Resveratrol as an antioxidant and pro-oxidant agent: Mechanisms and clinical implications

Abstract

Resveratrol (3,4',5-trihydroxystilbene) is found in various plants, including grapes, berries and peanuts. It is also present in wines, especially red wines. During the last years, it has been the focus of numerous in vitro and in vivo studies investigating its biological attributes, which include mainly antioxidant and anti-inflammatory activities, anti-platelet aggregation effect, anti-atherogenic property, oestrogen-like growth-promoting effect, growth-inhibiting activity, immunomodulation and chemoprevention. In fact, recently, it has been demonstrated that the stilbene blocks the multistep process of carcinogenesis at various stages: tumour initiation, promotion and progression. More recent results provide interesting insights into the effect of this compound on the life span of yeasts and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. Nevertheless, depending on the concentration of the phytoalexin and the cell type, it has also been shown that resveratrol can exhibit pro-oxidant properties, leading to oxidative breakage of cellular DNA in the presence of transition metal ions such as copper. Recently, it has been proposed that such a pro-oxidant action could be a common mechanism for anticancer and chemopreventive properties of plant polyphenols. The present paper is intended to provide the reader up-to-date information on the antioxidant and pro-oxidant properties of resveratrol and its clinical implications.

Full text

1156 Biochemical Society Transactions (2007) Volume 35, part 5
Resveratrol as an antioxidant and pro-oxidant
agent: mechanisms and clinical implications
C. Alarc
´
on de la Lastra
1
and I. Villegas
Department of Pharmacology, Faculty of Pharmacy, University of Seville, Seville, Spain
Abstract
Resveratrol (3,4

,5-trihydroxystilbene) is found in various plants, including grapes, berries and peanuts. It
is also present in wines, especially red wines. During the last years, it has been the focus of numerous
in vitro and in vivo studies investigating its biological attributes, which include mainly antioxidant and anti-
inflammatory activities, anti-platelet aggregation effect, anti-atherogenic property, oestrogen-like growth-
promoting effect, growth-inhibiting activity, immunomodulation and chemoprevention. In fact, recently, it
has been demonstrated that the stilbene blocks the multistep process of carcinogenesis at various stages:
tumour initiation, promotion and progression. More recent results provide interesting insights into the effect
of this compound on the life span of yeasts and flies, implicating the potential of resveratrol as an anti-
aging agent in treating age-related human diseases. Nevertheless, depending on the concentration of the
phytoalexin and the cell type, it has also been shown that resveratrol can exhibit pro-oxidant properties,
leading to oxidative breakage of cellular DNA in the presence of transition metal ions such as copper. Re-
cently, it has been proposed that such a pro-oxidant action could be a common mechanism for anticancer and
chemopreventive properties of plant polyphenols. The present paper is i ntended to provide the reader up-
to-date information on the antioxidant and pro-oxidant properties of resveratrol and its clinical implications.
Introduction
Resveratrol (3,4

,5-trihydroxystilbene) is a phytoalexin
found in a wide variety of dietary sources including grapes,
plums and peanuts. It is also present in wines, especially
redwinesandtoamuchlesserextentinwhitewines.
Its stilbene structure is related to the synthetic oestrogen
diethylstilbestrol. Resveratrol exists as cis-andtrans-isomers.
Trans-resveratrol is the preferred steric form and is relatively
stable if it is protected from high pH and light. The synthesis
of trans-resveratrol in the plants can be induced by microbial
infections, UV radiation and exposure to ozone [1–3].
