aviram m 1998 flavanoids inhibit
TRANSCRIPT
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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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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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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.