Cardiovascular Research 73 (2007) 341 – 347                                                                               ...
342                                     B. Halliwell / Cardiovascular Research 73 (2007) 341–347even the humble ethanol mo...
B. Halliwell / Cardiovascular Research 73 (2007) 341–347                                                  343several TAC a...
344                                        B. Halliwell / Cardiovascular Research 73 (2007) 341–347and ascorbate normally ...
B. Halliwell / Cardiovascular Research 73 (2007) 341–347                                                   345[14] Conte V...
346                                             B. Halliwell / Cardiovascular Research 73 (2007) 341–347[55] Neuhouser ML....
B. Halliwell / Cardiovascular Research 73 (2007) 341–347                                               347 [97] Zhao K, Wh...
Upcoming SlideShare
Loading in …5

Halliwell et al., cardiovascular res. 2007 dietary polyphenols good, bad or indifferent


Published on

Un articolo scientifico selezionato da Revidox

  • Be the first to comment

  • Be the first to like this

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Halliwell et al., cardiovascular res. 2007 dietary polyphenols good, bad or indifferent

  1. 1. Cardiovascular Research 73 (2007) 341 – 347 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 Downloaded from by guest on January 15, 2013Abstract 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 flavonoidsaccount for or contribute to the health benefits of diets rich in plant-derived foods and beverages is uncertain. Phenolic compounds may helpto protect the gastrointestinal tract against damage by reactive species present in foods or generated within the stomach and intestines. Theoverall health benefit of flavonoids is uncertain, and consumption of large quantities of them in fortified foods or supplements should not yetbe encouraged.© 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.Keywords: Atherosclerosis; Cell culture/isolation; Redox signalling1. 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 somemeta-analyses and other studies suggesting that these agents 2. Fruits and vegetablesnot only fail to protect against disease, but also that some ofthem may accelerate development of cancers or cardiovascular Among the few things uncontested by nutritionists aredisease 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 exerciseto the development of age-related diseases such as cancer is and a judicious consumption of red wine (or other alcoholicincorrect? Possibly, but I do not believe so (reviewed in [7]). beverages) seem associated with a lower risk of developingInstead, I think it to be more likely that the antioxidant cardiovascular disease, some forms of cancer, and perhapsadministrations simply failed to protect against oxidative Alzheimers disease [15,17–23]. However, foods anddamage (discussed in detail in [2,7–9]). For example, high beverages derived from plants are chemically complex, anddoses of α-tocopherol are poorly-effective at decreasing levels protective effects could arise from many components orof 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: lating nitric oxide production, cyclooxygenase inhibitors and0008-6363/$ - 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. 2. 342 B. Halliwell / Cardiovascular Research 73 (2007) 341–347even the humble ethanol molecule itself [2,17–28]. Are are pro-oxidant in vivo are (in my view) equivocal andfruits and vegetables beneficial because of these other inconclusive. Nor is the evidence that they are antioxidants acomponents? Or is it that fruits and vegetables act (in whole great deal better.or in part) by antioxidant actions, but that the activeantioxidants are not vitamin C, α-tocopherol or β-carotene? 4. Enter the flavonoidsSome 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 rangeputative biomarker of oxidative damage to DNA and DNA of reactive species, including hydroxyl radicals, peroxylprecursors [32,33], was decreased by feeding human radicals hypochlorous acid and (sometimes) superoxide Uvolunteers Brussels sprouts, but not by giving them α- radical, O2 − (reviewed in [46]). Flavonoids can also inhibittocopherol, 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 thateffect (e.g. [36]), and some registered increases in bio- flavonoids appear to scavenge less well. Many flavonoids Downloaded from by guest on January 15, 2013markers 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 formationall 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 biologicalin the food, on biomarkers of oxidative damage. Thus importance of flavonoids. First, phenolics in red wine wereVissers et al. [38] showed that olive oil administration to shown to be able to inhibit the oxidation of LDL in vitro andhuman 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 studyundergo oxidation in vitro, but feeding oil without