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Analysis and Antioxidant Capacity of AnthocyaninPigments. Part I: General Considerations ConcerningPolyphenols and FlavonoidsJulia Martín Bueno a , Fernando Ramos-Escudero b , Purificación Sáez-Plaza b , Ana MaríaMuñoz c , María José Navas b & Agustin G. Asuero ba Department of Analytical Chemistry , Higher Polytechnic School, The University of Seville ,Seville , Spainb Department of Analytical Chemistry , The University of Seville , Seville , Spainc Centro de Bioquímica y Nutrición, Facultad de Medicina, Universidad San Martin de Porres ,Lima , PerúPublished online: 23 Mar 2012.

To cite this article: Julia Martín Bueno , Fernando Ramos-Escudero , Purificación Sáez-Plaza , Ana María Muñoz , MaríaJosé Navas & Agustin G. Asuero (2012) Analysis and Antioxidant Capacity of Anthocyanin Pigments. Part I: GeneralConsiderations Concerning Polyphenols and Flavonoids, Critical Reviews in Analytical Chemistry, 42:2, 102-125, DOI:10.1080/10408347.2011.632312

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Critical Reviews in Analytical Chemistry, 42:102–125, 2012Copyright c© Taylor and Francis Group, LLCISSN: 1040-8347 print / 1547-6510 onlineDOI: 10.1080/10408347.2011.632312

Analysis and Antioxidant Capacity of AnthocyaninPigments. Part I: General Considerations ConcerningPolyphenols and Flavonoids

Julia Martın Bueno,1 Fernando Ramos-Escudero,2 Purificacion Saez-Plaza,2

Ana Marıa Munoz,3 Marıa Jose Navas,2 and Agustin G. Asuero2

1Department of Analytical Chemistry, Higher Polytechnic School, The University of Seville, Seville, Spain2Department of Analytical Chemistry, The University of Seville, Seville, Spain3Centro de Bioquımica y Nutricion, Facultad de Medicina, Universidad San Martin de Porres, Lima, Peru

Many epidemiological studies have shown the benefits of a diet rich in fruit and vegetables tohuman health and for the prevention of various diseases associated with oxidative stress, such ascancer and cardiovascular diseases. Anthocyanins, natural pigments belonging to the group offlavonoids, are common components of the human diet, as they are present in many foods, fruits,and vegetables, especially in berries. Their use as colorants has considerable interest because oftheir coloring properties. Moreover, they have an antioxidant activity. Various adverse effects onhealth have frequently been attributed to synthetic antioxidants. For these reasons, currently,there is a trend towards relying on antioxidants derived from natural products. The efficacy ofanthocyanins as antioxidants depends, to a large extent, upon their chemical structure. Theyact as antioxidants both in the foodstuffs in which they are found and in the organism afterintake of these foods. With this in mind, an introduction to polyphenols is made with emphasison their role as secondary metabolites, classification, and health relevance. Flavonoid intake,biological activities, databases, classification and structure, distribution, and dietary sources arethen considered. Aspects of anthocyanin concerning its early history and chemical structure,color, and intake are dealt with in the second part of the series. The extraction and analysis ofanthocyanin pigments and their antioxidant power, paying special attention to the oxidationprocess, will be the subject of the third part. Bioavailability and metabolism of anthocyanicpigments, the methods used for measuring the antioxidant activity of anthocyanins, and theinfluence of anthocyanins on the antioxidant activity of wine will finally be covered in thefourth part. The present review intends to reflect the interdisciplinary nature of the researchthat is currently carried out in this prolific area. Key research articles and reviews are mainlyreferenced, and we apologize to those researchers whose work is not cited directly by us.

Keywords polyphenols, flavonoids, secondary metabolites, classification, health relevance, dietaryintake, databases

INTRODUCTIONFruits, vegetables, cereals, nuts, seeds, flowers, bark, propo-

lis, olives, oil, and beverages such as wine (white and red),coffee, tea (green and black), chocolates and other cacao prod-ucts, and manufactured foods supply a number of micronutri-ents, such as minerals, fibers, and vitamins, as well as a wholeseries of compounds called phytochemicals (Cicerale et al.,2010; Gonzalez-Gallego et al., 2010; Jaganathan and Mandal,2009; Sharma and Rao, 2009; Heneman and Zidenberg-Cherr,

Address correspondence to Agustin G. Asuero, Dept. of AnalyticalChemistry, Faculty of Pharmacy, The University of Seville, 41012Seville, Spain. E-mail: asuero@us.es

2008; Han et al., 2007) (Figure 1). Although phytochemicalsmay be defined in the strictest sense as chemical produced byplants, this term is actually used to denote chemicals from plantsthat may have an influence on health, but are not essential (ElGharras, 2009). Advances in separation science, biology, andchemistry have boosted the interdisciplinary fields of pharma-cognosy and natural products chemistry research, yielding awealth of information about many classes of naturally occurringdietary phytochemicals (Bohlim et al., 2010; Dai and Mumper,2010; Garcıa-Salas et al., 2010; Kelm et al., 2005; Schreier,2005). Analytical chemistry has in this context a vital role,as has been stressed several times in this journal (Escudero,2011; Biesaga and Pyrzynska, 2009; Chrzaski, 2009; Peckova

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FIG. 1. Types of phytochemicals.

et al., 2009; Pohl et al., 2009; Zima et al., 2009; Harnly et al.,2007; Marszall and Kaliszan, 2007; Schoefs, 2004; Escarpa andGonzalez, 2001; Antolovich et al., 2000).

Special attention has been paid to analytical methodologiesinvolved in the isolation, determination, and characterizationof bioactive polyphenols in plants, fruits and vegetables, herbaldrugs, medicinal plants, and wines (Corradini et al., 2011; Ignatet al., 2011; Medic-Saric et al., 2009; van Beek et al., 2009;Stobiecki and Kachlicki, 2006; Rijke, 2005; Robards, 2003;Robards and Antolovich, 1997), including sample-handlingstrategies (Gonzalez and Gonzalez, 2010; Tura and Robards,2002), a feature of analysis often ignored. As examples ofapplications we have chromatographic techniques (Marston,2007; Sun et al., 2005), i.e., high-performance liquid chro-matography (HPLC) (Medic-Saric et al., 2011; Raczkowskaet al., 2011) and thin-layer and high-performance thin-layerchromatography (Cimpoiu, 2006), capillary electroseparationmethods (electrophoresis, electrochromatography) (Gotti,2011; Ganzera and Nischang, 2010; Hurtado-Fernandez et al.,2010), mass spectrometry (MS) (Vukics and Guttman, 2010;Cuyckens and Claeys, 2004; Stobiecki, 2000), HPLC/MS(Steinmann and Ganzera, 2011), nuclear magnetic resonance(NMR) (Eisenreich and Bacher, 2007), LC/NMR (Wolfenderet al., 2001), and spectrophotometry (Raczkowska et al., 2011;Harnafy and Amrani, 2008).

