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Archives of Biochemistry and Biophysics 476 (2008) 107–112

ABB
www.elsevier.com/locate/yabbi

Review

Are polyphenols antioxidants or pro-oxidants? What do we learn

from cell culture and in vivo studies?
Barry Halliwell *
Department of Biochemistry, National University of Singapore, University Hall, Lee Kong Chian Wing,
UHL #05-02G, 21 Lower Kent Ridge Road, Singapore 119077, Singapore

Received 13 November 2007, and in revised form 26 December 2007

Available online 7 February 2008

Abstract

Diets rich in polyphenols are epidemiologically associated with lower risk of developing some age-related diseases in humans. This
apparent disease-protective effect of polyphenols is often attributed to their powerful antioxidant activities, as established in vitro. How-
ever, polyphenols can also exert pro-oxidant activities under certain experimental conditions. Neither pro-oxidant nor anti-oxidant activ-
ities have yet been clearly established to occur in vivo in humans, nor are they likely given the limited levels of polyphenols that are
achievable in vivo after consumption of foods and beverages rich in them. Other actions of polyphenols may be more important
in vivo. Many studies of the biological effects of polyphenols in cell culture have been affected by their ability to oxidise in culture media,
and awareness of this problem can avoid erroneous claims.
Ó 2008 Elsevier Inc. All rights reserved.

Keywords: Polyphenols; Cell culture; Antioxidant; Pro-oxidant; Epigallocatechin gallate; Hydrogen peroxide; Ascorbate; Dulbecco’s modified Eagle’s
medium; Green tea; Red wine

Aerobic organisms produce a wide range of oxygen rad-
icals and other reactive oxygen species (ROS)1, both for
useful purposes (e.g. defence, redox signalling) and by
‘‘accidents of chemistry” (reviewed in [1]). These ROS are
metabolised by a series of antioxidant defences, some syn-
thesised in vivo and other diet-derived [1]. The purpose of
the ‘‘antioxidant defence network” [2] is not to remove
all ROS, but to control their levels so as to allow useful
functions whilst minimising oxidative damage (Fig. 1) [1–
4]. But how important are the diet-derived antioxidants
such as vitamins C and E to humans? In general, increased
intakes of these vitamins do not decrease levels of oxidative
damage very much (if at all) in well-nourished humans who
are already consuming the recommended dietary allow-
ances [1,5–7]. Indeed, it has been suggested that the main
*
Corresponding author. Fax: +65 6775 2207.
E-mail address: bchbh@nus.edu.sg
1
Abbreviations used: ROS, reactive oxygen species; LDL, low-density
lipoproteins; DMEM, Dulbecco’s Modified Eagle’s Medium.
biological function of a-tocopherol in humans is not as
an antioxidant [8].
Polyphenols as antioxidants
Foods and beverages rich in flavonoids and other poly-
phenols have been associated with decreased risk of age-
related diseases in several (but not all) epidemiological
studies [9–15]. Flavonoids have powerful antioxidant activ-
ities in vitro, being able to scavenge [16–23] a wide range of
reactive oxygen, nitrogen, and chlorine species, such as
superoxide O2  , hydroxyl radical OH , peroxyl radicals
RO2  , hypochlorous acid (HOCl), and peroxynitrous acid
(ONOOH). Flavonoids can also chelate metal ions, often
decreasing the pro-oxidant activity of metal ions [20,22].
They can inhibit the ability of myeloperoxidase to oxidise
low-density lipoproteins (LDL), a potential anti-athero-
sclerotic effect [24]. Because considerable evidence indicates
that increased oxidative damage is associated with, and may
contribute to the development of, all major age-related

0003-9861/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.abb.2008.01.028
108 B. Halliwell / Archives of Biochemistry and Biophysics 476 (2008) 107–112
Fig. 1. Balance of antioxidants and reactive species in vivo.
diseases [1–3], many have attributed the apparent disease-
protective effects of flavonoids to their antioxidant ability
(e.g. reviewed in [20]).
Polyphenols as pro-oxidants
Polyphenols oxidise readily in beverages [25–27] such as
green tea. They can also oxidise in cell culture media (see
below) and even in the oral cavity; holding or chewing
green tea in the mouth generates substantial levels of
H2O2 [28]. Often, these pro-oxidant effects involve interac-
tions of polyphenols with transition metal ions [1,29–35].
Oxidation of polyphenols produces O2  , H2O2 and a com-
plex mixture of semiquinones and quinones, all of which
are potentially cytotoxic [26,31,36,37]. It has been argued
that polyphenols may exert antioxidant and other cytopro-
tective effects in the gastrointestinal tract because of the
high levels that can be present [38–40]. However, since
there are often unabsorbed transition metal ions (especially
iron [41,42]) in the gastrointestinal tract, pro-oxidant
effects could conceivably occur there as well. Indeed, such
effects have been demonstrated in the gastrointestinal tracts
of certain insects consuming high levels of phenols [43,44].
