetables, because the TAC from
-64% Vegetables alcoholic beverages, tea, and coffee remained almost unchanged
+66%
-26% Others
0 compared with the WO period. The number of actual portions of
LT WO HT fruit and vegetable consumed, as calculated by the compliance
FIGURE 1. Contribution of food categories to daily dietary total antiox- charts, was 5.3 앐 0.6 and 5.0 앐 1.4 for the LT and HT periods,
idant capacity (TAC) in the high-TAC (HT), low-TAC (LT), and washout respectively (P ҃ 0.604).
(WO) periods. Vegetables represents the sum of vegetables, legumes, and
spices; others includes the contribution of chocolate, cereals and cereal-
derived products, nuts, sweets, soft drinks, and oils and dressings. FRAP, Biochemical variables
ferric reducing antioxidant power.
The study variables at the beginning and end of each dietary
intervention, as well as the changes observed during each dietary
(P 쏝 0.001). The intake of some antioxidants and TAC were also period, are shown in Table 4. Pre-post changes in concentrations
higher during the WO period than during the LT period (P 쏝 of hs-CRP, ALT, GGT, and alkaline phosphatase were signifi-
0.001 for vitamin E; P 쏝 0.001 for vitamin C; P 쏝 0.001 for cantly different between the HT period and the LT period. Be-
TAC) but were lower than during the HT period (P 쏝 0.001 for cause pre-LT and pre-HT values for hs-CRP differed (P 쏝 0.05),
vitamin C; P 쏝 0.001 for TAC). we recalculated the changes in hs-CRP as a percentage of initial

TABLE 4
Values for the study variables before and after the low and the high total antioxidant capacity (TAC) diets (LT and HT, respectively) and changes (⌬)
observed during each dietary period1

Pre-LT Post-LT ⌬LT2 Pre-HT Post-HT ⌬HT2 P3

Weight (kg) 73.6 앐 10.2 73.7 앐 10.3 0.07 앐 0.16 73.6 앐 10.2 73.9 앐 10.0 0.28 앐 0.18 0.308
SBP (mm Hg) 129.7 앐 14.4 126.2 앐 13.24 Ҁ3.58 앐 1.34 127.4 앐 14.0 126.7 앐 11.1 Ҁ0.76 앐 1.72 0.213
DBP (mm Hg) 84.2 앐 8.9 81.1 앐 7.85 Ҁ3.06 앐 0.99 84.1 앐 7.1 82.6 앐 7.8 Ҁ1.58 앐 0.86 0.307
Fasting glucose (mg/dL) 95.5 앐 9.3 95.4 앐 10.2 Ҁ0.15 앐 1.24 96.3 앐 8.3 95.6 앐 10.0 Ҁ0.70 앐 1.00 0.660
Fasting insulin (pmol/L) 58.7 앐 30.8 59.0 앐 33.2 0.29 앐 4.85 57.4 앐 30.7 57.9 앐 29.1 0.51 앐 5.09 0.775
HOMA-IR 2.24 앐 1.19 2.12 앐 1.19 Ҁ0.11 앐 0.17 2.08 앐 1.13 2.13 앐 1.23 Ҁ0.04 앐 0.23 0.561
Total cholesterol (mmol/L) 5.80 앐 0.90 5.67 앐 0.91 Ҁ0.12 앐 0.11 5.93 앐 0.88 5.73 앐 0.894 Ҁ0.21 앐 0.09 0.592
HDL cholesterol (mmol/L) 1.43 앐 0.34 1.40 앐 0.33 Ҁ0.02 앐 0.02 1.46 앐 0.37 1.39 앐 0.364 Ҁ0.07 앐 0.03 0.161
