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Plant Polyphenol Antioxidants and Oxidative Stress

INS URQUIAGA and FEDERICO LEIGHTON

Laboratorio de Citologa Bioqumica y Lpidos, Departamento de Biologa Celular y Molecular,Facultad de Ciencias Biolgicas, Pontificia Universidad Catlica de Chile, Casilla 114-D,

Santiago, Chile

Corresponding Author: Federico LeightonDep. Biologa Celular y MolecularFacultad de Ciencias BiolgicasP. Universidad Catlica de ChileCasilla 114-D, Santiago, Chile

Phone/fax: (56-2) 222-2577E-mail: [email protected]


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ABSTRACT

In recent years there has been a remarkable increment in scientific articles dealing with oxidativestress. Several reasons justify this trend: knowledge about reactive oxygen and nitrogen speciesmetabolism; definition of markers for oxidative damage; evidence linking chronic diseases and

oxidative stress; identification of flavonoids and other dietary polyphenol antioxidants present inplant foods as bioactive molecules; and data supporting the idea that health benefits associatedwith fruits, vegetables and red wine in the diet are probably linked to the polyphenol antioxidantsthey contain.

In this review we examine some of the evidence linking chronic diseases and oxidative stress, thedistribution and basic structure of plant polyphenol antioxidants, some biological effects ofpolyphenols, and data related to their bioavailability and the metabolic changes they undergo inthe intestinal lumen and after absorption into the organism.

Finally, we consider some of the challenges that research in this area currently faces, withparticular emphasis on the contributions made at the International Symposium "Biology andPathology of Free Radicals: Plant and Wine Polyphenol Antioxidants" held July 29-30, 1999, atthe Catholic University, Santiago, Chile and collected in this special issue of BiologicalResearch.

KEY TERMS:

Oxidative stress; antioxidant; plant polyphenol; flavonoid; chronic diseases; diet


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This review and the accompanying articles in this special issue of Biological Research reflect the

content of the presentations and discussions held on the occasion of the International Symposium

"Biology and Pathology of Free Radicals: Plant and Wine Polyphenol Antioxidants," July 29-30,

1999, at the Catholic University in Santiago, Chile.

Chronic diseases and oxidative stress

Chronic diseases constitute a major challenge for medicine and basic biology and will certainly

remain so for the next decades. We have seen the emergence, in epidemic proportions, of

modern chronic diseases in the latter part of the 20 th century, a process that is still in progress

(Wilks et al., 1998). In developing countries, this process is part of what is known as an

epidemiological transition (Vio & Albala, 2000), and it is particularly striking in the Americas

(Castillo-Salgado et al., 1999). Characteristically, infectious diseases are replaced by chronic ornon-communicable diseases as the primary cause of morbidity and mortality. This situation is

associated with changes in diet and lifestyle that contribute to the development of chronic

diseases. Among the risk behaviors characteristic of the transition are excessive dietary fat

intake, low intake of fruits and vegetables, sedentary life style, smoking, and environmental

contamination.

A primary focus of preventive medicine is the detection and treatment of individuals at

risk, and molecular tools are increasingly used to recognize risk. Today, chronic diseases are at

the interface of molecular genetics and preventive medicine. For chronic diseases such as

coronary heart disease, context-dependent effects are determinant; they include interactions

among genes (genetic epistasis) and between genes and environmental factors (gene-environment

interactions) (Ellsworth et al., 1999). Strikingly, there are some common risk factors and

pathophysiological conditions that affect most diseases grouped into the category of modern

chronic diseases: cardiovascular disease, hypertension, diabetes mellitus, and some forms of

cancer. Oxidative stress is a central risk factor for chronic diseases.

Oxidative stress, the consequence of an imbalance of prooxidants and antioxidants in the

organism, is rapidly gaining recognition as a key phenomenon in chronic diseases. It is directly

involved in the pathogenic mechanism of risk factors and in the protection exerted by various

environmental factors. And the quantification of oxidative stress in populations appears to be a

possible indicator for the magnitude of environmental risk factors. For example, it has been


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proposed that the relatively high cardiovascular mortality rate in post-communist countries is the

consequence of environmental conditions resulting in higher levels of oxidative stress (Ginter,

1996). Diet plays a major role in the environmental control of oxidative stress: fruits, vegetables

and red wine decrease oxidative stress, whereas the occidental diet, characteristically rich in fats,

induces oxidative stress (Leighton et al., 1999).

Compelling evidence has led to the conclusion that diet is a key environmental factor and

a potential tool for the control of chronic diseases. After tobacco, inadequate diet and activity

patterns are the most prominent contributors to mortality in USA (McGinnis and Foege, 1993).

Dietary recommendations for the prevention of cancer, atherosclerosis and other chronic diseases

have been established by various health agencies (Bronner, 1996; Munoz de Chavez and Chavez,

1998). More specifically, fruits and vegetables have been shown to exert a protective effect

(Gillman et al., 1995; Joshipura et al., 1999; Cox et al., 2000; Strandhagen et al., 2000). The highcontent of polyphenol antioxidants in fruits and vegetables is probably the main factor

responsible for these effects.