However, in practice pro-oxidant effects can also be ben-
eficial, since, by imposing a mild degree of oxidative stress,
the levels of antioxidant defences and xenobiotic-metabol-
ising enzymes might be raised, leading to overall cytopro-
tection [45], as illustrated in Fig. 1.
Are polyphenols pro-oxidants or antioxidants in vivo in
humans?
No data are available on whether polyphenols are anti-
oxidant or pro-oxidant in vivo in the human stomach, intes-
tines, and colon, where they can be present at significant
levels [38,39,46,47]. As for effects after absorption into the
body, multiple well-designed human studies have been done
using reliable biomarkers of oxidative damage in plasma
(F2-isoprostanes) and urine (F2-isoprostanes, isoprostane
metabolites, 8-hydroxy-20 -deoxyguanosine [8OHdG]),
essentially testing for systemic antioxidant or pro-oxidant
activity. The results have been reviewed in detail elsewhere
[40] and are quite variable, but overall no evidence for sys-
temic pro-oxidant effects of polyphenols has emerged. A
few studies report that administration of high doses of epi-
gallocatechin gallate to animals leads to the formation of
cysteine conjugates detectable in the urine, indicative of
some degree of oxidation in vivo [36]. However, these effects
may not be important at lower doses and may not be rele-
vant to humans [36].
Similarly, only limited and variable evidence for antiox-
idant effects of flavonoids in humans has been obtained
(reviewed in [40]). This is not, to the author, very surpris-
ing; although flavonoids can be absorbed through the gas-
trointestinal tract, maximal plasma concentrations
achieved are low, usually not more that 1 lmol/L, in part
because of rapid metabolism by human tissues [47–49].
Many of the products of metabolism, such as methylated
and glucuronidated forms, have decreased antioxidant (or
pro-oxidant) abilities because of the blocking of the pheno-
lic hydroxyl groups involved in such activities [23,48].
Therefore, plasma flavonoid concentrations in vivo seem
insufficient to exert systemic antioxidant effects.
Another point to consider in interpreting the published
human studies is that several groups have studied flavo-
noid-rich foods (e.g. pomegranate [50] or chocolate/cocoa
[51,52]) or beverages (e.g. green tea) rather than pure flavo-
noids, and such foods contain other constituents that might
be able to modulate oxidative damage. But are such foods
and beverages effective as antioxidants in vivo? Again, the
data are mixed. Some studies showed antioxidant effects
(e.g. [37,48,51–53]), others no effects (e.g. [54–57]) and yet
others some indication of mild pro-oxidant effects (e.g.
[58]). One must be careful in studies with foodstuffs, since
 B. Halliwell / Archives of Biochemistry and Biophysics 476 (2008) 107–112
the mere act of eating in a fasted individual can alter
parameters of oxidative damage. For example, dark soy
sauce has powerful antioxidant abilities in vitro [59,60].
Recently, we attempted to see if dark soy sauce decreases
oxidative damage in vivo in human volunteers, and indeed
it was able to decrease levels of F2-isoprostanes [61]. We
administered the soy sauce with rice, using a control con-
sisting of a placebo colouring on the same amount of rice.
The rice meal (devoid of antioxidants) also had effects on
F2-isoprostanes and urinary 8OHdG excretion [61],
although the soy sauce did better than the placebo in low-
ering F2-isoprostane levels. Similarly, Richelle et al. [62]
and Lee et al. [63] suggested that fasting may raise plasma
F2-isoprostane levels. As another example [64], olive oil
administration to human volunteers decreased the propen-
sity of LDL subsequently isolated from their blood to
undergo oxidation in vitro, but feeding oil without antiox-
idants had the same effect.
So overall, in vivo we have no evidence of systemic pro-
oxidant effects of flavonoids in humans, and little or no
clear evidence of antioxidant effects. Remember also that
flavonoids are not only anti- and pro-oxidants. They have
many other biological effects including the ability to inhibit
cyclooxygenases, lipoxygenases, metalloproteinases and
NADPH oxidases (reviewed in [1,40,65–69] and other
papers in the current volume). These other actions may
be more important in vivo than antioxidant effects,
although again many of them have been demonstrated
in vitro only at unphysiologically-high levels of
polyphenols.
Antioxidants in cell culture
Cell culture has often been used to study the cellular
effects of reactive species and of antioxidants, and many
useful data have resulted. However, one must be cautious,
for two reasons. First, normal culture conditions are a state
of hyperoxia [70,71]. Most cells in the human body are
exposed to O2 concentrations in the range of 1–10 mm Hg
(obvious exceptions include corneocytes, corneal and respi-
ratory tract lining cells). Yet culture under 95% air/5% CO2
is about 150 mm Hg of O2. Rates of production of ROS by
cellular enzymes (e.g. xanthine oxidase) or by leakage from
electron transport chains (especially in mitochondria)
appear to be O2-limited at 10 mm Hg and so production
of ROS will increase if O2 levels are raised [71–73]. In other
words, cells in culture are under an oxidative stress, which
can alter their properties in multiple ways [70], including
sometimes promoting proliferation [1,74].