LDL cholesterol (mmol/L) 3.85 앐 0.10 3.75 앐 0.14 Ҁ0.10 앐 0.11 3.95 앐 0.13 3.79 앐 0.10 Ҁ0.16 앐 0.08 0.629
Triacylglycerols (mmol/L) 1.12 앐 0.47 1.11 앐 0.45 Ҁ0.01 앐 0.06 1.14 앐 0.35 1.19 앐 0.56 0.05 앐 0.06 0.308
Uric acid (mg/dL) 4.8 앐 1.2 4.8 앐 1.2 Ҁ0.01 앐 0.08 5.0 앐 1.3 4.9 앐 1.2 Ҁ0.05 앐 0.08 0.851
AST (U/L) 22 (5)6 23 앐 4 0.33 앐 1.38 23 앐 5 24 앐 9 0.06 앐 0.53 0.303
ALT (U/L) 24 앐 9 22 (11)6 2.33 앐 2.58 24 앐 8 22 앐 74 Ҁ1.73 앐 1.02 0.008
GGT (U/L) 27 앐 17 21 (21)5,6 5.15 앐 2.98 27 앐 17 25 앐 13 Ҁ2.12 앐 1.45 0.048
Alk-P (U/L) 56 앐 16 61 앐 185 5.06 앐 2.00 58 앐 14 57 앐 13 Ҁ1.36 앐 1.34 0.009
hs-CRP (mg/L) 2.4 앐 2.23 1.5 (3.0)6 1.05 앐 0.60 3.0 앐 2.47 2.5 앐 2.1 Ҁ0.72 앐 0.37 0.007
Leucocytes (҂109/L) 5.3 앐 1.3 5.4 앐 1.2 0.08 앐 0.11 5.4 앐 1.5 5.2 앐 1.1 Ҁ0.17 앐 0.15 0.127
␣-Tocopherol (␮mol/L) 35.31 앐 7.18 33.40 앐 6.45 Ҁ1.91 앐 4.85 35.12 앐 6.66 36.12 앐 7.21 0.99 앐 4.86 0.013
TAC [␮mol Fe(II)/L] 1005.8 앐 206.7 1013.6 앐 194.8 7.8 앐 111.5 993.5 앐 163.8 970.4 앐 182.9 Ҁ23.1 앐 133.9 0.070
MDA (␮mol/L) 0.11 앐 0.04 0.10 앐 0.02 Ҁ0.01 앐 0.03 0.10 앐 0.02 0.10 앐 0.02 0.00 앐 0.01 0.038
Carbonyls (ng/mg protein) 0.12 앐 0.06 0.11 앐 0.05 Ҁ0.01 앐 0.06 0.12 앐 0.13 0.11 앐 0.05 Ҁ0.01 앐 0.13 0.623
oxLDL (␮mol/L) 79.0 앐 31.9 75.6 앐 26.3 Ҁ3.4 앐 12.5 81.3 앐 33.7 77.6 앐 28.9 Ҁ4.1 앐 23.5 0.999
All values are x៮ 앐 SD unless otherwise noted. SBP, systolic blood pressure; DBP, diastolic blood pressure; HOMA-IR, homeostasis model assessment
1

of insulin resistance; AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, ␥-glutamyltranspeptidase; Alk-P, alkaline phosphatase; hs-CRP,
high-sensitivity C-reactive protein; MDA, malondialdehyde; oxLDL, oxidized LDL. Comparisons were performed by using the Wilcoxon test for paired
samples.
2
x៮ 앐 SEM.
3
P values refer to comparisons between ⌬LT and ⌬HT.
4,5
Significantly different from prediet values: 4 P 쏝 0.05, 5 P 쏝 0.01.
6
Data were not normally distributed and are expressed as medians (interquartile range).
7
Significantly different from pre-LT, P 쏝 0.05.

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 EFFECT OF DIETARY TAC ON ANTIOXIDANT STATUS AND INFLAMMATION
values and obtained similar results (data not shown). No signif-
icant differences between dietary treatments were observed for
changes in body weight, plasma glucose, insulin, homeostasis
model assessment of insulin resistance index, lipid profile, uric
acid, aspartate aminotransferase, adipokines (leptin, adiponec-
tin, tumor necrosis factor-␣; see supplemental online material),
or leukocytes.