Polyphenols, Natural Antioxidants in Food and Beverages

Polyphenols are present in a variety of plants utilized as important components of both human

and animal diets (Bravo, 1998; Chung et al., 1998; Crozier et al., 2000). These include food

grains such as sorghum, millet, barley, dry beans, peas, pigeon peas, winged beans, and other

legumes; fruits such as apples, blackberries, cranberries, grapes, peaches, pears, plums,

raspberries, and strawberries; and vegetables such as cabbage, celery, onion and parsley also

contain a large quantity of polyphenols. Phenolic compounds are also present in tea and wine.

Forages such as crownvetch, lespedeza, lotus, sainfoin, and trefoil are also reported to contain

polyphenolic compounds.

Diets containing an abundance of fruit and vegetables are protective against a variety of

diseases, particularly cardiovascular disease and cancer. The primary nutrients thought to provide

the protection afforded by fruit and vegetables are the antioxidants (Eastwood, 1999). Potter

(1997) reviewed 200 epidemiological studies, the majority of which showed a protective effect of

increased fruit and vegetable intake. When the role of individual antioxidants, vitamins C and E,

and carotenoids, is examined by epidemiological studies or supplementation trials, the results are

not as clear-cut as those obtained for fruit and vegetables and are often disappointing. Potters


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conclusion was that fruit and vegetables provide the best polypharmacy against the development

of a chronic disease, considering that they contain a vast array of antioxidant components such as

polyphenols.

Diets rich in fruits and vegetables, such as vegetarian and Mediterranean diets, contain a

large quantity of polyphenols. Dietary habits consistent with protection from coronary heart

disease have been considered too restrictive (high in polyunsaturated fats and/or vegetarian);

however, the diet in some Mediterranean countries, such as France, Spain and Italy, is varied and

characterized by a low consumption of butter and high consumption of bread, vegetables, fruit,

cheese, vegetable fat, and wine: the so called Mediterranean type diet. In addition, other foods

high in saturated fat are eaten; 14-15 % of energy intake corresponds to saturated fat (Renaud and

de Lorgeril, 1992; Segasothy and Phillips, 1999). Certainly, a high consumption of vegetables

constitutes a healthy habit observed in Mediterranean countries in conjunction with moderatewine consumption. The univariate correlation coefficients between coronary heart disease

mortality and the intake of various foodstuffs, in a study based on statistics from the 21 most

industrialized wine-drinking countries, were as follows: vegetables, -0.48 (P


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population, and the main sources of flavonoids were apples and onions. Both groups found an

inverse association between intake of dietary flavonoids and cardiovascular disease. These

studies, however, consider only the intake of some specific flavonoids and do not look at other

phenolic compounds. Thus, an accurate estimation of total polyphenolic intake is not available.

Structure of Plant Polyphenols

Phenolic compounds, or polyphenols, constitute one of the most numerous and widely-distributed

groups of substances in the plant kingdom, with more than 8,000 phenolic structures currently

known. Polyphenols are products of the secondary metabolism of plants. The expression

"phenolic compounds" embraces a considerable range of substances that possess an aromatic ring

bearing one or more hydroxyl substituents. Most of the major classes of plant polyphenol are

listed in Table I, according to the number of carbon atoms of the basic skeleton. The structure ofnatural polyphenols varies from simple molecules, such as phenolic acids, to highly polymerized

compounds, such as condensed tannins (Harborne, 1980).

Flavonoids represent the most common and widely distributed group of plant phenolics.

Their common structure is that of diphenylpropanes (C6-C3-C6) and consists of two aromatic

rings linked through three carbons that usually form an oxygenated heterocycle (Harborne, 1980).

Figure 1 shows the basic structure and the system used for the carbon numbering of the flavonoid

nucleus. Structural variations within the rings subdivide the flavonoids into several families:

flavonols, flavones, flavanols, isoflavones, antocyanidins and others. These flavonoids often

occur as glycosides, glycosylation rendering the molecule more water-soluble and less reactive

toward free radicals. The sugar most commonly involved in glycoside formation is glucose,

although galactose, rhamnose, xylose and arabinose also occur, as well as disaccharides such as

rutinose. The flavonoid variants are all related by a common biosynthetic pathway, incorporating

precursors from both the shikimate and the acetate-malonate pathways (Crozier et al., 2000).

Further modification occurs at various stages, resulting in an alteration in the extent of

hydroxylation, methylation, isoprenylation, dimerization and glycosylation (producing O- or C-

glycosides).

Phenolic compounds act as antioxidants with mechanisms involving both free radical

scavenging and metal chelation. They have ideal structural chemistry for free radical-scavenging


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activities, and have been shown to be more effective antioxidants in vitro than vitamins E and C

on a molar basis (Rice- Evans et al., 1997).