A second problem is that cell culture media are fre-
quently deficient in antioxidants, especially tocopherols
and ascorbate [75]. Vitamin E is rarely added because it
is insoluble in water, and vitamin C because it is unstable
(discussed below). Thus cells are deprived of these antiox-
idants, a situation which can lead to over-interpretations
of the beneficial effects of added antioxidants. In other
words, antioxidants may appear to have beneficial effects
109
when added to cultured cells, but this is because a defi-
ciency is being corrected rather than being a real beneficial
effect of ‘extra antioxidants’. Deficiencies in selenium in
some cell culture media have been reported [76,77]. This
could decrease or prevent oxidative stress-triggered rises
in the activities of selenium-dependent antioxidant
enzymes, such as the glutathione peroxidase family and thi-
oredoxin reductase [77,78].
One factor that has bedevilled studies of the cellular
effects of flavonoids and other polyphenols is their instabil-
ity in commonly-used culture media, especially Dulbecco’s
Modified Eagle’s Medium (DMEM) [70,79]. Oxidation
products include H2O2 and quinones/semiquinones, which
can often react with and deplete cellular GSH [37,70,84].
Fig. 2 shows a striking example; epigallocatechin gallate
(EGCG) added to DMEM begins oxidizing immediately
and rapidly generates cytotoxic levels of H2O2. Such effect
may have led to artefacts in interpretations of the cellular
effects of high concentrations of added polyphenols. Table
1 summarises some published examples. Not all the cellular
effects of polyphenols are due to such artefacts (e.g. some
of those observed when lower levels, e.g. the lM range,
are added to cells), but it is necessary to consider the poten-
tial for error when determining what the true cellular effects
really are. Oxidation artefacts can also lead to false-posi-
tive results in in vitro genotoxicity testing using cultured
cells, where the generated H2O2 (or other oxidation prod-
ucts) rather than the compound under test is causing the
chromosomal aberrations detected [102,108–110].
Why do these effects occur? As well as its normal iron
content (due to contamination and iron-containing pro-
teins in foetal calf serum), DMEM contains added ferric
nitrate, i.e. there is ‘‘free” pro-oxidant iron, which would
be expected to catalyse autoxidation reactions [1]. Surpris-
ingly however, iron ion chelating agents such as desferriox-
Fig. 2. Generation of H2O2 on addition of epigallocatechin gallate
(EGCG) to Dulbecco’s modified Eagle’s medium. The final concentrations
of EGCG in the medium are shown. SD values are not shown to avoid
cluttering the figures. Note the rapid rate of H2O2 production from EGCG
as soon as it is added to DMEM (see legend to Table 2). Adapted from
[79].
110 B. Halliwell / Archives of Biochemistry and Biophysics 476 (2008) 107–112

Table 1
Examples of artefacts caused by oxidation of compounds added to cell culture media (Adapted with considerable updating from [70])
Observation Comment Reference
Induction of cell death by ascorbate in HL-60 or acute myeloid Due to generation of H2O2 by ascorbate oxidation in cell culture [80–82]
leukaemia cells or human fibroblasts media
Induction of apoptosis by green tea in PC12 cells Due to generation of H2O2 by oxidation of tea components in cell [83]
culture media
Induction of cell death by L-DOPA and dopamine in PC12 and M14 Due to H2O2, quinones, and semiquinones generated by oxidation [84]
cells of L-DOPA and dopamine in the culture medium
Toxicity of apple phenolics to cancer cells Due to oxidation to produce H2O2 in the culture medium [85]
Cytotoxicity of gallic acid Entirely or largely due to oxidation of gallic acid to produce H2O2 [86,87]
in culture medium
Addition of grape seed extract to CaCo-2 cell culture medium [88]
generates H2O2 due to oxidation of phenolics in the medium
Effects of polyphenols on c-jun phosphorylation in bronchial Shown to involve H2O2, although H2O2 was not specifically [89]
epithelial cell lines identified as coming from the culture medium
Epigallocatechin gallate induces apoptosis in human oral cell lines Due to production of H2O2 in the culture medium [90]
Toxicity of myricetin to Chinese hamster lung fibroblast V79 cells Due to H2O2 production, although H2O2 was not specifically [91]
identified as coming from the culture medium
Cell culture media found to generate ROS as detected by spin traps [92]
and fluorescent dyes