SECONDARY METABOLITESAmong these phytochemical compounds are the widespread

redox-active secondary metabolites of a phenolic nature, calledpolyphenols (Ferrazzano et al., 2011; Burton-Freeman, 2010;Chong et al., 2010; Crozier et al., 2009, 2010; Martin andAppel, 2010; Pereira et al., 2009; Boudet, 2007; Whiting,2001), although this term should be restricted to rathercomplex molecules, also referred to as tannins (Quideau

et al., 2011; Tarascou et al., 2010). Polyphenols, some ofwhich are ubiquitous in plants while others are restricted toparticular families, species, or organs, together with terpenic orisoprenoids (carotenoids, monoterpenes, phytosterols, essentialoils, squalene), sulfur-containing compounds (glucosinolatesof the Brassicaceae family, Alliaceae family derivatives), andnitrogen-containing compounds (alkaloids and heterocyclicaromatics) are the main secondary metabolites in plants (Carteaet al., 2011; Maiani et al., 2009; Verkerk et al., 2009; Hartmann,2007; Crozier et al., 2006; Juarez et al., 2005).

Secondary metabolites are distinct from the components ofintermediary (primary) metabolism (carbohydrates, proteins,amino acids, and lipids) in that they are nonessential for the ba-sic metabolic processes of growth and development of the plant.In spite of this, they are indeed crucial for many important func-tional aspects of plant life (Kroymann, 2011; Fraga et al., 2010;Lattanzio et al., 2009; Korkina, 2007; Duthie et al., 2003). Thephenomenon of secondary metabolism and its differentiationfrom basic primary metabolism was already recognized in thesecond half of the 19th century, by Julius Sachs (1873), one ofthe great pioneers of plant physiology (Neumann et al., 2009;Hartmann, 2007). Nevertheless, only recently has the worth ofsecondary metabolites come to be appreciated.

Secondary metabolites have structural roles in differing sup-porting or protective tissues, involvement in defense strategies,i.e., against predators and pathogens (viruses, mycoplasma,bacteria, and fungi), and signaling properties, particularlyin the interactions between plants and their environment (Liet al., 2010; Crozier et al., 2009; Lattanzio et al., 2009). Whenintroduced into the environment they have significant effectson soil composition and the microenvironments that plantsinhabit (Cohen and Kennedy, 2010; Shirley, 1996). In addition,secondary metabolites, in addition to providing plants withunique survival or adaptive strategies (Michalak, 2006) are ofcommercial significance to humankind.

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Secondary metabolites have been used as dyes, fibers, glues,oils, waxes, flavoring agents, traditional medicine, drugs, UVscreens, cosmetics, and perfumes and are viewed as potentialsources of new natural drugs, antibiotics, insecticides, andherbicides (Jaganatath and Crozier, 2010; Epstein, 2009;Gruenwald, 2009; Arct and Pytkowska, 2008; Korkina, 2007).Note that at least one-fourth of all prescribed pharmaceuticalsin industrialized countries contain compounds that are directlyor indirectly, via semi-synthesis, derived from plants. However,many of them are still in use today, and often no usefulsynthetic substitutes have been found that possess similarefficacy and pharmacological specificity (Neumann et al.,2009). In addition, 11% of the 252 basic and essential drugsconsidered by the World Health Organization, are exclusivelyderived from flowering plants (Rates, 2001).

POLYPHENOLSA large variety of plant phenols exist, being the most abun-

dant and the most widely represented class of plant naturalproducts. However, most polyphenols share a common origin:the amino acids phenylalanine (derived from the shikimic acidpathway) or tyrosine, which are deaminated to cinnamic acidsentering the phenylpropanoid pathway (Vogt, 2010; Emilianiet al., 2009; Gould et al., 2009; Pourcel et al., 2007). The abilityof plants to produce such an abundance of phenolic compoundsis based upon the continuous evolution of new genes broughtabout by gene duplication and mutation and subsequent recruit-ment and adaptation to specific functions (Boudet, 2007).

Phenolics are characterized by having at least one aromaticring with one or more hydroxyl groups attached (Tsao, 2010;Crozier et al., 2009; Pereira et al., 2009), ranging from sin-gle low molecular weight, single aromatic-ring compounds tothe large and complex (highly polymerized) tannins and de-rived polyphenols. Research into natural organic compounds.including phenols, was initiated by C. W. Scheele and L. N.Vauquelin, who were the first to isolate gallic acid and simpleorganic acids (Vacek et al., 2010). Tannin-containing plant ex-tracts have been used to process animal skin into leather sinceancient times (Quideau et al., 2011; Serrano et al., 2009). Theterm tannin was first introduced in 1796 and came from theuse of these compounds in tanneries. The first descriptions ofvegetable tannins were by Emil Fischer in the early 1900s, andfurther distinction between hydrolyzable and non-hydrolyzabletanning (condensed tannins) was later established by his discipleFreudenberg in 1920 (Tarascou et al., 2010; Haslam, 2007).

Polyphenols belong to four main classes (Figure 1):flavonoids, phenolic acids (hydroxyderivatives of benzoic acidand cinnamic acid, i.e., p-hydroxybenzoic, protocatechuic,vanillic, and syringic acids) and their esters (chlorogenic,caftaric, coutaric, and fertaric acids), stilbenes (resveratrol,pterostilbene, piceatannol), characterized by a double bond(1,2-diarylethene) connecting the phenolic rings, and lignans(pinoresinol, podophyllotoxin, steganacin), characterized by a1,4-diarylbutane structure, i.e., having 2-phenylpropane units.

Flavonoids and phenolic acids account for 60% and 30% re-spectively of total dietary polyphenols (Nichenametla et al.,2006).