Biological Effects of Polyphenols

Polyphenols exhibit a wide range of biological effects as a consequence of their antioxidant

properties. They inhibit LDL oxidation in vitro (Frankel et al., 1993). Moreover, LDL isolated

from volunteers supplemented with red wine or red wine polyphenols show reduced

susceptibility to oxidation (Fuhrman et al., 1995; Nigdikar et al., 1998). Thus, polyphenols

probably protect LDL oxidation in vivo with significant consequences in atherosclerosis. and also

protect DNA from oxidative damage with important consequences in the age-related

development of some cancers (Halliwell, 1999). In addition, flavonoids have antithrombotic and

anti-inflammatory effects (Gerritsen et al., 1995; Muldoon and Kritchevsky, 1996). Theantimicrobial property of polyphenolic compounds has been well documented (Chung et al.,

1998).

Several types of polyphenols (phenolic acids, hydrolysable tannins, and flavonoids) show

anticarcinogenic and antimutagenic effects. Polyphenols might interfere in several of the steps

that lead to the development of malignant tumors, inactivating carcinogens, inhibiting the

expression of mutant genes and the activity of enzymes involved in the activation of

procarcinogens and activating enzymatic systems involved in the detoxification of xenobiotics

(Bravo, 1998). However, some polyphenols have been reported to be mutagenic in microbial

assays and co-carcinogens or promoters in inducing skin carcinogenesis in the presence of other

carcinogens (Chung et al., 1998). This latter possibility warrants further research.

Several studies have shown that in addition to their antioxidant protective effect on DNA

and gene expression, polyphenols, particularly flavonoids, inhibit the initiation, promotion and

progression of tumors, possibly by a different mechanism.

Wine contains many compounds that apparently exhibit anti-cancer properties, including

gallic acid, caffeic acid, ferulic acid, catechin, quercetin and resveratrol, among others. Gallic

acid is antimutagenic with the Ames test (Hour et al., 1999) and hepato protective for carbon

tetrachloride toxicity (Kanai and Okano,1998). In an experiment with transgenic mice that

spontaneously develop skin tumors, the addition of red wine solid extract to their diet led to a

marked delay in tumor development (Clifford et al., 1996).


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Caffeic and ferulic acids react with nitrite in vitro and inhibit nitrosamine formation in

vivo. They inhibit the formation of skin tumors induced by 7,12-dimethyl-benz(a) anthracene in

mice (Kaul and Khanduja, 1998). They also inhibit tyrosine nitration mediated by peroxynitrite

(Pannala et al., 1998).

Resveratrol has been extensively studied. It has been isolated from several sources and

shown to inhibit the development of preneoplastic lesions in rat mammary gland tissue in cultures

in the presence of carcinogens; it also inhibits skin tumors in mice (Clifford et al., 1996; Jang et

al., 1997). Other researchers have shown that the combination of resveratrol and quercetine exerts

a synergic effect in the inhibition of growth and proliferation of human oral squamous carcinoma

cells (ElAttar and Virji, 1999). In this study, however, the best result was observed with diluted

red wine. Since resveratrol and quercetin are present in low concentrations, other polyphenols

could also be responsible for this effect and for the potentiation of cell growth inhibition.

Polyphenol Bioavailability and Metabolism

The knowledge of absorption, biodistribution and metabolism of polyphenols is partial and

incomplete, yet it is sufficient to state that in general, some polyphenols are bioactive compounds

that are absorbed from the gut in their native or modified form. They are subsequently

metabolized with products detected in plasma that retain at least part of the antioxidant capacity

and then excreted. Experimental studies in animals support the previous general statement (Dasand Griffiths, 1969; Das and Sothy, 1971; Griffiths and Smith, 1972; Manach et al., 1995;

Manach et al., 1997; Piskula and Terao, 1998; Morand et al., 1998; Okushio et al., 1999a;

1999b). In humans, studies aim at identifying native compounds and their metabolites in plasma

and urine after the administration of test meals or drinks. These studies also support the initial

general statement. Many of the studies performed with humans are centered on the detection of

quercetin after the consumption of onions, tea, and apple juice (Hollman et al., 1996,1997; Aziz

et al., 1998; Manach et al., 1998; Lean et al., 1999; McAnlis et al., 1999).

Some of these studies have addressed the question of the biological activity of rutin and

quercetin metabolites, such as the ability of quercetin and isorhamnetin to inhibit copper induced

LDL oxidation (Manach et al., 1998; Morand et al., 1998). These authors state that the plasma

metabolites retain antioxidant activity.


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After green tea consumption, epigallocatechin gallate and epicatechin gallate are detected

in plasma and urine (Yang et al., 1998). Red wine consumption leads to the accumulation of o-

methylcatechin, a catechin metabolic product, in plasma (Donovan et al. 1999). These findings

should be considered important initial contributions to the identification of the various

bioavailable polyphenols present in tea and wine, as well as the identification of their

metabolites. Pietta et al. (1998) employed green tea to attempt an overall evaluation of absorption

and metabolism. They detected green tea flavanols in plasma and some monohydroxy and

dihydroxybenzoic acids in urine, accounting for approximately 15% of the polyphenols

administered. These phenolic acids would result from bacterial metabolization of catechin and

quercetin in the gut. The intestinal flora has enzymes that cleave the benzopyranosic ring (Das

and Griffiths, 1969; Winter et al., 1989).