Ascorbate observed to inhibit cell proliferation and fibronectin Inhibition by catalase suggests may be due to H2O2 generation in [80,93]
synthesis in human skin fibroblasts the culture medium
Stimulation of SIRT1 activity by polyphenols in HT29 cells Results confounded by instability of polyphenols in the culture [94]
medium
Cyanidin-3-rutoside toxic to HL60 cells. Shown to involve peroxide, although H2O2 was not specifically [95]
identified as coming from the culture medium
EGCG and green tea extract cause oxidative stress responses in S. Involves H2O2 production in the medium [96]
cerevisiae
Cytotoxicity of EGCG to oral carcinoma cell lines Involves both H2O2 and quinones, although these did not account [97]
for all the effects
Activation of NF-jB in macrophages by coffee Due to H2O2; coffee contains substantial H2O2 levels [98] [99]
Toxicity of catechols to PC12-AC cells Involves H2O2, mainly generated in the extracellular space [100]
Toxicity of EGCG to Jurkat T cells Involves H2O2 generation in the culture medium [101]
Cytotoxicity and genotoxicity of green tea extract to H260 and Involves H2O2 generation, although H2O2 was not specifically [102]
RAW264.7 cells identified as coming from the culture medium
Toxicity of extracts of the oriental fungus Ganoderma lucidum to Involves H2O2 generation [103]
human lymphocytes
Toxicity of quercetin, catechin and ascorbate to pancreatic b-cells Involves H2O2 generation in the cell culture medium [104]
Toxicity of 4-methylcatechol to murine tumor cells Involves oxidation to form H2O2 and quinones/semiquinones in [105]
the cell culture medium
Toxicity of EGCG to ovarian cancer calls in DMEM Due to H2O2 formation, probably both intracellularly and in the [106]
culture medium
Stimulatory effects of garcinol on growth of intestinal cells Involves ROS production in the culture medium; low levels of [107]
H2O2 often stimulate cell proliferation [1,74]

Table 2
Levels of hydrogen peroxide in culture media under 95% air/5% CO2 containing 1 mM epigallocatechin gallate (EGCG)
Culture Media Mean H2O2 (lM) ± SD at various times (h)
0h 0.5 h 1.0 h 1.5 h 2.0 h
DMEM 75 ± 22 183 ± 8 275 ± 21 317 ± 35 334 ± 34
F-10 21 ± 10 34 ± 4 35 ± 3 37 ± 2 43 ± 3
F-12 65 ± 11 89 ± 4 85 ± 3 92 ± 4 121 ± 14
RPMI with Hepes 33 ± 3 99 ± 12 159 ± 9 212 ± 13 259 ± 17
RPMI without Hepes 82 ± 3 184 ± 32 257 ± 16 299 ± 23 332 ± 22
Mc Coy 5A 24 ± 1 79 ± 14 136 ± 10 192 ± 16 251 ± 19
Williams’ E 66 ± 8 143 ± 15 209 ± 20 278 ± 23 329 ± 15
Data are means ± SD, n = 3. Data selected from [110].
Levels of H2O2 were significantly greater than in medium alone (P < 0.05) at all time points for all media. Note the rapid H2O2 generation at t = 0,
indicating that EGCG has oxidized substantially when added to media in the few seconds before H2O2 measurement can be made. Media alone generated
no significant levels of H2O2 (<2 lM) after 2 h incubation at 37 °C.
 B. Halliwell / Archives of Biochemistry and Biophysics 476 (2008) 107–112
amine or ortho-phenantholine did not decrease the rate of
H2O2 production when gallic acid was added to DMEM
[111]. Effects can be even more complex when mixtures of
antioxidants are used. Thus both ascorbate [80] and poly-
phenols [79] generate H2O2 in DMEM, but if both are pres-
ent the amounts of H2O2 produced are much less than the
sum of the amounts with each compound alone [88,111].
Thus one should always be alert when adding polyphe-
nols to cells in culture; one must check for reactions taking
place in the culture medium that could lead to artefacts and
carefully distinguish effects of oxidation products from
‘‘real” effects of polyphenols. Addition of catalase can be
used to scavenge the H2O2, and GSH or N-acetylcysteine
to scavenge quinones and semiquinones [84]. Another
approach is to use a less ‘‘pro-oxidant” medium, since
other culture media seems less good at catalysing polyphe-
nol oxidation than is DMEM [109]. For example, Table 2
shows that F-10 and F-12 media seem far less ‘‘pro-oxi-
dant” than is DMEM.
Conclusion
Polyphenols are metabolized as ‘‘typical xenobiotics” by
the human body, and such metabolism decreases their anti-
oxidant and pro-oxidant abilities. It is now looking unli-
kely that polyphenols act as antioxidants in vivo, and
attention is turning to their other potential effects. Even
so, whether polyphenols contribute to human health by
any mechanism remains uncertain. Care is needed when
studying their effects in cell culture to use biologically-rele-
vant levels, to examine the effects of important metabolites,
and to allow for artefactual chemical processes in the cell
culture media.