anti- in the Netherlands, suggested an inverse correlation betweenoxidants had the same effect. In 2000, we reported [39] that the incidence of coronary heart disease and stroke and thedark soy sauce has powerful antioxidant abilities in vitro. dietary intake of flavonoids, especially quercetin [54]. SinceRecently, we attempted to see if dark soy sauce decreased then, several other epidemiological studies have confirmedoxidative damage in vivo in human volunteers, and indeed it similar associations, although a few have not, and there is littlewas able to decrease levels of F2-isoprostanes [40]. We evidence that flavonoids protect against cancer [55]. Someadministered the soy sauce with rice, using a placebo col- suggestions of protection against neurodegenerative diseaseouring 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 themeal did better than the placebo in lowering F2-isoprostane disease-protective effects of fruits and vegetables? If so, islevels. Similarly, Richelle et al. [41] and Lee et al. [42] this due to antioxidant effects? Many polyphenols aresuggested that fasting may raise plasma F2-isoprostane absorbed, although rarely completely, and most of thelevels. At the moment, the balance of evidence does suggest remainder are broken down in the colon to generate highthat antioxidant effects contribute to the benefits of a high levels of monophenols [60,61]. Are the amounts ofintake 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-richbe done on the effect of diet on oxidative damage, using foods and beverages and measuring biomarkers of oxidativesuitable controls. damage suggest yes, but others no (discussed in [35,62]). “Feeding effects” alluded to earlier could account for some3. 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 lowerstimulate oxidative damage in vivo, especially ascorbate, antioxidant activity because radical-scavenging –OH groups arealleged 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) areof ascorbate might kill cancer cells in vivo by oxidizing to often in the range of 1 mM or more (reviewed in [7]), it seemsproduce H2O2 [45]. We found small and transient increases difficult to imagine how an additional 1 μM polyphenol couldin oxidative DNA damage in human volunteers fed mixtures exert a powerful antioxidant effect in vivo. Some studies haveof ascorbate, β-carotene and α-tocopherol, but there was shown effects of flavonoid-rich foods in raising plasma TAC inwide variation between experiments [8]. Overall, the humans. But one must be cautious here; many such foods canavailable data that ascorbate, β-carotene or α-tocopherol increase plasma uric acid levels, and urate is detected by
  3. 3. B. Halliwell / Cardiovascular Research 73 (2007) 341–347 343several TAC assays [62–64]. Since elevated urate may be a risk against gastric, and possibly colonic, cancer, although againfactor 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 ofare complex molecules and have multiple potential actions other the flavonoids, or to flavonoids at all, rather than to otherthan antioxidant ones, including inhibiting telomerase, gluta- components in the foods. However, ingestion of green teamate dehydrogenase, cyclooxygenase, lipoxygenase, xanthine was reported to rapidly decrease prostaglandin E2 concen-oxidase, matrix metalloproteinases, angiotensin-converting trations in human rectal mucosa, consistent with inhibitionenzyme, 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 faecalinteracting with sirtuins [25,35,43,56,57,65–73]. Flavonoids water are fairly low (μM or less), but monophenols (manymay also interact with cellular drug transport systems, compete derived from polyphenol breakdown) are present at muchwith 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 ofties, 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- Downloaded from by guest on January 15, 2013these effects occur in vivo, given the low concentration of nols be important to the stomach and intestines? Thebioavailable 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 othersprotective effects of flavonoids and other phenolic com- are generated by chemical reactions of dietary componentspounds could occur before absorption, i.e. within the within the stomach [83,88]. Sources of reactive speciesstomach, intestines and colon (Fig. 1). This could account include H2O2 in beverages [89], the mixtures of ascorbatefor 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 isconsiderable intersubject variability in the efficiency of GI uptake of vitamin E. ▵Much H2O2 may be removed in the oral cavity by catalase and peroxidases insaliva, and by H2O2 diffusion into the oral and oesophageal epithelium followed by its rapid catabolism. Adapted from [7] with permission from Oxford U U UUniversity Press. RNS Reactive nitrogen species, OH hydroxyl radical, RO alkoxyl radical, RO2 peroxyl radical, RS reactive species, LOX lipoxygenase,COX-2 cyclooxygenase-2.