Methylation in one or more phenolic hydroxyls is another possibility in polyphenolmetabolism, having been observed for catechin, epicatechin and green tea flavonoids (Piskula

and Terao, 1998; Okushio et al., 1999a, 1999b). This reaction is apparently mediated by catechol-

O-methyl transferase, an enzyme present in liver and kidney. Epicatechin, methylated and

conjugated with glucuronic acid and sulfate, appears as the plasma metabolite with the longer

half life, after a single dose of epicatechin to rats (Piskula and Terao, 1998). In rats receiving

0.2% quercetin in their diet for three weeks, the most abundant metabolite was the glucuronic

acid and sulfate conjugate of isorhamnetin, the 3' methylation product of quercetin (Morand et

al., 1998).

Sulfate and glucuronic acid conjugation, which leads to increased water solubility, is a

common strategy for drug metabolism, and in general for xenobiotic metabolism, the products

can be more easily eliminated into the urine. Polyphenol glucuronidation occurs in the intestine

and in the liver (Sfakianos et al., 1997; Piskula and Terao, 1998; Morand et al., 1998), whereas

sulfation apparently occurs only in the liver (Shali et al., 1991; Piskula and Terao, 1998).

Challenges for Research on Polyphenols and their Relationship with Chronic Diseases

There are hundreds of polyphenols with antioxidant activity that are potential contributors to the

antioxidant mechanisms in humans and animals in general. These compounds are excellent

candidates to explain the health benefits of diets rich in fruits and vegetables, although there is


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still not enough information on food composition data, bioavailability, interaction with other food

components and biological effects (Institute of Medicine, 1998).

Through the number of indexed scientific publications and their distribution over time, it

is possible to evaluate the quantity and relative importance of scientific efforts on specific

subjects. Thus, we can see in Figure 2 that great emphasis has been placed on the subject of

chronic disease in recent decades. Vitamins E and C have received sustained attention in the last

few decades, perhaps with a particular increment in the last five years. In contrast, the subject of

oxidative stress has seen an explosive growth in recent years; 80% of the articles published on the

subject have appeared in the last five years.

There is evidence that polyphenols are metabolized by intestinal flora and that they and

their metabolites are absorbed. This information is, for the moment, restricted to a few

compounds. Similarly, we know that some species are metabolized after absorption. The extent,specificity and localization of polyphenol metabolism in the organism have not been established

systematically. In this respect, the known chelating capacity of polyphenols raises the question

of their participation in aspects related to metal metabolism and pathology (Morel et al., 1998;

Nez et al., 2000; Opazo et al., 2000; Zago et al., 2000). Another aspect of polyphenol

metabolism not yet characterized systematically corresponds to its reaction with other biological

antioxidants. Interactions between ascorbate and catechin have been shown (Lotito & Fraga,

2000), leading to the hypothesis that polyphenol antioxidants are part of the antioxidant network

of the organism. Indeed, their ability to interact with other antioxidant radicals and peroxyl

radicals can be predicted from their reduction potentials (Jovanovic et al., 1998). Attempts have

been made to estimate the relative contribution of polyphenols to the total antioxidant capacity in

plasma (Perez et al., 2000) but insufficient knowledge on the nature and concentration of

circulating polyphenol species renders these results very uncertain. Polyphenol-SH interactions is

another subject that remains to be explored systematically. In this respect, Hidalgo et al. (2000)

describe the effect of redox reagents on the activity of intracellular calcium release channels in

muscle and nerve cells, which raises the possibility of another target to explain the biological

effects of polyphenol antioxidants.

The interaction of nitric oxide with polyphenol antioxidants is highly relevant in

physiological and pathological cellular mechanisms. Atherogenesis is a process markedly

dependent of lipid oxidation products that are recognized by specific receptors (Moriel et al.,


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2000; Rigotti, 2000). Nitric oxide, a free radical itself, participates in the atherogenic process

(Rubbo et al., 2000) through membrane lipid and lipoprotein oxidation events (Boveris et al.,

2000). Nitric oxide apparently regulates mitochondrial respiration and polyphenol antioxidants

are also active at this level (Hodnick & Pardini, 1998; Carreras et al., 2000)

Another rapidly developing aspect of free radical metabolism is its participation in the

process of mediating and regulating cellular function. Nitric oxide and superoxide anion are

continuously produced in aerobic cells and regulate the mitochondrial function (Valdez et al.,

2000) and these and other free radicals can modulate signal transduction pathways and gene

expression (Foncea et al., 2000). Thus, it seems very likely that dietary polyphenol antioxidants

continuously participate in the regulation of cellular function.