Acknowledgment
I am grateful to the Biomedical Research Council of
Singapore for support (BMRC 01/1/21/18/213).
References
[1] B. Halliwell, J.M.C. Gutteridge, Free Radicals in Biology and
Medicine, fourth ed., Clarendon Press, Oxford, UK, 2007.
[2] J.J. Thiele, C. Schroeter, S.N. Hsieh, M. Podda, L. Packer, Curr.
Probl. Dermatol. 29 (2001) 26–42.
[3] C.K. Sen, Med. Sci. Sports Exerc. 33 (2001) 368–370.
[4] S.G. Rhee, Science (2006) 1882–1883.
[5] E.A. Meagher, O.P. Barry, J.A. Lawson, J. Rokach, G.A. FitzGer-
ald, JAMA 285 (2001) 1178–1182.
[6] H. Prieme, S. Loft, K. Nyyssonen, J.T. Salonen, H.E. Poulsen, Am.
J. Clin. Nutr. 65 (1997) 503–507.
[7] T.L. Duarte, J. Lunec, Free Radic. Res. 39 (2005) 671–686.
[8] J.M. Zingg, A. Azzi, Curr. Med. Chem. 11 (2004) 1113–1133.
[9] R.R. Huxley, H.A. Neil, Eur. J. Clin. Nutr. 57 (2003) 904–908.
[10] M.G.L. Hertog, E.J.M. Feskens, P.C.H. Hollman, M.B. Katan, D.
Kromhout D, Lancet 342 (1993) 1007–1011.
[11] J. Lin, K.M. Rexrode, Hu. F, C.M. Albert, C.U. Chae, E.B. Rimm,
M.J. Stampfer, J.E. Manson, Am. J. Epidemiol. 165 (2007) 1305–1313.
[12] L. Yochum, L.H. Kushi, K. Meyer, A.R. Folsom, Am. J. Epidemiol.
149 (1999) 943–949.
111
[13] T. Hirvonen, P. Pietinen, M. Virtanen, M.L. Oyaskainen, S.
Hakkinen, D. Albanes, J. Virtamo, Epidemiology 12 (2001) 62–67.
[14] J.M. Geleijnse, L.J. Launer, D.A.M. van der Kuip, A. Hofman,
J.C.M. Witteman, Am. J. Clin. Nutr. 75 (2002) 880–886.
[15] K.J. Mukamal, M. Maclure, J.E. Muller, J.B. Sherwood, M.A.
Mittleman, Circulation 105 (2002) 2476–2481.
[16] M.M. Silva, M.R. Santos, G. Caroco, R. Rocha, G. Justino, L.
Mira, Free Radic. Res. 36 (2002) 1219–1227.
[17] A.S. Pannala, C.A. Rice-Evans, B. Halliwell, S. Singh, Biochem.
Biophys. Res. Commun. 232 (1997) 164–168.
[18] M. Paya, B. Halliwell, J.R.S. Hoult, Biochem. Pharmacol. 44 (1992)
205–214.
[19] B.J. Boersma, R.P. Patel, M. Kirk, P.L. Jackson, D. Muccio, V.M.
Darley-Usmar, S. Barnes, Arch. Biochem. Biophys. 368 (1999) 265–
275.
[20] C. Rice-Evans (Ed.), Wake Up to Flavonoids, Royal Society of
Medicine Press, London, 2000, pp. 13–23.
[21] U. Ketsawatsakul, M. Whiteman, B. Halliwell, Biochem. Biophys.
Res. Commun. 279 (2000) 692–699.
[22] L. Mira, M.T. Fernandez, M. Santos, R. Rocha, M.H. Florencio,
K.R. Jennings, Free Radic. Res. 36 (2002) 1199–1208.
[23] M. Shirai, Y. Kawai, R. Yamanishi, T. Kinoshita, H. Chuman, J.
Terao, Free Radic. Res. 40 (2006) 1047–1053.
[24] Y. Steffen, T. Schewe, H. Sies, Free Radic. Res. 40 (2006) 1076–1085.
[25] H. Aoshima, S. Ayabe, Food Chem. 100 (2007) 350–355.
[26] S. Sang, M. Lee, Z. Hou, C. Ho, C.S. Yang, J. Agric. Food Chem.
53 (2005) 9478–9484.
[27] M. Akagawa, T. Shigemitsu, K. Suyama, Biosci. Biotechnol.
Biochem. 67 (2003) 2632–2640.
[28] J.D. Lambert, S.J. Kwon, J. Hong, C.S. Yang, Free Radic. Res. 41
(2007) 850–853.
[29] M.J. Laughton, P.J. Evans, M.A. Moroney, J.R.S. Hoult, B.
Halliwell, Biochem. Pharmacol. 42 (1991) 1673–1681.