A primary impetus for research on resveratrol was initiated
from the paradoxical observation that a low incidence of car-
diovascular diseases may co-exist with a high-fat diet intake
and moderate consumption of red wine [4,5], a phenomenon
known as the French paradox [1]. The possible mechanisms
by which resveratrol exerts its cardio- and vascular-protection
involve inhibition of platelet aggregation, arterial vasodilation
mediated by NO (nitric oxide) release, favourable changes
in lipid metabolism such as LDL (low-density lipoprotein)–
cholesterol oxidation, antioxidant effects, stimulation of
angiogenesis [6], induction of cardioprotective protein
expression, and insulin sensitization. Indeed, it reduces
the synthesis of certain lipids and eicosanoids that tend
to promote inflammation and atherosclerosis; likewise, it
suppresses certain cardiac arrhythmias [7]. Some of these
Key words: antioxidant, copper, DNA damage, pro-oxidant, reactive oxygen species, resveratrol.
Abbreviations used: COX, cyclo-oxygenase; LP, lipid peroxidation; LPS, lipopolysaccharide; NF-
κ B, nuclear factor κ B; NOS, nitric oxide synthase; iNOS, inducible NOS; RNS, reactive nitrogen
species; ROS, reactive oxygen species; SOD, superoxide dismutase; XO, xanthine oxidase.
1
To whom correspondence should be addressed (email calarcon@us.es).
effects may be due in part to resveratrol being a phyto-
oestrogen, i.e. a plant compound that has biologically similar
properties to those of oestrogens [8].
More recent results provide interesting insights into the
effect of this compound on the lifespan of yeasts and flies,
implicating its potential as an anti-aging agent in treating
age-related human diseases [9,10].
Additionally, some investigators have indicated a potential
neuroprotective activity for resveratrol based on its
beneficial effects in several brain damage models. Similarly,
several studies, including ours, have identified resveratrol as a
beneficial agent in the control of inflammatory disorders s uch
as arthritis and inflammatory bowel disease [11,12]. Potential
mechanisms implicated include: inhibition of synthesis and
release of pro-inflammatory mediators, modification of
eicosanoid synthesis, inhibition of activate immune cells and
inflammatory enzymes such as iNOS [inducible NOS (nitric
oxide synthase)] and COX-2 (cyclo-oxygenase-2) through
its inhibitory effects on NF-κ B (nuclear factor κ B) or the
AP-1 (activator protein-1) signalling pathways [9].
One of the most striking biological activities of resveratrol
intensely investigated during the last years has been its cancer-
chemopreventive or anticancer properties. These properties
were first appreciated when Jang et al. [13] demonstrated that
resveratrol possesses cancer-chemopreventive and cytostatic
properties via the three major stages of carcinogenesis, i.e.
initiation, promotion and progression [14]. Since then, there
has been a flurry of papers reporting the implication of res-
veratrol in cancer chemoprevention through a wide range of
actions that are poorly understood. It appears to help detoxify
carcinogens, to reduce the synthesis of various cancer-related
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Inflammation 1157
compounds and to interfere with cell survival programmes;
for instance, resveratrol has been shown to promote
apoptosis in cancer cells by blocking anti-apoptotic proteins
expression or by inhibiting signal transduction through
the PI3K (phosphoinositide 3-kinase), MAPK (mitogen-
activated protein kinase) or NF-κ B pathways [3,10,15].
Most of the scientific evidence for resveratrol’s benefits
is based on in vitro studies in which the diastereomers
trans-orcis-resveratrol have been tested. However,
from animal studies and human trials, we know that the
predominant isomer that is orally ingested with foods is
trans-resveratrol glucoside (piceid), which is biotransformed
and rapidly eliminated. In addition, these derivatives might
be less biologically active due to their esterified hydroxy
groups. However, the chemopreventive activity of orally
administered trans-resveratrol has almost been demonstrated
in cancer-induced animal models [16]. Nonetheless, future
studies are needed to know the effective dose required to
achieve the health benefits evidenced in experimental models.
Resveratrol as free radical scavenger and
antioxidant
Over the last few years, a number of studies have provided
evidence of an important role of ROS (reactive oxygen spe-
cies) in mediating the development of oxidative stress. Excess-
ive ROS accumulation may induce the oxidative modification
of cellular macromolecules (lipid, proteins and nucleic acids)
with deleterious potential. In fact, DNA damage by ROS
has been implicated in mutagenesis, oncogenesis and aging.