ACKNOWLEDGEMENTS

This work and the International Symposium "Biology and Pathology of Free Radicals: Plant and

Wine Polyphenol Antioxidants" held July 29-30, 1999, at the Catholic University, Santiago,

Chile, were partially supported by the Molecular Basis of Chronic Diseases Program of the

Catholic University (PUC-PBMEC99).


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REFERENCES

AZIZ AA, EDWARDS CA, LEAN MEJ, CROZIER A (1998) Absortion and excretion of

conjugated flavanols, including quercetin-4'-O--glucoside and isorhamnetin-4'-O--

glucoside by human volunteers after the consumption of onions. Free Rad Res

29:257-269

BOVERIS AD, GALATRO A, PUNTARULO S (2000) Effect of nitric oxide and plant

antioxidants on microsomal content of lipid radicals. THIS JOURNAL ISSUE

BRAVO L (1998) Polyphenols: Chemistry, dietary sources, metabolism, and nutritional

significance. Nutr Rev 56:317-333

BRONNER YL (1996) Nutritional status outcomes for children: ethnic, cultural, and

environmental contexts. J Am Diet Assoc 96:891-903

CASTILLO-SALGADO C, MUJICA O, LOYOLA E (1999) A subregional assessment of

demographic and health trends in the Americas: 1980-1998. Stat Bull Metrop Insur Co

80:2-12

CARRERAS MC, SCHPFER F, LISDERO C, RIOBO N, PODEROSO JJ (2000)

Mitochondrial function and nitric oxide utilization. THIS JOURNAL ISSUE

CHUNG KT, WONG TY, WEI CI, HUANG YW, LIN Y (1998) Tannins and human

health: a review. Crit Rev Food Sci Nutr 38:421-464

CROZIER A, BURNS J, AZIZ AA, STEWART AJ, RABIASZ HS, JENKINS GI,

EDWARDS CA, LEAN MEJ (2000) Antioxidant flavonols from fruits,

vegetables and beverages: measurements and bioavailability. THIS JOURNAL

ISSUE

CLIFFORD AJ, EBELER SE, EBELER JD, BILLS ND, HINRICHS SH, TEISSEDRE P-


13/24

13

L, WATERHOUSE AL (1996) Delayed tumor onset in transgenic mice fed an

amino acid-based diet supplemented with red wine solids. Am J Clin Nutr 64:748-

756

COX BD, WHICHELOW MJ, PREVOST AT (2000) Seasonal consumption of salad

vegetables and fresh fruit in relation to the development of cardiovascular disease

and cancer. Public Health Nutr 3:19-29

DAS NP, GRIFFITHS LA (1969) Studies on flavonoid metabolism. Metabolism of

(+)-[14C] catechin in the rat and guinea pig.Biochem J115:831-836

DAS NP, SOTHY SP (1971) Studies on flavonoid metabolism. Biliary and urinary

excretion of metabolites of (+)-(U- 14 C) catechin. Biochem J 125:417-423

DONOVAN JL, BELL JR, FASIM-KARAKAS S, GERMAN JB, WALZEM RL,

HANSEN RJ, WATERHOUSE AL (1999) Catechin is present as metabolites in

human plasma after consumption of red wine. J Nutr 129:1662-1668

EASTWOOD MA (1999) Interaction of dietary antioxidants in vivo: how fruit and

vegetables prevent disease? Q J Med 92:527-530

ELATTAR TMA, VIRJI AS (1999) The effect of red wine and its components on growth

and proliferation of human oral squamous carcinoma cells. Anticancer Res 19:5407-

5414

ELLSWORTH DL, SHOLINSKY P, JAQUISH C, FABSITZ RR, MANOLIO TA

(1999) Coronary heart disease. At the interface of molecular genetics and

preventive medicine. Am J Prev Med. 16:122-133

FONCEA R, CARVAJAL C, ALMARZA C, LEIGHTON F (2000) Endothelial cell

oxidative stress and signal transduction. THIS JOURNAL ISSUE

FRANKEL EN, KANNER J, GERMAN JB, PARKS E, KINSELLA JE (1993) Inhibition


14/24

14

of oxidation of human low-density lipoprotein by phenolic substances in red wine.

Lancet 341:454-457

FUHRMAN B, LAVY A, AVIRAM M (1995) Consumption of red wine with meals

reduces the susceptibility of human plasma and low-density lipoprotein to lipid

peroxidation. Am J Clin Nutr 61:549-554

GERRITSEN ME, CARLEY WW, RANGES GE, SHEN C-P, PHAN SA, LIGON GF,

PERRY CA (1995) Flavonoids inhibit cytokine-induced endothelial cell adhesion

protein gene expression. Am J Pathol 147:278-292

GILLMAN MW, CUPPLES LA, GAGNON D, POSNER BM, ELLISON RC,

CASTELLI WP, WOLF PA (1995) Protective effect of fruits and vegetables on

development of stroke in men. J Am Med Assoc 273:1113-1117

GINTER E (1996) High cardiovascular mortality in postcommunist countries: participation of

oxidative stress. Int J Vitam Nutr Res 66:183-189

GRIFFITHS LA, SMITH GE (1972) Metabolism of apigenin and related compounds in

the rat. Metabolite formation in vivo and by the intestinal microflora in vitro.