[30] M.J. Laughton, B. Halliwell, P.J. Evans. J.R.S. Hoult, Biochem.
Pharmacol. 38 (1989) 2859–2865.
[31] H.M. Awad, M.G. Boersma, S. Boeren, P.J. van Bladeren, J.
Vervoort, M.C.M. Rietjens, Chem. Res. Toxicol. 14 (2001) 398–408.
[32] C.H. Ko, K. Li, P.K. Ng, K.P. Fung, C.L. Li, R.P. Wong, K.M.
Chui, G.J. Gu, E. Yung, C.C. Wang, T.F. Fok, Int. J. Mol. Med. 18
(2006) 987–994.
[33] M. Sakano, M. Mizutani, M. Murata, S. Oikawa, Y. Hiraku, S.
Kawanishi, Free Radic. Biol. Med. 39 (2005) 1041–1049.
[34] S.M. Hadi, S.H. Bhat, A.S. Azmi, S. Hanif, U. Shamim, M.F. Ullah,
Semin. Cancer Biol. 17 (2007) 370–376.
[35] P. Otero, M. Viana, E. Herrera, B. Bonet, Free Radic. Res. 27 (1997)
619–626.
[36] J.D. Lambert, S. Sang, C.S. Yang, Chem. Res. Toxicol. 20 (2007)
583–585.
[37] S. Sang, I. Yang, B. Buckley, C. Ho, C.S. Yang, Free Radic. Biol.
Med. 43 (2007) 362–371.
[38] B. Halliwell, K. Zhao, M. Whiteman, Free Radic. Res. 33 (2000)
819–830.
[39] J. Kanner, T. Lapidot, Free Radic. Biol. Med. 31 (2001) 1388–1395.
[40] B. Halliwell, J. Rafter, A. Jenner, Am. J. Clin. Nutr. 81 (suppl)
(2005) 268S–276S.
[41] C.F. Babbs, Free Radic. Biol. Med. 8 (1990) 191–200.
[42] M.H. Blakeborough, R.W. Owen, R.F. Bilton, Free Radic. Res.
Commun. 6 (1989) 359–367.
[43] R. Barbehenn, S. Cheek, A. Gasperut, E. Lister, R. Maben, J. Chem.
Ecol. 31 (2005) 969–988.
[44] R. Barbehenn, Dodick. T, U. Poopat, B. Spencer, Arch. Insect
Biochem. Physiol. 60 (2005) 32–43.
[45] J.W. Fahey, T.W. Kensler, Chem. Res. Toxicol. 20 (2007) 572–576.
[46] A.M. Jenner, J. Rafter, B. Halliwell, Free Radic. Biol. Med. 38
(2005) 763–772.
[47] C. Manach, J.L. Donovan, Free Radic. Res. 38 (2004) 771–785.
[48] G. Williamson, D. Barron, K. Shimoi, J. Terao, Free Radic. Res. 39
(2005) 457–469.
112 B. Halliwell / Archives of Biochemistry and Biophysics 476 (2008) 107–112
[49] A.R. Rechner, G. Kuhnle, P. Bremner, G.P. Hubbard, K.P. Moore,
C.A. Rice-Evans, Free Radic. Biol. Med. 33 (2002) 220–235.
[50] V.M. Adhami, H. Mukhtar, Free Radic. Res. 40 (2006) 1095–1104.
[51] K.A. Cooper, J.L. Donovan, A.L. Waterhouse, G. Williamson, Br.
J. Nutr. 99 (2008) 1–11.
[52] J.A. Vinson, J. Proch, P. Bose, S. Muchler, P. Taffera, D. Shuta, N.
Samman, G.A. Agbor, J. Agric. Food Chem. 54 (2006) 8071–8076.
[53] M. Aviram, L. Dornfeld, M. Kaplan, R. Coleman, D. Gaitini, S.
Nitecki, A. Hoffman, M. Rosenblat, N. Volkova, D. Presser, J.
Attias, T. Hayek, B. Fuhrman, Drugs Exp. Clin. Res. 28 (2002) 49–
62.
[54] C. Sanchez-Moreno, M.P. Cano, B. de Ancos, L. Plaza, B.
Olmedilla, F. Granado, A. Martin, J. Nutr. Biochem. 17 (2006)
183–189.
[55] S.R. McAnulty, L.S. McAnulty, J.D. Morrow, D. Khardouni, L.
Shooter, J. Monk, S. Gross, V. Brown, Free Radic. Res. 39 (2005)
1241–1248.
[56] E. Paterson, M.H. Gordon, C. Niwat, T.W. George, L. Parr, S.
Waroonphan, J.A. Lovegrove, J. Nutr. 136 (2006) 2849–2855.
[57] R. Freese, L.O. Dragsted, S. Loft, M. Mutanen, Eur. J. Clin. Nutr.,
2007 (epub).
