Alarcon 2007
Alarcon 2007
Alarcon 2007
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 intended to provide the reader up-
to-date information on the antioxidant and pro-oxidant properties of resveratrol and its clinical implications.
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Inflammation 1157
compounds and to interfere with cell survival programmes; Figure 1 Resveratrol antioxidant potential
for instance, resveratrol has been shown to promote PUFA, polyunsaturated fatty acid.
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-κB pathways [3,10,15].
Most of the scientific evidence for resveratrol’s benefits
is based on in vitro studies in which the diastereomers
trans- or cis-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.
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1158 Biochemical Society Transactions (2007) Volume 35, part 5
resveratrol and oxyresveratrol on nitrosative and oxidative Figure 2 Inhibition of LP by resveratrol and its antioxidant
stress derived from microglial cells was investigated. mechanisms in carcinogenesis
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].
Recent results have provided interesting insight into the that OH played a minor role in LP [41]. In addition, it is well
䊉
effect of resveratrol on intracellular redox state. These results known that haem (iron-protoporphyrin IX) is a pro-oxidant
seem to support both anti- and pro-oxidant activities of this and its rapid degradation by haem oxygenase is believed
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Inflammation 1159
to be neuroprotective. Using primary neuronal cultures, Figure 3 Cytotoxic mechanism of resveratrol probably involves
resveratrol was able to significantly induce haem oxy- mobilization of endogenous copper ions
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 as a consequence of its pro-oxidant action, resveratrol can
binding DNA and forms a DNA–resveratrol–Cu(II) ternary sensitize cancer cells, which may result in synergistic anti-
complex. The high binding affinity of a 4-hydroxy group at tumour activities when resveratrol is combined with con-
the 4-position with both Cu(II) and DNA makes it possible ventional chemotherapeutic agents or cytotoxic compounds
and therefore cleaves DNA efficiently [49] (Figure 3). [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-
Clinical implications veratrol for the prevention and treatment of human diseases.
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
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