Oxidative lesions in DNA include base modifications, sugar
damage, strand breaks and abasic sites [17]. Since gene tran-
scription can be regulated by oxidants, antioxidants and other
determinants of the intracellular redox state, ROS can also
produce protein damage, inducing other types of mutations.
One of the biological activities that have been ascribed
to resveratrol involves its antioxidant potential. Resveratrol
is both a free radical scavenger and a potent antioxidant
because of its ability to promote the activities of a variety of
antioxidant enzymes (Figure 1). The ability of the polyphen-
olic compounds to act as antioxidants depends on the redox
properties of their phenolic hydroxy groups and the potential
for electron delocalization across t he chemical structure [18].
The common recognition of resveratrol as a natural
antioxidant was clarified by Zini et al. [19], who suggested
three different antioxidant mechanisms: (i) competition with
coenzyme Q and, to decrease the oxidative chain complex,
the site of ROS generation, (ii) scavenging O
2
䊉−
radicals
formed in the mitochondria and (iii) inhibition of LP (lipid
peroxidation) induced by Fenton reaction products. In
fact, numerous studies have demonstrated the ability of
resveratrol to scavenge both O
2
䊉−
and
䊉
OH radicals [20–22].
By contrast, in a study by Orallo et al. [23], using the
enzymatic hypoxanthine oxidase–XO (xanthine oxidase)
system, resveratrol neither affected the XO activity nor
scavenged O
2
䊉−
radicals in rat macrophage extracts.
Figure 1 Resveratrol antioxidant potential
PUFA, polyunsaturated fatty acid.
In order to protect tissues against the deleterious effects
of ROS, all cells possess numerous defence mechanisms
that include enzymes such as SOD (superoxide dismutase),
catalase, glutathione reductase and glutathione peroxidase.
Resveratrol can maintain the concentration of intracellular
antioxidants found in biological systems. For instance, in a
study by Losa [21], stilbene appeared to maintain the gluta-
thione content in p eripheral blood mononuclear cells isolated
ex vivo from a healthy human from oxidative damage caused
by 2-deoxy-
D-ribose. In a previous study, in human blood
platelets, resveratrol markedly decreased oxidation of thiol
groups of proteins in these cells [24]. Similarly, resveratrol
induced an increase in glutathione levels in a concentration-
dependent manner in human lymphocytes activated with
H
2
O
2
. In another study, resveratrol increased the amounts
of several antioxidant enzymes, including glutathione peroxi-
dase, glutathione S-transferase and glutathione reductase [25].
Effects of resveratrol on RNS (reactive
nitrogen species) generation
It is now widely accepted that a moderate concentration of
NO appears to play cardio- and neuro-protective effects,
and, along these lines, several reports have shown the role of
resveratrol in the regulation of NO production from vascular
endothelium in the ischaemic heart, brain or kidney [26,27].
However, abnormally high concentrations of NO and its
derivatives RNS have been associated with tumour growth
and vascular invasion. In a previous study [28], the effects of
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1158 Biochemical Society Transactions (2007) Volume 35, part 5
resveratrol and oxyresveratrol on nitrosative and oxidative
stress derived from microglial cells was investigated.
Phytoalexin considerably diminished NO production upon
the inducible isoform of NOS (iNOS expression), and it also
induced an inhibitory effect on the iNOS enzyme activity.
Bacterial endotoxic LPS (lipopolysaccharide) is one of the
most important stimuli for iNOS induction, resulting in NO
production that has bactericidal effects. For example, in LPS-
activated RAW 264.7 macrophages, pre-incubation of cells
with resveratrol reduced inflammation by down-regulation
of the iNOS and mRNA [29,30]. The results obtained
demonstrate that resveratrol is a potent inhibitor of the
antipathogen responses of rat macrophages and thus suggest
that this agent may have applications in the treatment of
diseases involving macrophage hyper-responsiveness [31,32].