Phenolic molecules not attached to sugar moieties are re-ferred to as the aglycone form; phenolic molecules existing ina conjugated form with one or more sugar residues are calledglycosides. Most phenolics are found in nature associated withmono- or polysaccharides or functional derivatives such as es-ters or methyl esters, varying widely in their hydroxylation pat-tern and can be glycosylated or acylated (Kren, 2008; Lin andHarnly, 2007).

POLYPHENOL HISTORY: A SHORT PRIMERPhenolic compounds have attracted the attention of re-

searchers for decades. Three British scientists managed to openthe door to both basic and applied knowledge of plant polyphe-nols today: E. C. Bate-Smith, Tony Swain, and Jeffrey B.Harbone (Quideau et al., 2011; Grayer and Williams, 2007;Cooper-Driver, 2001; Harborne, 1988, 1989; Anonymous,1988; Jones, 1988). These researchers were leading lights in theseparation, structural elucidation, and taxonomical distributionof phenolic compounds (Robins et al., 2007). They foundedthe Plant Phenolic Group, the forerunner of the PhytochemicalSociety of Europe (Lewis et al., 2003). In 1961 they cofoundedthe journal Phytochemistry, which in September 1980 wasdesignated as the official organ of the Phytochemical Society(Robins et al., 2007). Jeffrey Harborne, who came from thefield of organic chemistry, became an academic leader in thebiochemistry of secondary metabolites, particularly flavonoidsand other plant phenols (Prebble, 2010; Hanson, 2002), workingat the interface between chemistry and traditional areas of plantscience, systematics, and ecology, particularly as related tothe complex chemical language between plants, microbes, andanimals (Harborne, 2001).

In the 1950s Bate-Smith and Swain gave the lead into totallynew ways of looking at these substances (Haslam, 2007); theyconfirmed that leucoanthocyanidins, a term that was finally re-placed with proanthocyanidins (oligomers of the monomericflavan-3-ols), were identical with condensed tannins (Bate-Smith, 1954; Bate-Smith and Swain, 1953). In 1962 they cameup with their own proposal for a definition of plant polyphe-nols, later refined at the molecular level by Edwin Haslam, aBritish physical organic chemistry at the University of Sheffield(Quideau et al., 2011). Other outstanding contributions in thetannins field were made in the following decades by the groupsof Weinges, in Germany, of Haslam, in the UK, of Porter, inNew Zealand, and of Hemingway, in the USA (Tarascou et al.,2010).

Proposals about the formation of secondary metabolitesin plants, in the first half of the 20th century, were basedmainly on analogy with reactions of organic chemistry and oncomparison of structures rather than on biochemical evidence(Hartman, 2007). With the advantages of paper chromatographyand UV spectroscopy (Santos-Buelga and Williamson, 2003),

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it was possible around 1960 to recognize the widespread oc-currence of many plant molecules thought to be rare. Tracertechniques with radioactively labeled nuclides developed byMelvin Calvin allowed us for the first time to solve the mys-teries of the biosynthesis of polyphenols and other secondarymetabolites (Hartmann, 2007; Harborne, 2001), changing thescene dramatically. In the late 1970s, it was widely recognizedthat tannins, and specially protanthocyanidins, were widespreadand extremely abundant in numerous plant families, could befound in any plant organ, and also that only part of them could beextracted by usual solvents, a large proportion remaining insol-uble (Haslam, 2007). MS and NMR techniques saw a variety ofinstrumental developments and improvements from the 1970son (Eisenreich and Bacher, 2007; Hartmann, 2007), allowing ef-ficient application of precursors and intermediates labeled withstable nuclides, and thus chemical degradation was no longernecessary.

New advanced methods in sensitivity, combined with highresolution separation techniques with mass spectrometry detec-tion like gas chromatography (GC-MS) and liquid chromatogra-phy (LC-MS), gave fresh impetus to the chemical analysis of thecompounds (Corradini et al., 2011; Vukics and Guttman, 2010;Van Beek et al., 2009; Andersen, 2008; Daayf and Lattanzio,2008; Eisenreich and Bacher, 2007; Hartmann, 2007; Cuyckensand Claeys, 2004). While other more sophisticated techniquessuch as those mentioned above are becoming more popular asresearch tools, the relatively high capital costs are still an im-pediment to their routine use in enforcement laboratories, a factthat must be taken into consideration (Scotter, 2011).

POLYPHENOLS: NOW AND THENTraditionally, interest in polyphenols has mainly been re-

lated to their organoleptical properties such as color, astringency(tannins), bitterness (flavonols), and taste (Haslam, 2007;Cheynier, 2005; Tomas-Barberan and Espın, 2001), as well asto their physiological importance to plants because they play animportant role in plants as defense and signaling compounds inreproduction, pathogenesis, and symbiosis (involved in responsemechanisms against stress) (Grotewold, 2006a; Manetas, 2006;Michalak, 2006; Schaefer and Rolshause, 2006; Treutter, 2006;Mazza et al., 2000). It is well known that phenolic compoundsplay an important role in red wine color, bitterness, and as-tringency, as well as a range of other tactile or “mouth feel”characteristics (Mateus, 2009; Oberholster, 2008; Birse, 2007;Lesschaeve and Noble, 2005; Zimman et al., 2004). Despite thefact that most of the literature on plant phenolics focuses mainlyon those in fruits, vegetables, wines, and teas, many phenoliccompounds present in fruits and vegetables (phenolic acids andflavonoids) are also found in cereals (Dykes and Rooney, 2007;Lieberman, 2007; Naczk and Shadidi, 2006; Escribano-Bailonet al., 2004).

More recently polyphenols are increasingly being recognizedby their nutritional value, since they may help reduce the riskof chronic diseases (Ruel and Couillard, 2007; Willcox et al.,

2004) and, in general, have a positive effect on health, becauseof their free radical scavenging capacity, which, among otherbiological effects, increases antioxidant activity and preventscellular oxidation (Quideau et al., 2011; Jaganatah and Crozier,2010; Neveu et al., 2010; Terry et al., 2001). The capacity ofphenolic compounds to trap free radicals depends upon theirstructure, in particular of the hydrogen atoms of the aromaticgroup that can be transferred to the free radicals (Leopoldiniet al., 2011; Heim et al., 2002), and of the capacity of thearomatic compound to cope with the uncoupling of electrons as aresult of the surrounding displacement of the electron-π system(Quideau et al., 2011; Min and Boff, 2002; Parr and Bolwell,2000; Cao et al., 1997). Acid dissociation constants (Asuero andMichalowski, 2011; Asuero, 2007; Herrador et al., 1987; Asueroet al., 1986a, 1986b) are important physicochemical parametersthat describe the extent of ionization of functional groups as afunction of pH (Dufor and Dangles, 2005; Mielczarek, 2005;Amic et al., 1999). The antiradical properties, i.e., the abilityto react quickly and efficiently with electron-deficient radicals,depend on the acidity of phenolic hydroxyl groups and on thestability of the formed radical (Musialik et al., 2009).

