Un articolo scientifico selezionato da Revidox

1. Cardiovascular Research 73 (2007) 341 – 347
www.elsevier.com/locate/cardiores
Review
Dietary polyphenols: Good, bad, or indifferent for your health?
Barry Halliwell
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore,
8 Medical Drive, MD7 Level 2, 117597 Singapore, Singapore
Received 19 June 2006; received in revised form 16 August 2006; accepted 4 October 2006
Available online 13 October 2006
Time for primary review 27 days
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Abstract
Flavonoids and other polyphenolic compounds have powerful antioxidant effects in vitro in many test systems, but can act as pro-
oxidants in some others. Whether pro-oxidant, antioxidant, or any of the many other biological effects potentially exerted by flavonoids
account for or contribute to the health benefits of diets rich in plant-derived foods and beverages is uncertain. Phenolic compounds may help
to protect the gastrointestinal tract against damage by reactive species present in foods or generated within the stomach and intestines. The
overall health benefit of flavonoids is uncertain, and consumption of large quantities of them in fortified foods or supplements should not yet
be encouraged.
© 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
Keywords: Atherosclerosis; Cell culture/isolation; Redox signalling
1. Introduction mined. α-Tocopherol acts much more effectively as an anti-
oxidant in mice than it does in humans, and its ability to protect
The traditional “trio” of antioxidants (ascorbate, β-carotene, against atherosclerosis and neurodegeneration in mice is cor-
α-tocopherol) has had a bad press recently, with human respondingly greater [12–16].
intervention trials giving mostly-negative results, and some
meta-analyses and other studies suggesting that these agents 2. Fruits and vegetables
not only fail to protect against disease, but also that some of
them may accelerate development of cancers or cardiovascular Among the few things uncontested by nutritionists are
disease in certain subjects [1–6]. Does this mean that the that increased consumption of grains, fruits, and vegetables,
concept that free radicals and other reactive species contribute decreased saturated fat intake, a moderate degree of exercise
to the development of age-related diseases such as cancer is and a judicious consumption of red wine (or other alcoholic
incorrect? Possibly, but I do not believe so (reviewed in [7]). beverages) seem associated with a lower risk of developing
Instead, I think it to be more likely that the antioxidant cardiovascular disease, some forms of cancer, and perhaps
administrations simply failed to protect against oxidative Alzheimer's disease [15,17–23]. However, foods and
damage (discussed in detail in [2,7–9]). For example, high beverages derived from plants are chemically complex, and
doses of α-tocopherol are poorly-effective at decreasing levels protective effects could arise from many components or
of lipid peroxidation in humans, as measured by reliable mixtures of components present, including fibre, immunos-
biomarkers such as F2-isoprostanes [7,10,11]. Whether other timulatory agents, inducers of antioxidant or xenobiotic-
tocopherols, or tocotrienols, work better remains to be deter- metabolizing enzymes, monounsaturated fatty acids, agents
that modulate cholesterol synthesis, B-vitamins, folic acid
(which may minimize homocysteine levels), agents modu-
E-mail address: bchbh@nus.edu.sg. lating nitric oxide production, cyclooxygenase inhibitors and
0008-6363/$ - see front matter © 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2006.10.004

2. 342 B. Halliwell / Cardiovascular Research 73 (2007) 341–347
even the humble ethanol molecule itself [2,17–28]. Are are pro-oxidant in vivo are (in my view) equivocal and
fruits and vegetables beneficial because of these other inconclusive. Nor is the evidence that they are antioxidants a
components? Or is it that fruits and vegetables act (in whole great deal better.
or in part) by antioxidant actions, but that the active
antioxidants are not vitamin C, α-tocopherol or β-carotene? 4. Enter the flavonoids
Some studies suggested yes to the latter question [29–31].
For example, Verhagen et al. [29] found that urinary Flavonoids and other polyphenols have powerful antiox-
excretion of 8-hydroxy-2′-deoxyguanosine (8OHdG), a idant activities in vitro, being able to scavenge a wide range
putative biomarker of oxidative damage to DNA and DNA of reactive species, including hydroxyl radicals, peroxyl
precursors [32,33], was decreased by feeding human radicals hypochlorous acid and (sometimes) superoxide
U
volunteers Brussels sprouts, but not by giving them α- radical, O2 − (reviewed in [46]). Flavonoids can also inhibit
tocopherol, ascorbate, or β-carotene [34]. biomolecular damage by peroxynitrite in vitro [47–49],
Several other authors have shown that consumption of although they are less good at doing this in the presence of
−
antioxidant-rich foods decreases levels of oxidative damage physiological levels of HCO3 /CO2 [49,50]. Peroxynitrite
−
in vivo in humans (reviewed in [35]). Others have found little reacts fast with CO2/HCO3 to form reactive products that
effect (e.g. [36]), and some registered increases in bio- flavonoids appear to scavenge less well. Many flavonoids
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markers of oxidative protein damage, such as 2-aminoadipic chelate transition metal ions such as iron and copper,
and γ-glutamyl semialdehydes [37]. One must be cautious in decreasing their ability to promote reactive species formation
all such studies to rule out confounding effects of refeeding [46,51,52].