Antioxidant activity of resveratrol and
carcinogenesis
Resveratrol prevents the initial DNA damage by two
different pathways: (i) acting as an antimutagen through
the induction of Phase II enzymes, such as quinine
reductase, capable of metabolically detoxifying carcinogens
by inhibiting COX and cytochrome P450, and (ii) acting as
an antioxidant through inhibition of DNA damage by ROS
[33]. It has been proposed that ROS derived from LP may
function as tumour initiators [20]. Leonard et al. [20] have
shown that resveratrol exhibits a protective effect against LP
in cell membranes and DNA damage caused by ROS.
The antipromotional properties of resveratrol can be partly
attributed to its ability to enhance gap-junctional intercellular
communications in cells exposed to tumour promoters such
as PMA [34]. The tumour-promoting activity mediated by
PMA has also been associated with oxidative stress by in-
creased production of O
2
䊉−
and H
2
O
2
, reduction of SOD
activity and interference with glutathione metabolism. In a
model of PMA application to mouse skin, resveratrol induced
the restoration of H
2
O
2
and glutathione levels, and also my-
eloperoxidase, glutathione reductase and SOD activities [35].
The development of skin cancer is related to accumulative
exposure to solar UVB as well as the nuclear transcription
factor NF-κ B, which plays a critical role in skin biology.
NF-κ B is involved in the inflammatory and carcinogenic
signalling cascades, and resveratrol was able to block
the damage caused by UVB exposure via its antioxidant
properties blocking UVB-mediated NF-κB activation.
Finally, resveratrol could inhibit tumour progression, partly
by an inhibition of DNA polymerase and deoxyribo-
nucleotide synthesis through its ability to scavenge the
essential tyrosine radical of the ribonucleotide reductase and
partly by inducing cell cycle arrest [18] (Figure 2).
Effects of resveratrol on intracellular redox
state
Recent results have provided interesting insight into the
effect of resveratrol on intracellular redox state. These results
seem to support both anti- and pro-oxidant activities of this
Figure 2 Inhibition of LP by resveratrol and its antioxidant
mechanisms in carcinogenesis
compound, depending on the concentration of resveratrol
and the cell type, leading to oxidative breakage of cellular
DNA. Lately, it has been proposed that such pro-oxidant
action could be an important action mechanism of its
anticancer and apoptotic inducing properties. Furthermore,
it has been shown that there is an interesting correlation
among the antioxidant and pro-oxidant activities and
cytotoxicity of dietary polyphenols [36].
Every antioxidant is in fact a redox (reduction–oxidation)
agent and thus might become a pro-oxidant to accelerate
LP and/or induce DNA damage under special conditions.
Studies have revealed pro-oxidant effects of antioxidant
vitamins and several classes of plant-derived polyphenols
such as flavonoids [37], tannins [38] and curcumin [39].
Ahmad et al. [40] observed that exposure of human
leukaemia cells to low concentrations of resveratrol (4–
8 µM) inhibited caspase activation and DNA fragmentation
induced by incubation with H
2
O
2
. At these concentrations,
resveratrol elicited pro-oxidant properties as evidenced by an
increase in intracellular O
2
䊉−
concentration. Likewise, in rat
hepatocytes exposed to ferrylmyoglobin-induced oxidative
stress, physiological concentrations (100 pM–100 nM) of
resveratrol exerted pro-oxidant activities [22]. It has also
been shown that resveratrol has a pro-oxidative effect on
DNA damage during interaction with ADP-Fe
3+
in the
presence of H
2
O
2
in tumour cell line cultures [34].