Biochem J128: 901-911

HALLIWELL B (1999) Establishing the significance and optimal intake of dietary

antioxidants: The biomarker concept. Nutr Rev 57:104-113

HARBORNE JB (1980 ) Plant phenolics. In: BELL EA, CHARLWOOD BV (eds) Encyclopedia

of Plant Physiology, volume 8 Secondary Plant Products, Springer-Verlag, Berlin

Heidelberg New York. Pp:329-395

HERMANSEN K (2000) Diet, blood pressure and hypertension. Br J Nutr 83 Suppl

1:S113-S119

HERTOG MGL, FESKENS EJM, HOLLMAN PCH, KATAN MB, KROMHOUT D


15/24

15

(1993) Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen

elderly study. Lancet 342:1007-1011

HIDALGO C, BULL R, MARENGO JJ, PEREZ CF, DONOSO P (2000) SH oxidation

stimulates calcium release channels (ryanodin receptors) from excitable cells. THIS

JOURNAL ISSUE

HODNICK WF, PARDINI RS (1998) Inhibition of mitochondrial function by flavonoids.

In: RICE-EVANS, PACKER L (eds) Flavonoids in Health and Disease. New York:

Marcel Dekker Inc., New York. pp:179-197

HOLLMAN PC, DER GAAG M, MENGELERS MJ, VAN TRIJP JM, DE VRIES

JH, KATAN MB (1996) Absorption and disposition kinetics of the dietary

antioxidant quercetin in man. Free Radic Biol Med21:703-707

HOLLMAN PC, VAN TRIJP JM, MENGELERS MJ, DE VRIES JH, KATAN MB

(1997) Bioavailability of the dietary antioxidant flavonol quercetin in man.

Cancer Lett114:139-140

HOUR TC, LIANG YC, CHU IS, LIN JK (1999) Inhibition of eleven mutagens by various

tea extracts, (-) epigallocatechin-3-gallate, gallic acid and caffiene. Food Chem

Toxicol 37:569-579

INSTITUTE OF MEDICINE (US) (1998) Dietary reference intakes. Proposed definition and plan

for review of dietary antioxidants and related compounds. Food and nutrition board.

Washington DC: IOM. National Academy Press, Washington, D.C., USA

JANG M, CAI L, UDEANI GO, SLOWING KV, THOMAS CF, BEECHER CWW,

FONG HHS, FARNSWORTH NR, KINGHORN AD, MEHTA RG, MOON RC,

PEZZUTO JM (1997) Cancer chemopreventive activity of resveratrol, a natural

product derived from grapes. Science 275:218-220


16/24

16

JOSHIPURA KJ, ASCHERIO A, MANSON JE, STAMPFER MJ, RIMM EB, SPEIZER

FE, HENNEKENS CH, SPIEGELMAN D, WILLETT WC (1999) Fruit and

vegetable intake in relation to risk of ischemic stroke. J Amer Med Assoc 282:1233-1239

JOVANOVIC SV, STEENKEN S, SIMIC MG, HARA Y (1998) Antioxidant properties of

flavonoids: reduction potentials and electron transfer reactions of flavonoid radicals.

In: RICE-EVANS, PACKER L (eds) Flavonoids in Health and Disease. New York:

Marcel Dekker Inc., New York. p:137-161

KANAI S, OKANO H (1998) Mechanism of protective effects of sumac gall extract and

gallic acid on progression of CC14-induced acute liver injury in rats. Am J Chin

Med 26:333-341

KAUL A, KHANDUJA KL (1998) Polyphenols inhibit promotional phase of tumorigenesis:

relevance of superoxide of superoxide radicals. Nurt Cancer 32:81-85

KNEKT P, JRVINEN R, REUNANEN A, MAATELA J (1996) Flavonoid intake and

coronary mortality in Finland: a cohort study. Brit Med J 312:478-481

LEAN ME, NOROOZI M, KELLY I, BURNS J, TALWAR D, SATTAR N, CROZIER

A (1999) Dietary flavonols protect diabetic human lymphocytes against oxidative

damage to DNA. Diabetes48:176-181

LEIGHTON F, CUEVAS A, GUASCH V, PEREZ DD, STROBEL P, SAN MARTIN A,

URZUA U, DIEZ MS, FONCEA R, CASTILLO O, MIZON C, ESPINOZA MA,

URQUIAGA I, ROZOWSKI J, MAIZ A, GERMAIN A (1999) Plasma polyphenols

and antioxidants, oxidative DNA damage and endothelial function in a diet and wine