fasted individuals, as opposed to the effects of antioxidants Two observations drew attention to the potential biological
in the food, on biomarkers of oxidative damage. Thus importance of flavonoids. First, phenolics in red wine were
Vissers et al. [38] showed that olive oil administration to shown to be able to inhibit the oxidation of LDL in vitro and
human volunteers decreased the propensity of low-density this was suggested as an explanation of the “French paradox”
lipoproteins (LDL) subsequently isolated from their blood to [19,53]. Second, the Zutphen study, an epidemiological study
undergo oxidation in vitro, but feeding oil without anti- in the Netherlands, suggested an inverse correlation between
oxidants had the same effect. In 2000, we reported [39] that the incidence of coronary heart disease and stroke and the
dark soy sauce has powerful antioxidant abilities in vitro. dietary intake of flavonoids, especially quercetin [54]. Since
Recently, we attempted to see if dark soy sauce decreased then, several other epidemiological studies have confirmed
oxidative damage in vivo in human volunteers, and indeed it similar associations, although a few have not, and there is little
was able to decrease levels of F2-isoprostanes [40]. We evidence that flavonoids protect against cancer [55]. Some
administered the soy sauce with rice, using a placebo col- suggestions of protection against neurodegenerative disease
ouring on the same amount of rice as a control. The rice meal have been made [22,23,43,56–58], although it is unclear to
(devoid of antioxidants) also had effects on F2-isoprostanes what extent flavonoids can enter the human brain [59].
and urinary 8OHdG excretion [40], although the soy sauce Thus could flavonoids be major contributors to the
meal did better than the placebo in lowering F2-isoprostane disease-protective effects of fruits and vegetables? If so, is
levels. Similarly, Richelle et al. [41] and Lee et al. [42] this due to antioxidant effects? Many polyphenols are
suggested that fasting may raise plasma F2-isoprostane absorbed, although rarely completely, and most of the
levels. At the moment, the balance of evidence does suggest remainder are broken down in the colon to generate high
that antioxidant effects contribute to the benefits of a high levels of monophenols [60,61]. Are the amounts of
intake of fruits and vegetables (reviewed in [35,43]) but the polyphenols absorbed sufficient to exert significant antiox-
extent of their contribution is uncertain. More work needs to idant effects? Several studies administering flavonoid-rich
be done on the effect of diet on oxidative damage, using foods and beverages and measuring biomarkers of oxidative
suitable controls. damage suggest yes, but others no (discussed in [35,62]).
“Feeding effects” alluded to earlier could account for some
3. Pro-oxidant effects of the apparent positive effects. Are significant antioxidant
effects likely in vivo? Plasma levels of unconjugated flavo-
Some authors have claimed that “antioxidants” can noids rarely exceed 1 μM and the metabolites tend to have lower
stimulate oxidative damage in vivo, especially ascorbate, antioxidant activity because radical-scavenging –OH groups are
alleged in several studies to increase oxidative DNA damage blocked by methylation, sulphation, or glucuronidation
(reviewed in [44]). Indeed, it was suggested that mega-doses [60,61]. Since plasma total antioxidant capacities (TAC) are
of ascorbate might kill cancer cells in vivo by oxidizing to often in the range of 1 mM or more (reviewed in [7]), it seems
produce H2O2 [45]. We found small and transient increases difficult to imagine how an additional 1 μM polyphenol could
in oxidative DNA damage in human volunteers fed mixtures exert a powerful antioxidant effect in vivo. Some studies have
of ascorbate, β-carotene and α-tocopherol, but there was shown effects of flavonoid-rich foods in raising plasma TAC in
wide variation between experiments [8]. Overall, the humans. But one must be cautious here; many such foods can
available data that ascorbate, β-carotene or α-tocopherol increase plasma uric acid levels, and urate is detected by

3. B. Halliwell / Cardiovascular Research 73 (2007) 341–347 343
several TAC assays [62–64]. Since elevated urate may be a risk against gastric, and possibly colonic, cancer, although again
factor for some diseases, the alleged “antioxidant benefit” may it must not be assumed that any protective effect of fla-
not be what it seems [62]. Finally, flavonoids and other phenols vonoid-rich foods is attributable to antioxidant actions of
are complex molecules and have multiple potential actions other the flavonoids, or to flavonoids at all, rather than to other
than antioxidant ones, including inhibiting telomerase, gluta- components in the foods. However, ingestion of green tea
mate dehydrogenase, cyclooxygenase, lipoxygenase, xanthine was reported to rapidly decrease prostaglandin E2 concen-
oxidase, matrix metalloproteinases, angiotensin-converting trations in human rectal mucosa, consistent with inhibition
enzyme, proteasome, cytochrome P450 and sulphotransferase of cyclooxygenase activity, a potential anti-cancer mecha-
enzyme activities, affecting signal transduction pathways and nism [25]. The levels of individual flavonoids in faecal
interacting with sirtuins [25,35,43,56,57,65–73]. Flavonoids water are fairly low (μM or less), but monophenols (many
may also interact with cellular drug transport systems, compete derived from polyphenol breakdown) are present at much
with glucose for transmembrane transport, interfere with higher concentrations [84]. By contrast to the colon, poly-
regulation of the cell cycle, inhibit protein glycation, modulate phenols are likely to be present in the stomach and intes-
paraoxonase, myeloperoxidase and thyroid peroxidase activi- tines at high (≥ mM) concentrations after consumption of
ties, increase endothelial nitric oxide production and affect polyphenol-rich foods and beverages.