The polyphenol field is gaining attention, and its fertility isreflected by the frequency of recently published relevant reviews(Table 1). However, the physiological mechanisms linking theantioxidant chemical characteristics of polyphenols with theirhealth effects are still the subject of discussion (Halliwell, 2005,2011; D’Archivio et al., 2010; Gutteridge and Halliwell, 2010;Moiseeva and Manson, 2009; Lotito and Frei, 2006; Cheynier,2005; Williams et al., 2004). It should be pointed out that thebioavailability of polyphenols in humans and experimental ani-mals remains largely unknown (Crozier et al., 2010; Halliwell,2007; Karakaya, 2004).

The percentage of absorbed natural polyphenols is usuallyquite low. Instead, researchers have seen a large quantity ofmetabolites of polyphenols in the form of simple phenolic acidsin the blood (Wang et al., 2010a; Forester and Waterhouse,2009; Galvano et al., 2008). The amount and form in whichplant phenolic substances are administered influence greatly thephysiological effects connected with their consumption (Vaceket al., 2010). Nonetheless, the physiological activity of thesemolecules has been related to their structure and geometry(Aparicio, 2010; Amic et al., 2007; Sakata et al., 2006; Rackovaet al., 2005; Rasulev et al., 2005; Rice-Evans et al., 1996; VanAcker et al., 1996).

During the past two decades the interest in polyphenolshas increased considerably, especially among food scientists,nutritionists, the agricultural industry, and consumers (Neveuet al., 2010). The French have high smoking rates and a dietrich in fats, but reduced rates of coronary heart disease in com-parison with people from northern European countries. Thisobservation, called the “French Paradox,” has been ascribed tothe consumption of red wines rich in phenolic compounds andhas awaked a growing interest in polyphenol research (Lippiet al., 2010; De Leiris et al.; 2008; De Lange, 2007; Simoni,

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TABLE 1Some recently published reviews on polyphenols

Content Reference

Emerging findings on the anti-cariogenic properties of polyphenols, which have beenobtained from several in vitro studies investigating the effects of these bioactive moleculesagainst Streptococcus mutans, as well as in vivo studies

Ferrazzano et al., 2011

Overview of recent reports on the influence of dietary polyphenols on gut microbiota tosummarize the main interactions between dietary polyphenols and beneficial andpathogenic intestinal bacteria

Hervert-Hernandez and Goni,2011

Overview of the research carried out in the field of antioxidant polyphenolic compounds,employing theoretical and computational methods. Mechanism of flavonoids andpolyphenols as antioxidants

Leopoldini et al., 2011

Chemical properties, biological activities, and synthesis of polyphenols. The state of the artand the most significant advances in the field of polyphenol research

Quideau et al., 2011

Effect of fruits and their inherent phenolic compounds in human subjects on postrandiallipaemia, glycaemia/insulinaemia, and associated events, such as oxidative stress andinflammation

Burton-Freeman, 2010

Bioavailability and biological activities of olive oil phenolic compounds Cicerale et al., 2010The effects of fruit polypenols on four risk factors of CVD: platelet function, blood pressure,

vascular function, and blood lipidsChong et al., 2010

Phenolic extraction, purification, analysis, and quantification as well as its antioxidantproperties

Dai and Mumper, 2010

Bioavailability and evidence of protective effects of berry flavonoids and phenolics Del Rio et al., 2010aBioavailability of dietary phenolic compounds in humans, the difficulties and the

controversies surrounding the studies aimed at determining the bioavailability of thesecompounds

D’Archivio et al., 2010

Focuses on the encapsulation of the more widely used polyphenols, discussing theireffectiveness, variations, developments, and trends

Fang and Bhandari, 2010

The most important mechanisms proposed for the actions of polyphenols in animal settings Fraga et al., 2010The effects of fruit and tea flavonoid and its metabolites on inflammation and immunity.

Mechanisms of the effects, including those on enzyme function and regulation of gene andprotein expression

Gonzalez-Gallego et al., 2010

The effects of berry polyphenolics on vision physiology and their bioavailability in oculartissues

Hanneken et al., 2010

Effects of dietary polyphenols on specific epigenetic alterations: effective chemopreventivestrategies for reducing the health burden of cancer and other diseases in humans

Link et al., 2010

Polyphenols as dietary supplements Martin and Appel, 2010Polyphenols in cardiovascular protection Morand, 2010Dynamic capacity of polyphenols to protect against age-associated disorders through a variety

of important mechanismsQueen and Tollefsbol, 2010

Plant phenolic composition; analytical methods Tarascou et al., 2010The chemistry and biochemistry of polyphenols as related to classification, extraction,

separation, and analytical methods, their occurrence and biosynthesis in plants, and thebiological activities and implications in human health

Tsao, 2010

Polyphenols in the diet: classification and sources, antioxidant hypothesis, bioaccessibility,bioavailability, and effects on health

Weichselbaum and Buttriss, 2010

Biological activity and effects on health of polyphenols Williamson and Clifford, 2010Dietary polyphenols: chemistry, bioavailability, and effects on health Crozier et al., 2009Cosmeceuticals and polyphenols: need to develop adequate physiological models supporting

antioxidant activity of polyphenolsEpstein, 2009

The known metabolism of each major class of wine and grape phenolics, the means tomeasure them, and ideas for future investigations

Forester and Waterhouse, 2009

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TABLE 1Some recently published reviews on polyphenols (Continued)

Content Reference

Polyphenols: the main organoleptic attributes and biological properties related to healthbenefits of red wine

Mateus, 2009

Beneficial, toxicological, and/or optionally endocrine disrupting activities of phenolics.Immunochemical detection and/or isolation method development