  4. 4. 344 B. Halliwell / Cardiovascular Research 73 (2007) 341–347and ascorbate normally present in gastric juice [90]), and than would be expected from the rate of its generation byingested 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 ispresent in foods include lipid peroxides, cytotoxic possible that polyphenols could oxidize there as well. Thisaldehydes, and isoprostanes [91–95]. Nitrite is present at might even be good for you, generating a pro-oxidanthigh levels in saliva and in foods [96]. It is converted to challenge that raises levels of xenobiotic-metabolizing andHNO2 by gastric acid, and HNO2 can then form nitrosating antioxidant defence enzymes in the GI tract.and DNA-deaminating species [97]. Activation of immunecells naturally present in the GI tract by diet-derived bacteria 7. A caution about supplementsand toxins can also increase ROS production [98]. Flavonoids and other phenolic compounds might exert Flavonoid-rich foods appear good for us, although todirect protective effects in the gastrointestinal tract, by what extent (if any) the flavonoids contribute to this benefitscavenging reactive species and/or preventing their forma- is uncertain. Other possible protective components in foodstion. For example, polyphenols can inhibit haem protein- were listed in Section 1. So should we consume flavonoidinduced 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 Downloaded from by guest on January 15, 2013derived 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 asdefence enzymes in the GI tract, and chelate transition metal such and rapidly removed from the circulation. They may beions [83]. Dietary iron is usually not completely absorbed, beneficial in the gut in the correct amounts. But too muchespecially among subjects on Western diets. Unabsorbed may not be good and thus, I suggest that one should bedietary 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,diets rich in fat and low in fibre may aggravate this pro- Referencesoxidant effect [102]. Phenolic compounds, by chelating iron,may help to alleviate pro-oxidant actions of colonic iron. [1] Bjelakovic G, Nikolova D, Simonetti RG, Gluud C. Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2004;364:1219–28.6. Flavonoids as pro-oxidant xenobiotics [2] Halliwell B. Polyphenols; antioxidant treats for healthy living or covert toxins. J Sci Food Agric 2006;86:1992–5. Why do hot beverages often contain high levels of H2O2? [3] Lawlor DA, Davey Smith G, Kundu D, Bruckdorfer KR, Ebrahim S.Simply because the polyphenols within them oxidize readily at Those confounded vitamins: what can we learn from the differenceshigh temperatures [89,103–105]. Polyphenols can also oxidize between observational versus randomised trial evidence? Lancet 2004;363:1724–7.readily in cell culture media, and several claims of the [4] Lee DH, Folsom AR, Harnack L, Halliwell B, Jacobs Jr DR. Doescytotoxic effects of flavonoids on malignant, and other, cells in supplemental vitamin C increase cardiovascular disease risk inculture may have been led astray by this artefact. Flavonoids women with diabetes? Am J Clin Nutr 2004;80:1194–200.oxidize especially readily in Dulbeccos Modified Eagles [5] Miller III ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ,medium (DMEM), but also do so in most other cell culture Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37–, at a slower rate [106,107]. Oxidation generates H2O2, [6] Neuhouser ML, Patterson RE, Thornquist MD, Omenn GS, King IB,quinones and semiquinones that can contribute to (and Goodman GE. Fruits and vegetables are associated with lower lungsometimes entirely account for) cytotoxicity [106–110]. For cancer risk only in the placebo arm of the beta-carotene and retinolexample, the apparent toxicity of green tea to PCI2 cells efficacy trial (CARET). Cancer Epidemiol Biomarkers Prevappeared entirely due to oxidation products generated in the 2003;12:350–8. [7] Halliwell B, Gutteridge JMC. Free radicals in biology and medicine.culture medium [109]. This is not to say that all the observed 4th ed. Clarendon Press; 2006.cellular effects of flavonoids are artefacts; indeed, they may [8] Halliwell B. Establishing the significance and optimal intake of dietaryexert different effects on different cell types, those on vascular antioxidants: the biomarker concept. Nutr Rev 1999;57:104–13.endothelial cells and other cells of the vascular system perhaps [9] Halliwell B. The antioxidant paradox. Lancet 2000;355:1179–80.being especially important physiologically [43,82]. However, [10] Meagher EA, Barry OP, Lawson JA, Rokach J, FitzGerald GA. Effects of vitamin E on lipid peroxidation in healthy persons. JAMAmost work with cultured cells has failed to separate real effects 2001;285:1178–82.from artefacts and may need to be repeated under conditions [11] Morrow JD. Quantification of isoprostanes as indices of oxidantthat slow or prevent phenol oxidation. stress and the risk of atherosclerosis in humans. Arterioscler Thromb The mechanism of polyphenol oxidation in cell culture Vasc Biol 2005;25:279– is unclear. Metal ions may be involved (since DMEM [12] Pratico D, Tangirala RK, Rader DJ, Rokach J, FitzGerald GA. Vitamin E suppresses isoprostane generation in vivo and reducesis rich in iron ions, added to it as ferric nitrate), but it is not atherosclerosis in ApoE-deficient mice. Nat Med 1998;4:1189–92.simply an iron-catalysed oxidation of polyphenols [110]. [13] Cyrus T, Yao Y, Rokach J, Tang LX, Pratico D. Vitamin E reducesAscorbate also oxidizes in DMEM to make H2O2, but progression of atherosclerosis in low-density lipoprotein receptor-deficientmixtures of ascorbate and flavonoids generate less H2O2 mice with established vascular lesions. Circulation 2003;107:521–3.