[58] L.O. Dragsted, A. Pedersen, A. Hermetter, S. Basu, M. Hansen,
G.R. Haren, M. Kall, V. Breinholt, J.J. Castenmiller, J. Stagsted, J.
Jakobsen, L. Skibsted, S.E. Rasmussen, S. Loft, B. Sandstrom, Am.
J. Clin. Nutr. 79 (2004) 1060–1072.
[59] L.H. Long, D.C. Kwee, B. Halliwell, Free Radic. Res. 32 (2000)
619–629.
[60] H. Wang, A.M. Jenner, C.Y. Lee, G. Shui, S.Y. Tang, M.
Whiteman, M.R. Wenk, B. Halliwell, Free Radic. Res. 41 (2007)
479–488.
[61] C.Y. Lee, H.B. Issac, H. Wang, S.H. Huang, L.H. Long, A.M.
Jenner, R.P. Kelly, B. Halliwell, Biochem. Biophys. Res. Commun.
344 (2006) 906–911.
[62] M. Richelle, M.E. Turini, R. Guidoux, I. Tavazzi, S. Metairon, L.B.
Fay, FEBS Lett. 459 (1999) 259–262.
[63] C.Y. Lee, A.M. Jenner, B. Halliwell, Biochem. Biophys. Res.
Commun. 320 (2004) 696–702.
[64] M.N. Vissers, P.L. Zock, R. Leenen, A.J. Roodenburg, K.P. van
Putte, M.B. Katan, Free Radic. Res. 35 (2001) 619–629.
[65] Y. Fang, H. Fang, W. Xu, Mini Rev. Med. Chem. 7 (2007) 663–678.
[66] T. Schewe, C. Sadik, L.O. Klotz, T. Yoshimoto, H. Kuhn, H. Sies,
Biol. Chem. 382 (2001) 1687–1696.
[67] K.T. Howitz, K.J. Bitterman, H.Y. Cohen, D.W. Lamming, S.
Lavu, J.G. Wood, R.E. Zipkin, P. Chung, A. Kisielewski,
L.L. Zhang, B. Scherer, D.A. Sinclair, Nature 425 (2003) 191–
193.
[68] A. Boumendjel, A. Di Pietro, C. Dumontet, D. Barron, Med. Res.
Rev. 22 (2002) 512–529.
[69] J.C. Vera, A.M. Reyes, J.G. Carcamo, F.V. Velasquez, C.I. Rivas,
R.H. Zhang, P. Strobel, R. Iribarren, H.I. Scher, J.C. Slebe, D.W.
Golde, J. Biol. Chem. 271 (1996) 8719–8724.
[70] B. Halliwell, FEBS Lett. 540 (2003) 3–6.
[71] H. De Groot, A. Littauer, Free Radic. Biol. Med. 173 (1989) 541–
551.
[72] T. Yusa, J.D. Crapo, B.A. Freeman, Biochim. Biophys. Acta 798
(1987) 167–174.
[73] J.F. Turrens, B.A. Freeman, J.G. Levitt, J.D. Crapo, Arch.
Biochem. Biophys. 217 (1982) 401–410.
[74] B. Halliwell, Biochem. J. 401 (2007) 1–11.
[75] E.E. Kelley, G.R. Buettner, C.P. Burns, Arch. Biochem. Biophys.
319 (1995) 102–109.
[76] M. Leist, B. Raab, S. Maurer, U. Rosick, R. Brigelius-Flohe, Free
Radic. Biol. Med. 21 (1996) 297–306.
[77] R. Ebert, M. Ulmer, S. Zeck, J. Meissner-Weigl, D. Schneider, H.
Stopper, N. Schupp, M. Kassem, F. Jakob, Stem Cells 24 (2006)
1226–1235.
[78] L.V. Papp, J. Lu, A. Holmgren, K.K. Khanna, Antioxid. Redox
Signal. 9 (2007) 775–806.
[79] L.H. Long, M.V. Clement, B. Halliwell, Biochem. Biophys. Res.
Commun. 273 (2000) 50–53.
[80] M.V. Clement, R. Jeyakumar, L.H. Long, B. Halliwell, Antiox.
Redox Signal. 3 (2001) 157–164.
[81] S. Park, S. Han, C.H. Park, E. Hahm, S.J. Lee, H.K. Park, S. Lee,
W.S. Kim, C.W. Jung, K. Park, H.D. Riordan, B.F. Kimler, K.
Kim, J. Lee, Int. J. Biochem. Cell Biol. 36 (2004) 2180–2195.
[82] T.L. Duarte, G.M. Almeida, G.D.D. Jones, Toxicol. Lett. 170
(2007) 57–65.
[83] P.C. Chai, L.H. Long, B. Halliwell, Biochem. Biophys. Res.
Commun. 304 (2003) 650–654.