Meulenberg, 2009

Biological effects of plant polyphenols in the context of relevance to human health Pandey and Rizvi, 2009Several aspects related to phenolic chemistry. The increasing interest in phenolic biological

activitiesPereira et al., 2009

Preventive polyphenol activity against oral diseases Petti and Scully, 2009The history and progress of the polyphenolic chemistry of tea and coffee, as well as their

stability and the trapping activity of reactive oxygen species and reactive carbonyl speciesWang and Ho, 2009

In vitro antioxidant activity of foods, emphasizing the main role of phenolic compounds.Biological significance of these values and the biological significance of in vivomeasurements

Fernandez-Pachon et al., 2008

Polyphenols as antioxidants or pro-oxidants. Effects in cell culture Halliwell, 2008Dietary polyphenols in connection with cancer prevention Ramos, 2008The role of polyphenols from fruits, vegetables, and beverages in neuroprotection and

particularly in Alzheimer’s disease and the research challenges in this areaSingh et al., 2008

The problems associated with polyphenol-intake predictions: strengths, limitations, andapplication in nutritional research

Spencer et al., 2008

The potential health benefits of dietary polyphenols from the point of view of bioavailability Yang et al., 2008Dietary polyphenol. Phenolic compounds to protect the gastrointestinal tract against damage

by reactive species present in foods or generated within the stomach and intestinesHalliwell, 2007

Biological mechanisms of action and protective effects of dietary polyphenols Han et al., 2007Phenolics, inflammation, and nutrigenomics. Mechanism of action of food

derived-components playing an active role in prevention of inflammationEvans et al., 2006

Research on grape and wine phenolics. Justification for continued research Kennedy et al., 2006Effects and mechanism of bioactive polyphenolic compounds commonly found in many fruits

and vegetables on cancerNichenametla et al., 2006

The reaction mechanisms involving polyphenols and the structures of the resulting products.Effects on organoleptic and nutritional quality

Cheynier, 2005

Studies on the prevention of cardiovascular diseases by polyphenols Manach et al., 2005The antioxidant effects of polyphenols and their relevance for health. The experimental

evidence supporting a protective role of polyphenols against the main degenerative diseasesScalbert et al., 2005

Bioavailability of phenolic compounds. The importance of antioxidant activities of phenoliccompounds and their possible usage in processed foods as natural antioxidants

Vita, 2005

Absorption, metabolism, and bioavailability of phenolic compounds Karakaya, 2004The nature and contents of the various polyphenols present in food sources and the influence

of agricultural practices and industrial processesManach et al., 2004

Activity and mechanism of action of polyphenols Duthie et al., 2003Overview of the kinetic, structural, and mechanistic properties of the various polyphenolic

antioxidants and their respective radicalsBors and Michel, 2002

Polyphenolic compounds: physiological effects. Antioxidant activity Sanchez Moreno, 2002aPolyphenolic compounds: structure and classification. Bioavailability and metabolism Sanchez Moreno, 2002bKnowledge and methodology of natural phenolics chemistry Whiting, 2001Plant polyphenols: antioxidant activity and anticarcinogenic and anti-atherogenic effects Duthie et al., 2000The functions of phenolics both in plants and in human beings. Biosynthesis of phenolics in

plants, identification and isolation of the genes coding for phenolic biosynthetic enzymes orregulatory proteins

Parr and Bolwell, 2000

Polyphenols: dietary intake, amounts consumed, bioavailability, and the factors controllingtheir bioavailability

Scalbert and Williamson, 2000

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2000; Renaud and Lorgeril, 1992). A need for dietary com-positional information on polyphenols has been generated tofacilitate epidemiological and intervention studies with humansubjects (Spencer et al., 2008; Duthie et al., 2003).

POLYPHENOL DATABASE AND INTAKESeveral thousand polyphenols have been characterized in

plants and several hundreds of them are found in food plants.Dietary polyphenols differ widely in their physicochemicalproperties, bioavailability, biological properties, and healtheffects (Darvesh et al., 2010; Martin and Appel, 2010; Crozieret al., 2009; Pandey and Rizvi, 2009; Scalbert el al., 2005;Williamson and Manach, 2005; Parr and Bolwell, 2000). About1 g of polyphenols per day is commonly ingested with foods,which is significant when compared with the estimated dailyconsumption of other phytonutrients such as carotenoids,vitamin E, and vitamin C, estimated at 5, 12, and 90 mg/d,respectively (Wallace, 2011). Polyphenols are therefore themost abundant antioxidant in the diet (Scalbert et al., 2005;Slanina and Taborska, 2004), i.e., about 10 times higher thanthe intake of vitamin C and 100 times that of vitamin E.

The estimated daily intake of polyphenols in the US was449.8 mg using per capita consumption data for 34 commonlyconsumed fresh fruits and vegetables (Chun et al., 2005).The total intake of polyphenols estimated in the Dutch dietis 863 ± 415 mg/day (Ovaskainen et al., 2008). The maindaily intake of polyphenols in the Spanish diet was estimatedbetween 2590 and 3016 mg/person/day (Saura-Calixto et al.,2007). The amount of non-extractable polyphenol was almostdouble that of extractable polyphenols. The main total intake ofpolyphenols in Finnish adults was 863 ± 415 mg/d (Ovaskainenet al., 2008). Phenolic acids comprised the dominant groupof polyphenols (75% of total intake) followed by proantho-cyanidins (14%) and other flavonoids (10%). However, therisk of toxicity from the food supply, in spite of a high dietaryconsumption of polyphenols, is relatively low, largely due topoor absorption (Martin and Appel, 2010). Nevertheless, theincreasing use of dietary bioactive agents through food basepolyphenol enrichment (i.e., with purified agents) could renderpolyphenol consumption potentially problematic.

Interest in food composition and its properties in relation tohuman health has a long history (Colombani, 2011). The his-tory and applications of food composition databases is givenby Black et al. (2011), Church (2005, 2006), and Williamson(2005). In the United States, the Department of Agriculture(USDA) has maintained food composition tables for over 115years (Haytowitz et al., 2008), since the pioneering work ofAtwater and Woods in1892 (Atwater, 1895). Currently, theUSDA’s Nutrient Databank System incorporates data for ap-proximately 7500 foods and up to 140 nutrient components(Haytowitz et al., 2009).