Similarly, the pro-oxidant effects of resveratrol were shown
on rat liver microsomal systems. Resveratrol inhibited LP;
however, resveratrol increased
䊉
OH generation, indicating
that
䊉
OH played a minor role in LP [41]. In addition, it is well
known that haem (iron-protoporphyrin IX) is a pro-oxidant
and its rapid degradation by haem oxygenase is believed
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Inflammation 1159
to be neuroprotective. Using primary neuronal cultures,
resveratrol was able to significantly induce haem oxy-
genase 1. This study indicated that the increase of haem
oxygenase activity by resveratrol is a unique pathway by
which this compound can exert its neuroprotective actions
[42]. Further corroborating the pro-oxidant activity of
resveratrol, there are data that demonstrate its inefficiency
in protecting proteins (BSA) from oxidative damage induced
by metal-catalysed reaction or alkylperoxyl radicals [43].
Fukuhara and Miyata [44] first reported the pro-oxidant
activity of resveratrol in a plasmid-based DNA cleavage
assay in the presence of transition metal ions such as copper.
DNA degradation by resveratrol in the presence of cop-
per (10–100 µM) or alone (200 µM) (in the absence of added
copper) has also been shown in a cellular system of peripheral
lymphocytes isolated from human blood [45,46].
Copper is one of the most redox-active metal ions present
in the nucleus, serum and tissues [47]. Approximately 20%
of copper is located in the nucleus and is closely associated
with DNA bases, in particular, guanine [48]. Furthermore,
it has been shown that the concentration of copper is greatly
increased in various malignancies [45]. Copper ions from
chromatin can be mobilized by metal-chelating agents, giving
rise to internucleosomal DNA fragmentation, a property
that is the hallmark of cells undergoing apoptosis [17].
The cytotoxic mechanism of resveratrol probably involves
mobilization of endogenous copper ions, possibly chromatin-
bound copper. First, resveratrol undergoes oxidation in the
presence of Cu(II). The oxidative product of resveratrol is a
dimer, which possibly might be formed by dimerization of
resveratrol phenoxyl radical as a result of the reductive activa-
tion of molecular oxygen. Indeed, this initial electron transfer
generates the reduction of Cu(II) to Cu(I). Interestingly,
DNA strand scission occurred at neutral pH, indicating that
resveratrol can induce DNA cleavage without the oxygena-
tion of the benzene nuclei to the catechol moiety. However,
the structural feature of the copper–peroxide complex as the
reactive species responsible for the DNA cleavage is still un-
known. Secondly, the Cu(II)–peroxide complex is capable of
binding DNA and forms a DNA–resveratrol–Cu(II) ternary
complex. The high binding affinity of a 4-hydroxy group at
the 4-position with both Cu(II) and DNA makes it possible
and therefore cleaves DNA efficiently [49] (Figure 3).
Clinical implications
The body of evidence presented here speaks volumes
about the clinical potential of resveratrol as an antioxidant and
pro-oxidant. Insufficient activation of apoptosis because of
defects in apoptosis programmes or because of the dominance
of survival signals may result in cancer cell resistance. Despite
aggressive therapies, resistance of many tumours to current
treatment protocols still constitutes a major problem in cancer
therapy. Poly-mechanistic phytochemicals such as resveratrol
may offer the advantage over targeted therapeutics and may
open new perspectives in cancer therapy. By blocking survival
and anti-apoptotic mechanisms or causing DNA degradation,
Figure 3 Cytotoxic mechanism of resveratrol probably involves
mobilization of endogenous copper ions
as a consequence of its pro-oxidant action, resveratrol can
sensitize cancer cells, which may result in synergistic anti-
tumour activities when resveratrol is combined with con-
ventional chemotherapeutic agents or cytotoxic compounds
[15,50]. However, further insights into the signalling network
and interaction points modulated by resveratrol may provide
the basis for novel discovery programmes to exploit res-
veratrol for the prevention and treatment of human diseases.
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doi:10.1042/BST0351156
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