intervention study in humans. Drugs Exp Clin Res 25:133-141

LOTITO SB, FRAGA CG (2000) Ascorbate protects (+)-catechin from oxidation both

in pure chemical system and human plasma. THIS JOURNAL ISSUE


17/24

17

MANACH C, MORAND C, TEXIER O, FAVIER ML, AGULLO G, DEMIGNE C,

REGERAT F, REMESY C (1995) Quercetin metabolites in plasma of rats fed

diets containing rutin or quercetin.J Nutr125:1911-1922

MANACH C, MORAND C, DEMIGNE C, TEXIER O, REGERAT F, REMESY C

(1997) Bioavailability of rutin and quercetin in rats. FEBS Lett409:12-16

MANACH C, MORAND C, CRESPY V, DEMIGNE C, TEXIER O, REGERAT F,

REMESY C (1998) Quercetin is recovered in human plasma as conjugated

derivatives which retain antioxidant properties. FEBS Lett426:331-336

MCANLIS GT, MCENENY J, PEARCE J, YOUNG IS (1999) Absorption and

antioxidant effects of quercetin from onions, in man.Eur J Clin Nutr53:92-96

MCGINNIS JM, FOEGE WH (1993)Actual causes of death in the United States. J Amer

Med Assoc 270:2207-2212

MORAND C, CRESPY V, MANACH C, BESSON C, DEMIGNE C, REMESY C

(1998) Plasma metabolites of quercetin and their antioxidant properties.Am J

Physiol275:R212-R219

MOREL I, CILLARD P, CILLARD J (1998) Flavonoid-metal interactions in biological

systems. In: RICE-EVANS, PACKER L (eds) Flavonoids in Health and Disease.

New York: Marcel Dekker Inc. pp:163-177

MORIEL P, PLAVNIK FL, ZANELLA MT, BERTOLAMI MC, ABDALLA DSP (2000)

Lipid peroxidation and antioxidants in hyperlipidemia and hypertension.

THIS JOURNAL ISSUE

MULDOON MF, KRITCHEVSKY SB (1996) Flavonoids and heart disease. Brit Med J

312:458-459

MUNOZ DE CHAVEZ M, CHAVEZ A (1998) Diet that prevents cancer: recommendations


18/24

18

from the American Institute for Cancer Research. Int J Cancer Suppl 11:85-89

NIGDIKAR SV, WILLIAMS NR, GRIFFIN BA, HOWARD AN (1998) Consumption of

red wine polyphenols reduces the susceptibility of low-density lipoproteins to

oxidation in vivo. Am J Clin Nutr 68:258-265

NUEZ MT, GARATE MA, ARREDONDO M, TAPIA V, MUOZ P (2000) The

cellular mechanisms of body iron homeostasis. THIS JOURNAL ISSUE

OKUSHIO K, SUZUKI M, MATSUMOTO N, NANJO F, HARA Y (1999a)

Identification of (-)-epicatechin metabolites and their metabolic fate in the

rat. Drug Metab Dispos 27:309-316

OKUSHIO K, SUZUKI M, MATSUMOTO N, NANJO F, HARA Y (1999b)

Methylation of tea catechins by rat liver homogenates.Biosci Biotechnol

Biochem63:430-432

OPAZO C, RUIZ FH, INESTROSA NC (2000) Amyloid -peptide reduces copper(II)

to copper(I) independent of its aggregation state. THIS JOURNAL ISSUE

PANNALA AS, RAZAQ R, HALLIWELL B, SINGH S, RICE-EVANS CA (1998)

Inhibition of peroxynitrite dependent tyrosine nitration by hydroxycinnamates:

nitration or electron donation? Free Radic Biol Med 24:594:606

PEREZ DD, LEIGHTON F, ASPEE A, ALIAGA C, LISSI E (2000) A comparison of

methods employed to evaluate antioxidant capabilities. THIS JOURNAL ISSUE

PIETTA PG, SIMONETTI P, GARDANA C, BRUSAMOLINO A, MORAZZONI P,

BOMBARDELLI E (1998) Catechin metabolites after intake of green tea

infusions. Biofactors 8:111-118

PISKULA MK, TERAO J (1998) Accumulation of (-) epicatechin metabolites in rat


19/24

19

plasma after oral administration and distribution of conjugation enzymes in rat

tissues. J Nutr128: 1172-1178

POTTER JD (1997) Cancer prevention: epidemiology and experiment. Cancer Lett 114:7-9

RENAUD S, DE LORGERIL M (1992) Wine, alcohol, platelets, and the French paradox

for coronary heart disease. Lancet 339:1523-1526

RENAUD S, RUF JC (1994) The French paradox: vegetables or wine. Circulation 90:3118-