Plasma ␣-tocopherol rose after the HT diet and decreased after
the LT diet, and the changes from before to after were signifi-
cantly different between treatments. Unexpectedly, plasma mal-
ondialdehyde decreased during the LT period and the changes
from before to after were significantly different between treat-
ments. Other markers of antioxidant status (TAC, antibodies
against ox-LDL, and protein carbonyls) remained unaffected.
To explore whether the presence of liver steatosis played a role
in the differential effect that both diets had on plasma concen-
trations of hs-CRP and liver enzymes, we performed a general
linear models analysis considering liver steatosis as a between-
subject factor. Neither the sex distribution nor plasma concen-
trations of hs-CRP or liver enzymes were significantly different
between the groups with or without liver steatosis at baseline
(data not shown). Moreover, the liver steatosis ҂ treatment in-
teraction was not significant (P ҃ 0.125).
DISCUSSION
Previous dietary intervention studies performed to evaluate
the biological effects of antioxidants in foods were aimed at
increasing the intake in the intervention arm of single
antioxidant-rich foods or food groups, while scarcely controlling
for other dietary factors (30, 31). To our knowledge, this is the
first study designed to extensively modify antioxidant intake
from food sources by selecting, within a given food group, items
with either the highest or the lowest TAC while maintaining
underlying dietary habits. Indeed, the HT and LT diets did not
differ regarding the intake of macronutrients, dietary fiber, alco-
hol, or daily servings of fruit and vegetables, but ensured signif-
icantly different intakes not only of dietary TAC but also of single
antioxidant molecules.
Compliance with the intervention is supported by the recipro-
cal changes in plasma ␣-tocopherol during the LT and HT peri-
ods, which mirrored dietary intake and differed significantly
between the diets. Nevertheless, plasma TAC was practically
unmodified by dietary TAC, as already reported in the literature
(31, 32). Steady plasma TAC concentrations corresponded with
a relative stability of oxidative stress biomarkers, which either
did not change during the dietary interventions or even showed
slight but significant modifications in unexpected directions.
The lack of effect of an increased antioxidant intake on the
balance between antioxidant status and oxidative stress could
indicate a homeostatic mechanism in which endogenous antioxi-
dants fluctuate to compensate for a reduced or increased influx of
dietary antioxidants (33). The duration of treatment could also
have played a role: 2 wk may be long enough to appreciate
modifications in the plasma concentration of single antioxidant
molecules, but may not be sufficient to allow substantial modi-
fications in total antioxidant balance.
Conversely, a mild but significant beneficial effect of dietary
antioxidants on systemic inflammation and liver dysfunction
was observed. Specifically, we noted a decrease in ALT, alkaline
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1295
phosphatase, and GGT activities as well as in plasma concentra-
tions of hs-CRP with a diet naturally rich in antioxidants com-
pared with a diet low in antioxidants. The biological plausibility
of these results is sustained by previous evidence in different
ways.
First, large cross-sectional studies have shown that ALT and
GGT activities are inversely related to plasma antioxidants, and
ALT and GGT have therefore been proposed as markers of ox-
idative stress (34 –36). Actually, reactive oxygen species are
increasingly produced in the liver after fat accumulation and are
known to impair mitochondrial oxidation and function (19). Be-
cause antioxidant compounds can neutralize reactive oxygen
species, an increased influx of antioxidants to the liver could be
likely to induce a decrease in markers of liver damage, as in our
study (37).
Second, ALT, GGT, and alkaline phosphatase have shown a
strong and direct relation with hs-CRP in population studies (18,
38), which in turn appears to be inversely related to dietary TAC
independently of other factors known to decrease hs-CRP, in-
cluding single antioxidant vitamins and carotenoids (17). Thus,
our observation that a high-TAC diet has the simultaneous effect
of decreasing liver enzymes and hs-CRP compared with a low-
TAC diet further supports the contribution of hepatic inflamma-
tion to low-grade systemic inflammation associated with the
metabolic syndrome (18, 38) and confirms the possibility of
modifying such independent risk factors for type 2 diabetes and
CVD with a diet naturally rich in antioxidants (39 – 43).