  5. 5. B. Halliwell / Cardiovascular Research 73 (2007) 341–347 345[14] Conte V, Uryu K, Fujimoto S, Yao Y, Rokach J, Longhi L, et al. Vitamin oxidative DNA damage estimated by 8-oxo-7,8-dihydro-2′-deoxy- E reduces amyloidosis and improves cognitive function in Tg2576 mice guanosine excretion in smokers. Am J Clin Nutr 1997;65:503–7. following repetitive concussive brain injury. J Neurochem 2004;90: [35] Halliwell B, Rafter J, Jenner A. Health promotion by flavonoids, 758–64. tocopherols, tocotrienols, and other phenols: direct or indirect effects?[15] Martin I, Grotewiel MS. Oxidative damage and age-related functional Antioxidant or not? Am J Clin Nutr 2005;81:268S–76S. declines. Mech Ageing Dev 2006;127:411–23. [36] McAnulty SR, McAnulty LS, Morrow JD, Khardouni D, Shooter L,[16] Zhao L, Pratico D, Rader DJ, Funk CD. 12/15-Lipoxygenase gene Monk J, et al. Effect of daily fruit ingestion on angiotensin converting disruption and vitamin E administration diminish atherosclerosis and enzyme activity, blood pressure, and oxidative stress in chronic oxidative stress in apolipoprotein E deficient mice through a final smokers. Free Radic Res 2005;39:1241–8. common pathway. Prostaglandins Other Lipid Mediat 2005;78:185–93. [37] Dragsted LO, Pedersen A, Hermetter A, Basu S, Hansen M, Haren[17] Rimm EB, Ascherio A, Giovannucci E, Spiegelman D, Stampfer MJ, GR, et al. The 6-a-day study: effects of fruit and vegetables on Willett WC. Vegetable, fruit, and cereal fiber intake and risk of markers of oxidative stress and antioxidative defense in healthy coronary heart disease among men. JAMA 1996;275:447–51. nonsmokers. Am J Clin Nutr 2004;79:1060–72.[18] Lloyd T, Chinchilli VM, Rollings N, Kieselhorst K, Tregea DF, [38] Vissers MN, Zock PL, Leenen R, Roodenburg AJ, van Putte KP, Henderson NA, et al. Fruit consumption, fitness, and cardiovascular Katan MB. Effect of consumption of phenols from olives and extra health in female adolescents: the Penn State Young Womens Health virgin olive oil on LDL oxidizability in healthy humans. Free Radic Study. Am J Clin Nutr 1998;67:624–30. Res 2001;35:619–29.[19] Szmitko PE, Verma S. Antiatherogenic potential of red wine: clinician [39] Long LH, Kwee DC, Halliwell B. The antioxidant activities of update. Am J Physiol Heart Circ Physiol 2005;288:H2023–30. seasonings used in Asian cooking. Powerful antioxidant activity of Downloaded from by guest on January 15, 2013[20] de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. dark soy sauce revealed using the ABTS assay. Free Radic Res Mediterranean diet, traditional risk factors, and the rate of cardio- 2000;32:181–6. vascular complications after myocardial infarction: final report of the [40] Lee CY, Isaac HB, Wang H, Huang SH, Long LH, Jenner AM, et al. Lyon Diet Heart Study. Circulation 1999;99:779–85. Cautions in the use of biomarkers of oxidative damage; the vascular[21] Pietinen P, Rimm EB, Korhonen P, Hartman AM, Willett WC, and antioxidant effects of dark soy sauce in humans. Biochem Albanes D, et al. Intake of dietary fiber and risk of coronary heart Biophys Res Commun 2006;344:906–11. disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta- [41] Richelle M, Turini ME, Guidoux R, Tavazzi I, Metairon S, Fay LB. Carotene Cancer Prevention Study. Circulation 1996;94:2720–7. Urinary isoprostane excretion is not confounded by the lipid content[22] Lau FC, Shukitt-Hale B, Joseph JA. The beneficial effects of fruit of the diet. FEBS Lett 1999;459:259–62. polyphenols on brain aging. Neurobiol Aging 2005;26(Suppl 1):128–32. [42] Lee CY, Jenner AM, Halliwell B. Rapid preparation of human urine and[23] Staehelin HB. Micronutrients and Alzheimers disease. Proc Nutr Soc plasma samples for analysis of F2-isoprostanes by gas chromatography- 2005;64:565–70. mass spectrometry. Biochem Biophys Res Commun 2004;320:696–702.