3119

RICE-EVANS CA, MILLER NJ, PAGANGA G (1997) Antioxidant properties of phenolic

compounds. Trends in Plant Science 2:152-159

RIGOTTI A (2000) Scavenger receptors and atherosclerosis. THIS JOURNAL ISSUE

RUBBO H, BATTHYANY C, RADI R (2000) Nitric oxide-oxygen radical interactions in

atherosclerosis. THIS JOURNAL ISSUE

SEGASOTHY M, PHILLIPS PA (1999) Vegetarian diet: panacea for modern lifestyle

disease? Q J Med 92:531-544

SFAKIANOS J, COWARD L, KIRK M, BARNES S (1997) Intestinal uptake and biliary

excretion of the isoflavone genistein in rats.J Nutr127:1260-1268

SHALI NA, CURTIS CG, POWELL GM, ROY AB (1991) Sulphation of the flavonoids

quercetin and catechin by rat liver. Xenobiotica21:881-893

STRANDHAGEN E, HANSSON PO, BOSAEUS I, ISAKSSON B, ERIKSSON H (2000)

High fruit intake may reduce mortality among middle-aged and elderly

men. The study of men born in 1913.Eur J Clin Nutr 54:337-341

VALDEZ LB, ARNAIZ SL, BUSTAMANTE J, ALVAREZ S, COSTA LE, BOVERIS A (2000)

Free radical chemistry in biological systems. THIS JOURNAL ISSUE

VIO F, ALBALA C (2000) Nutrition policy in the Chilean transition. Public Health Nutr


20/24

20

3:49-55

WILKS R, BENNETT F, FORRESTER T, MCFARLANE-ANDERSON N (1998)

Chronic diseases: the new epidemic. West Indian Med J 47 Suppl 4:40-44

WINTER J, MOORE LH, DOWELL VR JR, BOKKENHEUSER VD (1989) C-ring

cleavage of flavonoids by human intestinal bacteria. Appl Environ Microbiol

55:1203-1208

YANG CS, CHEN L, LEE MJ, BALENTINE D, KUO MC, SCHANTZ SP (1998) Blood

and urine levels of tea catechins after ingestion of different amounts of green tea by

human volunteers. Cancer Epidemiol Biomarkers Prev 7:351-354

ZAGO MP, VERSTRAETEN SV, OTEIZA PI (2000) Zinc in the prevention of Fe2+-

initiated lipid and protein oxidation. THIS JOURNAL ISSUE


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Table I: The major classes of phenolic compounds in plants

Number

of carbon

atoms

Basic

skeleton

Class Examples

6 C6 Simple phenols

Benzoquinones

Catechol, hydroquinone

2,6-Dimethoxybenzoquinone

7 C6-C1 Phenolic acids Gallic, salicylic

8 C6-C2 Acetophenones

Tyrosine derivatives

Phenylacetic acids

3-Acetyl-6-

methoxybenzaldehyde

Tyrosol

p-Hydroxyphenylacetic

9 C6-C3 Hydroxycinnamic acids

Phenylpropenes

Coumarins

Isocoumarins

Chromones

Caffeic, ferulic

Myristicin, eugenol

Umbelliferone, aesculetin

Bergenon

Eugenin

10 C6-C4 Naphthoquinones Juglone, plumbagin

13 C6-C1-C6 Xanthones Mangiferin

14 C6-C2-C6 Stilbenes

Anthraquinones

Resveratrol

Emodin

15 C6-C3-C6 Flavonoids

Isoflavonoids

Quercetin, cyanidin

Genistein

18 (C6-C3)2 Lignans

Neolignans

Pinoresinol

Eusiderin

30 (C6-C3-C6)2 Biflavonoids Amentoflavone

n (C6-C3)n(C6)n(C6-C3-C6)n

Lignins

Catechol melanins

Flavolans (Condensed

Tannins)

From Harborne (1980)


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Figure 1: Flavonoids (C6-C3-C6)Basic structure and system used for carbon numbering of the flavonoid nucleus.Structural variations within the rings subdivide the flavonoids into several families.

Flavonol Flavan-3-ol

Flavone Anthocyanidin

O

OH

OH

OH

R

R'

O

OH

OH

OH

R

O

R'O

OH

OH

OH

OH

R

R'

+

O

OH

OOH

OH

OH

A C

B

87

65 4

3

21

2'3'

4'

5'

R

R'


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23

0

10

20

30

40

50

60

70

80

90

1965

-1969

1970-1974

1975

-1979

1980-1984

1985

-1989

1990-1994

1995

-2000

percentofpublications

Ox Stress

Natl Antiox

Flavonoids

0

10

20

30

40

50

60

70

80

90

1965

-1969

1970-1974

1975

-1979

1980-1984

1985

-1989

1990-1994

1995

-2000

percentofpublications

Chronic Dis.

vitE-vitC


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Figure 2

Evolution of the scientific interest in antioxidants, oxidative stress and chronic diseases.

The curves correspond to the relative distribution of Medline indexed publications for the period1965-2000, expressed in five year periods. The total number of indexed publications in the

period for oxidative stress, natural antioxidants, flavonoids, chronic diseases, and vitamins E andC, was 12,083; 1,230; 2,159; 125,042 and 21,128, respectively.

aviram m 1998 flavanoids inhibit

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