platelet function [74–82]. Again, it is uncertain whether some of Why should antioxidant protective effects of polyphe-
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these effects occur in vivo, given the low concentration of nols be important to the stomach and intestines? The
bioavailable polyphenols. gastrointestinal (GI) tract is constantly exposed to reactive
species. Some are released by the GI tract itself, eg.
5. Do polyphenols work pre-absorption? superoxide and H2O2 production by NADPH oxidases and
“dual oxidases” in epithelial cells [85–87]. Some reactive
It has been proposed [83] that antioxidant and other species are present in food and beverages, and yet others
protective effects of flavonoids and other phenolic com- are generated by chemical reactions of dietary components
pounds could occur before absorption, i.e. within the within the stomach [83,88]. Sources of reactive species
stomach, intestines and colon (Fig. 1). This could account include H2O2 in beverages [89], the mixtures of ascorbate
for the suggested ability of flavonoid-rich foods to protect and Fe2+ in the stomach (dietary iron, dietary ascorbate,
Fig. 1. Dietary antioxidants and the gastrointestinal (GI) tract. ⁎Except when supplements are taken. This figure refers to normal dietary intake. +, There is
considerable intersubject variability in the efficiency of GI uptake of vitamin E. ▵Much H2O2 may be removed in the oral cavity by catalase and peroxidases in
saliva, and by H2O2 diffusion into the oral and oesophageal epithelium followed by its rapid catabolism. Adapted from [7] with permission from Oxford
U U U
University Press. RNS Reactive nitrogen species, OH hydroxyl radical, RO alkoxyl radical, RO2 peroxyl radical, RS reactive species, LOX lipoxygenase,
COX-2 cyclooxygenase-2.

4. 344 B. Halliwell / Cardiovascular Research 73 (2007) 341–347
and ascorbate normally present in gastric juice [90]), and than would be expected from the rate of its generation by
ingested haem proteins, which can promote oxidation of either compound alone [110].
dietary lipids [88]. Other reactive species that can be Since there are transition metal ions in the GI tract, it is
present in foods include lipid peroxides, cytotoxic possible that polyphenols could oxidize there as well. This
aldehydes, and isoprostanes [91–95]. Nitrite is present at might even be good for you, generating a pro-oxidant
high levels in saliva and in foods [96]. It is converted to challenge that raises levels of xenobiotic-metabolizing and
HNO2 by gastric acid, and HNO2 can then form nitrosating antioxidant defence enzymes in the GI tract.
and DNA-deaminating species [97]. Activation of immune
cells naturally present in the GI tract by diet-derived bacteria 7. A caution about supplements
and toxins can also increase ROS production [98].
Flavonoids and other phenolic compounds might exert Flavonoid-rich foods appear good for us, although to
direct protective effects in the gastrointestinal tract, by what extent (if any) the flavonoids contribute to this benefit
scavenging reactive species and/or preventing their forma- is uncertain. Other possible protective components in foods
tion. For example, polyphenols can inhibit haem protein- were listed in Section 1. So should we consume flavonoid
induced peroxidation in the stomach [88,99] and decrease supplements or the flavonoid-enriched foods (e.g. cocoa,
DNA base deamination or nitrosamine formation by HNO2- chocolate) now coming onto the market in some countries? I
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derived reactive nitrogen species [97,100]. Phenols might would be cautious until we know more [2,77,111]. To me,
also increase levels of toxin-metabolizing or antioxidant dietary polyphenols are typical xenobiotics, metabolized as
defence enzymes in the GI tract, and chelate transition metal such and rapidly removed from the circulation. They may be
ions [83]. Dietary iron is usually not completely absorbed, beneficial in the gut in the correct amounts. But too much
especially among subjects on Western diets. Unabsorbed may not be good and thus, I suggest that one should be
dietary iron enters the faeces, where it could represent a pro- content with eating a good diet for now.
oxidant challenge to the colon and rectum [101]. Indeed,
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