[24] Brouwer IA, van Dusseldorp M, West CE, Meyboom S, Thomas CM, [43] Issa AY, Volate SR, Wargovich MJ. The role of phytochemicals in Duran M, et al. Dietary folate from vegetables and citrus fruit inhibition of cancer and inflammation: new directions and perspec- decreases plasma homocysteine concentrations in humans in a dietary tives. J Food Compos Anal 2006:405–19. controlled trial. J Nutr 1999;129:1135–9. [44] Duarte TL, Lunec J. Review: when is an antioxidant not an[25] August DA, Landau J, Caputo D, Hong J, Lee MJ, Yang CS. antioxidant? A review of novel actions and reactions of vitamin C. Ingestion of green tea rapidly decreases prostaglandin E2 levels in Free Radic Res 2005;39:671–86. rectal mucosa in humans. Cancer Epidemiol Biomarkers Prev [45] Chen Q, Espey MG, Krishna MC, Mitchell JB, Corpe CP, Buettner 1999;8:709–13. GR, et al. Pharmacologic ascorbic acid concentrations selectively kill[26] Al-Abed Y, Mitsuhashi T, Li H, Lawson JA, FitzGerald GA, Founds cancer cells: action as a pro-drug to deliver hydrogen peroxide to H, et al. Inhibition of advanced glycation endproduct formation by tissues. Proc Natl Acad Sci U S A 2005;102:13604–9. acetaldehyde: role in the cardioprotective effect of ethanol. Proc Natl [46] Rice-Evans C, editor. Wake up to flavonoids. London: Royal Society Acad Sci U S A 1999;96:2385–90. of Medicine Press; 2000.[27] Kris-Etherton PM, Yu-Poth S, Sabate J, Ratcliffe HE, Zhao G, [47] Pannala AS, Rice-Evans CA, Halliwell B, Singh S. Inhibition of Etherton TD. Nuts and their bioactive constituents: effects on serum peroxynitrite-mediated tyrosine nitration by catechin polyphenols. lipids and other factors that affect disease risk. Am J Clin Nutr Biochem Biophys Res Commun 1997;232:164–8. 1999;70:504S–11S. [48] Heijnen CG, Haenen GR, van Acker FA, van der Vijgh WJ, Bast A.[28] Myzak MC, Dashwood RH. Chemoprotection by sulforaphane: keep Flavonoids as peroxynitrite scavengers: the role of the hydroxyl one eye beyond Keap1. Cancer Lett 2006;233:208–18. groups. Toxicol In Vitro 2001;15:3–6.[29] Verhagen H, de Vries A, Nijhoff WA, Schouten A, van Poppel G, [49] Santos MR, Mira L. Protection by flavonoids against the peroxyni- Peters WH, et al. Effect of Brussels sprouts on oxidative DNA- trite-mediated oxidation of dihydrorhodamine. Free Radic Res damage in man. Cancer Lett 1997;114:127–30. 2004;38:1011–8.[30] Rehman A, Bourne LC, Halliwell B, Rice-Evans CA. Tomato [50] Ketsawatsakul U, Whiteman M, Halliwell B. A reevaluation of the consumption modulates oxidative DNA damage in humans. Biochem peroxynitrite scavenging activity of some dietary phenolics. Biochem Biophys Res Commun 1999;262:828–31. Biophys Res Commun 2000;279:692–9.[31] Sanchez-Moreno C, Cano MP, de Ancos B, Plaza L, Olmedilla B, [51] Hajji HE, Nkhili E, Tomao V, Dangles O. Interactions of quercetin Granado F, et al. Mediterranean vegetable soup consumption with iron and copper ions: complexation and autoxidation. Free Radic increases plasma vitamin C and decreases F2-isoprostanes, prosta- Res 2006;40:303–20. glandin E2 and monocyte chemotactic protein-1 in healthy humans. [52] Mira L, Fernandez MT, Santos M, Rocha R, Florencio MH, Jennings J Nutr Biochem 2006;17:183–9. KR. Interactions of flavonoids with iron and copper ions: a mechanism[32] Halliwell B, Whiteman M. Measuring reactive species and oxidative for their antioxidant activity. Free Radic Res 2002;36:1199–208. damage in vivo and in cell culture: how should you do it and what do [53] Frankel EN, Kanner J, German JB, Parks E, Kinsella JE. Inhibition of the results mean? Br J Pharmacol 2004;142:231–55. oxidation of human low-density lipoprotein by phenolic substances in[33] Cooke MS, Evans MD, Lunec J. DNA repair: insights from urinary red wine. Lancet 1993;341:454–7. lesion analysis. Free Radic Res 2002;36:929–32. [54] Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D.[34] Prieme H, Loft S, Nyyssonen K, Salonen JT, Poulsen HE. No effect of Dietary antioxidant flavonoids and risk of coronary heart disease: the supplementation with vitamin E, ascorbic acid, or coenzyme Q10 on Zutphen Elderly Study. Lancet 1993;342:1007–11.