The present study, a controlled intervention aimed at drasti-
cally changing antioxidant intake from foods and beverages
while maintaining the same dietary pattern, may help to elucidate
the dissociation between the theoretical benefit from antioxi-
dants in the prevention of nonalcoholic fatty liver disease, type 2
diabetes, and CVD risk, and the practical lack of evidence from
intervention studies, with the possible exception of effects of
high doses of vitamin E given as a supplement on hs-CRP (44)
and markers of nonalcoholic steatohepatitis (45, 46). Actually,
most interventions have provided supplements of antioxidant
vitamins or carotenoids, which may not be as efficient in restor-
ing the redox network as are antioxidants present in mixed diets
(47, 48).
Esmaillzadeh et al (49) recently reported an inverse relation
between plasma CRP, the risk of metabolic syndrome, and the
quintile of fruit and vegetable intake of a group of 486 Iranian
female teachers. Those authors concluded that dietary recom-
mendations to increase fruit and vegetable intake are a primary
preventive measure against CVD. However, an indication given
by the present work is that the effect of increasing the amount of
fruit and vegetables on human health may greatly depend on the
TAC of such food items, and this should be taken into consider-
ation when exploring the effects of fruit and vegetable consump-
tion on disease prevention. An indication in this direction was
already given by 2 prospective cohort studies in which a lower
incidence of type 2 diabetes and lower concentrations of glyco-
sylated hemoglobin were not linked to the consumption of fruit
and vegetables per se but specifically to the consumption of those
with the highest antioxidant capacity (6, 7). Similarly, Agudo et
al (50) recently reported that, beside the amount, the TAC from
fruit and vegetables was associated with reduced mortality in the
EPIC Spanish cohort.
Obvious limitations of the present study are the small sample
size, the short duration of the intervention, and, consequently, the
 1296 VALTUEÑA ET AL
use of surrogate markers of disease as endpoints. For example,
we cannot exclude an effect of dietary antioxidants on blood
pressure, lipid profile or adipokines, because sample sizes were
not calculated for these secondary outcomes, nor on insulin re-
sistance, because the clamp technique was not available. Simi-
larly, some evidence supports an association between improved
aminotransferase concentrations and liver biopsy findings in
nonalcoholic fatty liver disease patients under treatment (51), as
well as a benefit of reduced hs-CRP and liver enzymes on the risk
of type 2 diabetes and CVD (39 – 43). However, whether risk of
the above chronic diseases can effectively be reduced through
dietary antioxidants needs to be confirmed in larger, long-term
intervention trials.
In conclusion, qualitatively selecting food items on the basis of
their TAC was a useful and effective approach to demonstrate
that, in addition to the quantity, the quality of certain food groups
may be crucial to decreasing hepatic and systemic inflammation,
both of which are independent risk factors for chronic disease.
That such a result was achieved without modifying biomarkers of
antioxidant status opens new perspectives to investigate the
mechanisms of action of antioxidant-rich foods. In the meantime,
giving preference to foods naturally high in TAC could be a
simple approach to further improving dietary habits.
We thank Elisa Campanini and Dirce Gennari from the Department of
Public Health and the Department of Internal Medicine and Biomedical
Sciences, respectively, for their skilful assistance in laboratory analyses;
Filippo Numeroso from the Department of Internal Medicine and Biomedical
Sciences for performing the liver ultrasound examinations; and Serena Marks
for kindly revising our English writing.
The contributions of the authors were as follows—SV, LF, DA, and MAB:
participated in requesting approval from the ethics committee, subject re-
cruitment, collection and interpretation of the clinical data, and subjects’
management; IZ: responsible for requesting approval from the ethics com-
mittee, subject recruitment, collection and interpretation of the clinical data,
and subjects’ management; DDR, MAB, NP, and FS: responsible for the
collection and interpretation of dietary and laboratory data of antioxidant
status biomarkers; PP: supervised the analysis and interpretation of biochem-
ical data; SV, NP, DDR, and FB: were the primary authors of the manuscript,
and all other authors provided input; FB and NP: were responsible for study
concept and design; FB and IZ: secured the funding for the study. None of the
authors had any personal or financial conflicts of interest.
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