Considerable information on polyphenol content of food isscattered in up to 1000 peer-reviewed publications. The newPhenol-Explorer database was been compiled, managed by the

Institute Nationale de la Recherche Agronomique (Scalbert,n.d.), which covers over 60,000 foods useful to epidemiolo-gists, food scientists, and food manufacturers (Neveu et al.,2010; Perez-Jimenez et al., 2010b). A list of the 100 richestdietary sources of polyphenols was produced with the aid of thePhenol-Explorer database, the content ranging from 15000 mgper 100 g in cloves to 10 mg per 100 mL in rose wine (Perez-Jimenez et al., 2010a). Another database within the frameworkof the European Food Information Resources Network, EuroFir,is available (Hollman et al., 2009; Westenbrink et al., 2009). Eu-roFir is serving as a basis to build national food compositiondatabases in different countries, i.e., Spanish (Burgos et al.,2009) and Irish (Black et al., 2011) databases.

However, original food sampling and description uncertainty,complexity of fruit and vegetable phytochemical content acrossspecies, cultivar, and growing and processing conditions (het-erogeneous sources), diversity and concentration of polyphenolspresent in foods, and limited systematic approaches to compre-hensively characterize and quantify polyphenols in plants foodusing standardized analytical methods make it difficult to build acomplete database (Kay, 2010; Spencer et al., 2008). A databaseconcerning the antioxidant capacities of both the lipophilic andhydrophilic components of foods (Wu et al., 2004) has beenbuilt. An algorithm to estimate total antioxidant capacity (TAC)of the U.S. diet (Floegel et al., 2010) has also been developedand validated.

FLAVONOIDSCarotenoids (xanthopylls, carotenes), tetrapyrrole derivatives

(i.e., chlorophylls), and flavonoids are three of the most impor-tant natural pigments (Bechtold and Mussak, 2009; Delgado-Vargas et al., 2000; Merken and Beecher, 2000). The flavonoidsconstitute the largest group of polyphenols (of low molecularweight) and are considered to be responsible for the color andtaste of many fruits and vegetables (Grotewold, 2006a). Theyare present particularly in the epidermis of leaves and the skinof fruits (Crozier et al., 2009; Onylagha and Grotewold, 2004;Iwashina, 2000). Flavus means yellow in Latin, the collectivename of flavonoids for this group being applied by Geissman(1949). The flavonoids group shows extraordinary diversity andvariation, and many of these compounds are yellow in color, asthe Latin root suggests.

Flavonoids are secondary plant metabolites, which togetherwith other plant phenols share a common origin: the aminoacid phenylalanine and the acetate coenzyme A esters (Pourcellet al., 2007; Parr & Bowell, 2000). These compounds aregenerally biosynthesized by the shikimate pathway, fromwhich they are produced using intermediates of carbohydratemetabolism. Rapid and substantial progress in the research onthe phenylpropanoid pathway was carried out from the 1970sto the 1990s, the focus being mainly centered (Shirley, 1996;Koes et al., 1994) on a broad understanding of the metabolicpathway. More recently, efforts were carried out from abiochemical and a molecular point of view (Korkina, 2007;

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ANTHOCYANIN PIGMENTS, PART I 109

Woo et al., 2005), by using a variety of approaches (transposontagging, positional cloning, coimmuno-precipitation, affinitychromatography, hybrid experiments). In the past few yearsnew information concerning the (transcriptional) regulationof the phenylpropanoid pathway has been obtained, derivedfrom studies in a variety of plant species (Hichri et al., 2011;Jaganatah and Crozier, 2010; Vogt, 2010). The flavonoidbiosynthesis pathway is probably the most thoroughly studiedplant secondary metabolism pathway. New analytical and bio-physical methods, such as the implementation and applicationof nanotechnology to solve biological problems, are currentlybeing developed for new approaches towards resolving a mostcomplex scenario of biological systems (Vogt, 2010).

Flavonoids can accumulate in vacuolar compartments, or besecreted, for example, as part of root exudates. Most intrigu-ing is the accumulation of flavonoids on the surface of leavesand flowers (Onyilagha and Grotewold, 2004). Flavonoids haveroles in many facets of plant physiology. One of the most impor-tant roles is to influence the transport of the plant hormone auxin(Buer et al., 2010; Peer and Murphy, 2007). The flavonoids ofdietary significance are widely distributed in the plant kingdom(Biesaga and Pyrzinska, 2009), and they are present in edibleplants in widely varying combinations; flavonols, flavanones,flavones, flavonols (essentially flavan-3-ol), isoflavones, and an-thocyanins are the most relevant for human diet.

Since first identified in the mid-1800s, more than 9,000flavonoid structures have been described, with formulas, ref-erences, and biological information (Fraga, 2010; He andGiusti, 2010; Motohashi and Motohashi, 2008; Veitch andGrayer, 2008; Andersen and Markham, 2006; Grotewold,2006b; Williams and Grayer, 2004), and the list is constantlygrowing. These include over 600 different naturally occurringanthocyanins that are widely distributed among at least 27 fam-ilies, 73 genera, and innumerable species (Andersen, 2008;Andersen and Jordhein, 2006), and more are continually be-ing isolated. It has been shown that, of the flavonoids stud-ied, around 5,000 have antioxidant activity (Motohashi andSakagami, 2008). Because the number of phytochemicals al-ready identified is only a small part of those that exist in nature,there is considerable interest in new methods of separation, iso-lation, and characterization of polyphenol structures from foods(Soto et al., 2011; Garcıa-Salas et al., 2010; Valls et al., 2009;Liu et al., 2008; Sticher, 2008; Marston, 2007; Yrjonen, 2004;Marston and Hostettmann, 1991).

STRUCTURE AND CLASSIFICATION OF FLAVONOIDSFlavonoids have structures consisting of two aromatic rings

linked by three carbons in an oxygenated heterocycle (Wolfeand Liu, 2008; Andersen and Markham, 2006; Nichenametlaet al., 2006) (Figure 2), i.e., a flavan (2-phenyl-benzo-γ pyran)nucleus consisting of two benzene rings combined with anoxygen-containing pyran ring, the parent compound bearinga tricyclic (C6-C3-C6) skeleton. The heterocyclic benzopyran

FIG. 2. Top: basic flavonoid skeleton; middle: flavonol skeleton;bottom: flavone skeleton.

ring is known as the C ring, the fused aromatic ring as the Aring, and the phenyl constituent as the B ring.