  6. 6. 346 B. Halliwell / Cardiovascular Research 73 (2007) 341–347[55] Neuhouser ML. Dietary flavonoids and cancer risk: evidence from [77] Ferreira AC, Lisboa PC, Oliveira KJ, Lima LP, Barros IA, Carvalho human population studies. Nutr Cancer 2004;50:1–7. DP. Inhibition of thyroid type 1 deiodinase activity by flavonoids.[56] Mandel S, Amit T, Reznichenko L, Weinreb O, Youdim MB. Green Food Chem Toxicol 2002;40:913–7. tea catechins as brain-permeable, natural iron chelators–antioxidants [78] Aviram M, Dornfeld L, Kaplan M, Coleman R, Gaitini D, Nitecki S, for the treatment of neurodegenerative disorders. Mol Nutr Food Res et al. Pomegranate juice flavonoids inhibit low-density lipoprotein 2006;50:229–34. oxidation and cardiovascular diseases: studies in atherosclerotic mice[57] Schroeter H, Boyd C, Spencer JP, Williams RJ, Cadenas E, Rice- and in humans. Drugs Exp Clin Res 2002;28:49–62. Evans C. MAPK signaling in neurodegeneration: influences of [79] Steffen Y, Schewe T, Sies H. Myeloperoxidase-mediated LDL flavonoids and of nitric oxide. Neurobiol Aging 2002;23:861–80. oxidation and endothelial cell toxicity of oxidized LDL; attenuation[58] Zbarsky V, Datla KP, Parkar S, Rai DK, Aruoma OI, Dexter DT. by (−)-epicatechin. Free Radic Res 2006;40:1076–85. Neuroprotective properties of the natural phenolic antioxidants [80] Rechner AR, Kroner C. Anthocyanins and colonic metabolites of curcumin and naringenin but not quercetin and fisetin in a 6-OHDA dietary polyphenols inhibit platelet function. Thromb Res 2005;116: model of Parkinsons disease. Free Radic Res 2005;39:1119–25. 327–34.[59] Zini A, Del Rio D, Stewart AJ, Mandrioli J, Merelli E, Sola P, et al. [81] Wu CH, Yen GC. Inhibitory effect of naturally occurring flavonoids Do flavan-3-ols from green tea reach the human brain? Nutr Neurosci on the formation of advanced glycation endproducts. J Agric Food 2006;9:57–61. Chem 2005;53:3167–73.[60] Manach C, Donovan JL. Pharmacokinetics and metabolism of dietary [82] Schroeter H, Heiss C, Balzer J, Kleinbongard P, Keen CL, Hollenberg flavonoids in humans. Free Radic Res 2004;38:771–85. NK, et al. (−)-Epicatechin mediates beneficial effects of flavanol-rich[61] Williamson G, Barron D, Shimoi K, Terao J. In vitro biological cocoa on vascular function in humans. Proc Natl Acad Sci U S A Downloaded from by guest on January 15, 2013 properties of flavonoid conjugates found in vivo. Free Radic Res 2006;103:1024–9. 2005;39:457–69. [83] Halliwell B, Zhao K, Whiteman M. The gastrointestinal tract: a major[62] Halliwell B. Plasma antioxidants: health benefits of eating chocolate? site of antioxidant action? Free Radic Res 2000;33:819–30. Nature 2003;426:787. [84] Jenner AM, Rafter J, Halliwell B. Human fecal water content of[63] Lotito SB, Frei B. The increase in human plasma antioxidant capacity phenolics: the extent of colonic exposure to aromatic compounds. after apple consumption is due to the metabolic effect of fructose on Free Radic Biol Med 2005;38:763–72. urate, not apple-derived antioxidant flavonoids. Free Radic Biol Med [85] Kuwano Y, Kawahara T, Yamamoto H, Teshima-Kondo S, Tominaga 2004;37:251–8. K, Masuda K, et al. Interferon-gamma activates transcription of[64] Henning SM, Niu Y, Liu Y, Lee NH, Hara Y, Thames GD, et al. NADPH oxidase 1 gene and upregulates production of superoxide Bioavailability and antioxidant effect of epigallocatechin gallate anion by human large intestinal epithelial cells. Am J Physiol Cell administered in purified form versus as green tea extract in healthy Physiol 2006;290:C433–43. individuals. J Nutr Biochem 2005;16:610–6. [86] Ha EM, Oh CT, Bae YS, Lee WJ. A direct role for dual oxidase in[65] Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood Drosophila gut immunity. Science 2005;310:847–50. JG, et al. Small molecule activators of sirtuins extend Saccharomyces [87] El Hassani RA, Benfares N, Caillou B, Talbot M, Sabourin JC, cerevisiae lifespan. Nature 2003;425:191–6. Belotte V, et al. Dual