[84] M.V. Clement, L.H. Long, J. Ramalingam, B. Halliwell, J. Neuro-
chem. 81 (2002) 414–421.
[85] T. Lapidot, M.D. Walker, J. Kanner, J. Agric. Food Chem. 50
(2002) 3156–3160.
[86] K. Isuzugawa, M. Inone, Y. Ogihara, Biol. Pharm. Bull. 24 (2001)
1022–1026.
[87] K. W Lee, H.J. Hur, H.J. Lee, C.Y. Lee, J. Agric. Food Chem. 53
(2005) 1990–1995.
[88] S.C. Roques, N. Landrault, P.L. Teissedre, C. Laurent, P. Besancon,
J.M. Rovanet, B. Caporiccio, Free Radic. Res. 36 (2002) 593–599.
[89] G.Y. Yang, J. Liao, C. Li, J. Chung, E.J. Yurkow, C.T. Ho, C.S.
Yang, Carcinogenesis 21 (2000) 2035–2039.
[90] H. Sakagami, H. Arakawa, M. Maeda, K. Satoh, T. Kadofuku, K.
Fukuchi, K. Gomi, Anticancer Res. 21 (2001) 2633–2642.
[91] K. Kajiya, M. Ichiba, M. Kuwabara, S. Kumazawa, T. Nakayama,
Biosci. Biotechnol. Biochem. 65 (2001) 1227–1229.
[92] G. Bartosz, Acta Biochim. Pol. 47 (2000) 1197–1198.
[93] G. Peterszegi, F.B. Dagonet, J. Labat-Robert, L. Robert, Eur. J.
Clin. Invest. 32 (2002) 372–380.
[94] V. C de Boer, M.C. de Goffau, I.C. Arts, P.C. Hollman, J. Keijer,
Mech. Ageing Dev. 127 (2006) 618–627.
[95] R. Feng, H.M. Ni, S.Y. Wang, I.L. Tourkova, M.R. Shurin, H.
Harada, X.M. Yin, J. Biol. Chem. 282 (2007) 13468–13476.
[96] K. Maeta, W. Nomura, Y. Takatsume, S. Izawa, Y. Inoue, Appl.
Environ. Microbiol. 73 (2007) 572–580.
[97] T. Yamamoto, J. Lewis, J. Wataha, D. Dickinson, B. Singh, W.B.
Bollag, E. Ueta, T. Osaki, M. Athar, G. Schuster, S. Hsu, J.
Pharmacol. Exp. Ther. 308 (2004) 317–323.
[98] L.H. Long, B. Halliwell, Free Radic. Res. 32 (2000) 463–467.
[99] S. Muscat, J. Pelka, J. Hegele, B. Weigle, G. Munch, M. Pischets-
rieder, Mol. Nutr. Food Res. 51 (2007) 525–535.
[100] A. Chichirau, M. Flueraru, L.L. Chepelev, J.S. Wright, W.G.
Willmore, T. Durst, H.H. Hussain, M. Charron, Free Radic. Biol.
Med. 38 (2005) 344–355.
[101] H. Nakagawa, K. Hasumi, J.T. Woo, K. Nagai, M. Wachi,
Carcinogenesis 25 (2004) 1567–1574.
[102] L. Elbling, R.M. Weiss, O. Teufelhofer, M. Uhl, S. Knasmueller, R.
Schulte-Hermann, W. Berger, M. Micksche, FASEB J. 19 (2005)
807–809.
[103] S. Wachtel-Galor, S.W. Choi, I.F.F. Benzie, Redox Rep. 10 (2005)
145–149.
[104] T. Lapidot, M.D. Walker, J. Kanner, J. Agric. Food Chem. 50
(2002) 7220–7225.
[105] K. Morita, H. Arimochi, Y. Ohnishi, J. Pharmacol. Exp. Ther. 306
(2003) 317–323.
[106] M.M. Chan, K.J. Soprano, K. Weinstein, D. Fong, J. Cell Physiol.
207 (2006) 389–396.
[107] J. Hong, S.J. Kwon, S. Sang, J. Ju, J.N. Zhou, C.T. Ho, M.T.
Huang, C.S. Yang, Free Radic. Biol. Med. 42 (2007) 1211–1221.
[108] D.J. Kirkland, M. Aardema, N. Banduhn, P. Carmichael, R. Fautz,
J.R. Meunier, S. Pfuhler, Mutagenesis 22 (2007) 161–175.
[109] D.J. Kirland, M. Hayashi, D. Jacobson-Kram, P. Kasper, J.T.
MacGregor, L. Muller, Y. Uno, Mutat. Res. 627 (2007) 5–9.
[110] L.H. Long, D. Kirkland, J. Whitwell, B. Halliwell, Mutat. Res. 634
(2007) 177–183.
[111] L.M. Wee, L.H. Long, M. Whiteman, B. Halliwell, Free Radic. Res.
37 (2003) 1123–1130.