The structural differences in each flavonoid family resultfrom variations in the number/substitution pattern of the hy-droxyl and methoxy groups, as well as different glycosylationpatterns (Table 2), and the presence of a C2-C3 double bondin the heterocycle pyran ring (Andersen and Markham, 2006;Nichenametla et al., 2006). These structural variations are re-sponsible for differences in antioxidant activities of flavonoidscompounds (Galleano et al., 2010; Wolfe and Liu, 2008;Amic et al., 2007; Rasulev et al., 2005; Woodman et al.,2005; Martınez-Flores et al., 2002; Voskeresensky and Levitsky,2002). The biological action of flavonoids is usually attributed totheir ability to exert an antioxidant action by scavenging reactivespecies, or through their possible influence on the intracellularredox status. This point of view based on hydrogen-donating an-tioxidant activity cannot account for the bioactivity of flavonoidsin vivo, particularly in the brain, where they are found at verylow concentrations (Spencer, 2009), and it is an open question.

Note that sugar moieties attached to flavonoids increase po-larity of the molecule for their storage in plant cell vacuoles. Theearly chemistry of flavonoid compounds has been well workedout, largely through the research of Kostanecki, Perkin, Asahina,Willstatter, Robinson, Seshadri, and others (Todd, 1987; Toddand Cornforth, 1976; Geissman, 1949; Robinson and Robinson,1932).

Depending on their structure, flavonoids may be classifiedinto about a dozen groups. The following representativemodifications of the basic skeleton occur in nature (Leopoldiniet al., 2011; Han et al., 2007; Andersen and Markham, 2006;Geissman, 1949):

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110 J. M. BUENO ET AL.

TABLE 2Some recently published reviews on flavonoids

Content Reference

Effects of flavonoids and related polyphenolic compounds on inflammation, with a focus onstructural requirements, the mechanisms involved, and pharmacokinetic considerations

Ballester et al., 2011

Flavonoids: anticancer activity and molecular mechanisms, including the treatment of mammaryand prostate cancer and some advanced derivatives

Chahar et al., 2011

Overview of flavonoids: their classification, structures, and analytical methods for theirdetermination

Corradini et al., 2011

Safety issues surrounding high-dose supplemental flavonoid consumption Egert and Rimbach, 2011The role of platelets in cardiovascular disease: the potential anti-platelet effect of flavonoids,

focusing on the various platelet signaling pathways modulated by flavonoids, includingoxidative stress, protein tyrosine phosphorylation, calcium mobilization, and nitric oxidepathway

El Haouari and Rosado, 2011

Overview of neuroprotection by different classes of flavonoids on cellular cultures and modelanimals

Gutierrez-Merino et al., 2011

Effects of flavonoids on the CNS Jager and Saabi, 2011Dietary flavonoids and human health Stoclet and Schini-Kerth, 2011Current advances on flavonoids in food with emphasis on mechanism aspects on the basis of the

published literatureXiao et al., 2011

Advancements on potential cancer preventive effects and mechanical insight on dietaryflavonoids

Yao et al., 2011

Recent advances on flavonoid research, physiological processes, and approaches to identify thecellular targets of flavonoids

Buer et al., 2010

Human studies on the bioavailability of dietary flavonoids and related compounds in which theidentification of metabolites, catabolites, and parent compounds in plasma, urine, and ilealfluid was based on mass spectrometric methodology

Crozier et al., d2010

Bioavailability and evidence of protective effects of berry flavonoids and phenolics Del Rio et al., 2010aAnalysis of mechanisms proposed for polyphenol biological actions, especially antioxidant

reactions, based on chemical, thermodynamic, and kinetic dataGalleano, 2010

Chemical nature, mechanism of action, current status, pharmacodynamic/pharmacokineticstudies, industrial significance, nutritive values and analysis of flavonoids with the recenttechnology

Gupta et al., 2010

The future of flavonoid research: the use of databases as very powerful tools for the design andinterpretation of clinical and epidemiological studies

Kay, 2010

Recent advances of patents concerning of natural flavonoids and their synthetic analogues in thetreatment of cancers, and new synthetic approaches and possible structure-activityrelationships of flavonoids

Liu et al., 2010

Mechanisms of anti-inflammatory activities of flavonoids and their implicated effects on thedevelopment of various chronic inflammatory diseases

Pan et al., 2010

Synthetic photochemical transformations of the different classes of flavonoids Sisa et al., 2010Overview of the status quo of flavonoid biosynthesis as related to flower color with genetic

engineering modifications includedTanaka et al., 2010

Effects of flavones and flavonols on liposomal membranes consisting of different unsaturatedphospholipids and cholesterol

Tsuchiya, 2010

Biocatalytic structural modification of flavonoids by different kinds of enzymes ormicroorganisms, the process and possible mechanism

Wang et al., 2010a

Dietary flavonoids: phytoestrogens as natural prodrugs in cancer prevention Arroo et al., 2009Membrane transport of flavonoids, a critical determinant of their bioavailability Passamonti et al., 2009The potential for flavonoids to influence memory, learning, and neurocognitive performance and

attempt to clarify the probable mechanisms that underpin such actions in the brainSpencer, 2009

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ANTHOCYANIN PIGMENTS, PART I 111

TABLE 2Some recently published reviews on flavonoids (Continued)

Content Reference

Bioavailability and biotransformation of flavonoids and the mechanisms of activity at themolecular, cellular, organ, and organism levels that may contribute to their anti-inflammatoryeffects

Gomes et al., 2008

The potential of tea and tea flavonoids to improve endothelial function and reduce blood pressure,oxidative damage, blood cholesterol concentrations, inflammation, and risk of thrombosis

Hodgson, 2008

Functionality of anthocyanins as alternative medicine Motohasi and Sakagami, 2008Flavonoids as nutraceuticals Tapas et al., 2008Neuroprotective actions of flavonoids within the brain, including the potential to protect neurons

against injury induced by neurotoxins, an ability to suppress neuroinflammation, and thepotential to promote memory, learning, and cognitive function

Vauzour et al., 2008

New examples of naturally occurring flavonoids found either as aglycones or glycosides Veitch and Crayer, 2008Flavonoid oxidation in plants: from biochemical properties to physiological functions Pourcell et al., 2007The availability of recombinant flavonoids for the rational preparation of pharmaceuticals Serrano, 2007Biosynthesis, regulation, and contribution to flower coloration of floral pigments Grotewold, 2006aContribution of dietary flavonoids to the total antioxidant capacity of plasma in humans Lotito and Frei, 2006Significance of flavonoids in plant resistance Treutter, 2006The roles that flavonoids play in developmental processes of plants, such as auxin transport,

pollen germination, and signaling to microorganisms, and their allelopathic and anti-tumoractivities

Taylor and Grotewold, 2005

Flavonoids: a new role in cell cycle regulation Woo et al., 2005Mechanisms of action of dietary flavonoids in their potential role in disease prevention.