oxidase2 is expressed all along the digestive[66] Van Hoorn DE, Nijveldt RJ, Van Leeuwen PA, Hofman Z, MRabet L, tract. Am J Physiol Gastrointest Liver Physiol 2005;288:G933–42. De Bont DB, et al. Accurate prediction of xanthine oxidase inhibition [88] Kanner J, Lapidot T. The stomach as a bioreactor: dietary lipid based on the structure of flavonoids. Eur J Pharmacol 2002;451:111–8. peroxidation in the gastric fluid and the effects of plant-derived[67] Laughton MJ, Evans PJ, Moroney MA, Hoult JR, Halliwell B. antioxidants. Free Radic Biol Med 2001;31:1388–95. Inhibition of mammalian 5-lipoxygenase and cyclo-oxygenase by [89] Halliwell B, Long LH, Yee TP, Lim S, Kelly R. Establishing flavonoids and phenolic dietary additives. Relationship to antioxidant biomarkers of oxidative stress: the measurement of hydrogen activity and to iron ion-reducing ability. Biochem Pharmacol 1991;42: peroxide in human urine. Curr Med Chem 2004;11:1085–92. 1673–81. [90] Waring AJ, Drake IM, Schorah CJ, White KL, Lynch DA, Axon AT,[68] Naasani I, Oh-Hashi F, Oh-Hara T, Feng WY, Johnston J, Chan K, et al. et al. Ascorbic acid and total vitamin C concentrations in plasma, Blocking telomerase by dietary polyphenols is a major mechanism for gastric juice, and gastrointestinal mucosa: effects of gastritis and oral limiting the growth of human cancer cells in vitro and in vivo. Cancer supplementation. Gut 1996;38:171–6. Res 2003;63:824–30. [91] Aw TY. Intestinal glutathione: determinant of mucosal peroxide[69] Katiyar SK. Matrix metalloproteinases in cancer metastasis: molec- transport, metabolism, and oxidative susceptibility. Toxicol Appl ular targets for prostate cancer prevention by green tea polyphenols Pharmacol 2005;204:320–8. and grape seed proanthocyanidins. Endocr Metab Immune Disord [92] Grootveld M, Atherton MD, Sheerin AN, Hawkes J, Blake DR, Drug Targets 2006;6:17–24. Richens TE, et al. In vivo absorption, metabolism, and urinary[70] Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP. excretion of alpha,beta-unsaturated aldehydes in experimental Dietary flavonoids as proteasome inhibitors and apoptosis inducers in animals. Relevance to the development of cardiovascular diseases human leukemia cells. Biochem Pharmacol 2005;69:1421–32. by the dietary ingestion of thermally stressed polyunsaturate-rich[71] Actis-Goretta L, Ottaviani JI, Fraga CG. Inhibition of angiotensin culinary oils. J Clin Invest 1998;101:1210–8. converting enzyme activity by flavanol-rich foods. J Agric Food [93] Kawai K, Matsuno K, Kasai H. Detection of 4-oxo-2-hexenal, a novel Chem 2006;54:229–34. mutagenic product of lipid peroxidation, in human diet and cooking[72] Moon YJ, Wang X, Morris ME. Dietary flavonoids: effects on xenobiotic vapor. Mutat Res 2006;603:186–92. and carcinogen metabolism. Toxicol In Vitro 2006;20:187–210. [94] Gopaul NK, Halliwell B, Anggard EE. Measurement of plasma[73] Li C, Allen A, Kwagh J, Doliba NM, Qin W, Najafi H, et al. Green tea F2-isoprostanes as an index of lipid peroxidation does not appear to be polyphenols modulate insulin secretion by inhibiting glutamate confounded by diet. Free Radic Res 2000;33:115–27. dehydrogenase. J Biol Chem 2006;281:10214–21. [95] Surh J, Kwon H. Estimation of daily exposure to 4-hydroxy-2-[74] Morris ME, Zhang S. Flavonoid–drug interactions: effects of alkenals in Korean foods containing n-3 and n-6 polyunsaturated fatty flavonoids on ABC transporters. Life Sci 2006;78:2116–30. acids. Food Addit Contam 2005;22:701–8.[75] Singh RP, Agarwal R. Natural flavonoids targeting deregulated cell [96] Pannala AS, Mani AR, Spencer JP, Skinner V, Bruckdorfer KR, cycle progression in cancer cells. Curr Drug Targets 2006;7:345–54. Moore KP, et al. The effect of dietary nitrate on salivary, plasma, and[76] Shimizu M, Kobayashi Y, Suzuki M, Satsu H, Miyamoto Y. Regulation of urinary nitrate metabolism in humans. Free Radic Biol Med 2003;34: intestinal glucose transport by tea catechins. Biofactors 2000;13:61–5. 576–84.
  7. 7. B. Halliwell / Cardiovascular Research 73 (2007) 341–347 347 [97] Zhao K, Whiteman M, Spencer JP, Halliwell B. DNA damage by [105] Akagawa M, Shigemitsu T, Suyama K. Production of hydrogen peroxide nitrite and peroxynitrite: protection by dietary phenols. Methods by polyphenols and polyphenol-rich beverages under quasi-physiological Enzymol 2001;335:296–307. conditions. Biosci Biotechnol Biochem 2003;67:2632–40. [98] Chamulitrat W. Activation of the superoxide-generating NADPH [106] Long LH, Clement MV, Halliwell B. Artifacts in cell culture: rapid oxidase of intestinal lymphocytes produces highly reactive free generation of hydrogen peroxide on addition of (−)-epigallocatechin, radicals from sulfite. Free Radic Biol Med 1999;27:411–21. (−)-epigallocatechin gallate, (+)-catechin, and quercetin to commonly [99] Lapidot T, Granit R, Kanner J. Lipid hydroperoxidase activity of used cell culture media. Biochem Biophys Res Commun 2000;273: myoglobin and phenolic antioxidants in simulated gastric fluid. J Agric 50–3. Food Chem 2005;53:3391–6. [107] Halliwell B. Oxidative stress in cell culture: an under-appreciated[100] Lee SY, Munerol B, Pollard S, Youdim KA, Pannala AS, Kuhnle GG, problem? FEBS Lett 2003;540:3–6. et al. The reaction of flavanols with nitrous acid protects against [108] Lapidot T, Walker MD, Kanner J. Can apple antioxidants inhibit N-nitrosamine formation and leads to the formation of nitroso deriva- tumor cell proliferation? Generation of H2O2 during interaction of tives which inhibit cancer cell growth. Free Radic Biol Med 2006;40: phenolic compounds with cell culture media. J Agric Food Chem 323–34. 2002;50:3156–60.[101] Babbs CF. Free radicals and the etiology of colon cancer. Free Radic [109] Chai PC, Long LH, Halliwell B. Contribution of hydrogen peroxide Biol Med 1990;8:191–200. to the cytotoxicity of green tea and red wines. Biochem Biophys Res[102] Kato I, Dnistrian AM, Schwartz M, Toniolo P, Koenig K, Shore RE, Commun 2003;304:650–4. et al. Iron intake, body iron stores and colorectal cancer risk in [110] Wee LM, Long LH, Whiteman M, Halliwell B. Factors affecting the women: a nested case-control study. Int J Cancer 1999;80:693–8. ascorbate- and phenolic-dependent generation of hydrogen peroxide in Downloaded from by guest on January 15, 2013[103] Arakawa H, Maeda M, Okubo S, Shimamura T. Role of hydrogen Dulbeccos Modified Eagles Medium. Free Radic Res 2003;37:1123–30. peroxide in bactericidal action of catechin. Biol Pharm Bull 2004;27: [111] Skibola CF, Smith MT. Potential health impacts of excessive 277–81. flavonoid intake. Free Radic Biol Med 2000;29:375–83.[104] Mochizuki M, Yamazaki S, Kano K, Ikeda T. Kinetic analysis and mechanistic aspects of autoxidation of catechins. Biochim Biophys Acta 2002;1569:35–44.