Absorption, metabolism, and bioavailabilityHollman, 2004

Key differences in absorption, metabolism, and pharmacokinetics between the major flavonoidspresent in the diet

Manach and Donovan, 2004

Associations of dietary flavonoid intake with cancer risk Neuhouser, 2004The potential of various new flavonoid derivatives in hormone replacement therapy Vaya and Tamir, 2004Flavonoids: absorption, metabolism, and bioactivity. The impact of membrane transporters as

well as metabolic enzymes on the cellular availabilityWalle, 2004

New flavonoid structures. The biological activity of some of the compounds Williams and Grayer, 2004The current advances in flavonoids in food, with emphasis on health aspects Yao et al., 2004Nomenclature, occurrence in foods, and intake of flavonoids with emphasis on those prevalent in

teaBeecher, 2003

Recent contributions to the role of phenolics, especially flavonoids, in different aspects ofinsect-plant interactions

Simmonds, 2003

Dietary flavonols: chemistry, food sources, dietary intakes, bioavailability, and metabolism Aherne and O’Brien, 2002The treatment of the effects of flavonoids on animal biochemistry from a medical point of view Havsteen, 2002Flavonoid antioxidants: chemistry, metabolism, and structure-activity as central determinants of

free radical scavenging, chelation, and prooxidant activityHeim et al., 2002

Review of flavonoid properties and their antioxidant activities Martınez-Flores et al., 2002Dietary flavonoids: absorption and bioavailability, metabolic and health effects Ross and Kasum, 2002The role of dietary flavonoids as antioxidants in vivo Rice-Evans, 2001Recent research on the biological properties of flavonoids Harborne and Williams, 2000Chemical structures of flavonoids and their distribution in nature Iwashina, 2000Bioavailability of flavonoids and their bioactivity in vivo. Factors influencing the absorption by

the gastrointestinal tract, nature of the conjugates and metabolites in the circulationRice-Evans et al., 2000

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112 J. M. BUENO ET AL.

(i) Those in which the C3 fragment of the structure exists inthe open-chain form (chalcones, dihydrochalcones). Chal-cones are directly or indirectly converted to a range of otherflavonoids in a pathway of intersecting branches with in-termediate compounds being involved in the formation ofmore than one type of end product (Davies, 2004).

(ii) Those in which the C3 fragment is a part of a five-membered heterocyclic ring: benzalcoumaranones, a rareclass of floral pigments, extensively studied by Harborneand Geissman, for which Bate-Smith and Geissman (1951)proposed the name of aurone (Grayer and Williams, 2007;Boumendjel, 2003);

(iii) Those in which the C3 fragment is present in asix-membered heterocyclic ring, by far the largestclass.

Differences in the structure of the heterocycle, or C ring,classify them in subgroups including as flavonols, flavones(catechins), flavanones, chalcones, dihydrochalcones and di-hidroflavonols, anthocyanins, and isoflavonoids (isoflavones)(Leopoldini et al., 2011; Garcıa-Salas et al., 2010; Liu et al.,2008; Wolfe and Liu, 2008; Han et al., 2007), varying in theoxidation state (degree of saturation) of the heterocyclic centralpyran ring (Table 2). When unsaturation is present, the geom-etry of the molecule is planar, as in the case of anthocyanins,flavones, and flavanols.

Flavones are structurally very similar to flavonols and differonly in the absence of hydroxylation at the 3 position on theC ring. Flavan-3-ols are structurally the most complex subclassof flavonoids, ranging from the simple monomers (+)- catechinand its isomer (-)-epicatechin to the oligomeric and polymericproanthocyanidins (condensed tannins). Two structural features,the absence of a C2-C3 double bond and the presence of a chiralcenter at the carbon-2, characterize flavanones. Optical activitymay also be present in flavonoids due to glycosidic substituents.In the majority of naturally occurring flavanones, the C ring isattached to the B ring at C2 in the α configuration. Unlike othersubgroups of flavonoids with the same C6–C3–C6 skeleton, an-thocyanins (Figure 3) have a positive charge in their structureat acidic pH. Isoflavonoids differ from other flavonoid classesin having a basic structural feature where a B ring attachesto C-3 but not C-2. In a few cases, the six-membered hetero-cyclic C ring occurs in an isomeric open form or is replaced

FIG. 3. Structure of anthocyanins.

by a five-membered ring, as in the case of chalcone (reductivering closure of chalcone results in the formation of a flavone).Other flavonoid groups, which quantitatively are relatively mi-nor dietary components, are dihydroflavones, flavan-3,4-diols,coumarins, and aurones.

Oligomers and polymers of flavonoids are called tannins(Haslam, 2007). Condensed tannins, also known as proantho-cyanidins or procyanidins, are oligomers of flavanols, and theirchemical structures are defined by both the kind of monomerand the kind of link between monomers. Hydrolizable tanninsare polymers readily hydrolyzed by acids into a central core con-stituted of a polyol (a sugar, generally D-glucose, or a flavonoid,such as catechin) and a phenolic carboxylic acid esterifying par-tially or totally that core molecule (Quideau et al., 2011; Fragaet al., 2010).

The number of different flavonoid structures that are theo-retically possible is astronomical (William and Grayer, 2004),based on the assumption that ten carbons of the flavonoid skele-ton can be substituted by a range of different groups (i.e., hy-droxyl, methoxyl, methyl, isoprenyl, and benzyl substituents).Flavonoids are often hydroxilated in positions 3, 5, 7, 3′, 4′,and/or 5′. Frequently, one or more of these hydroxyls are methy-lated, acetylated, prenylated, or sulfated. In biological fluids(serum, plasma, and urine) flavonoids exist as glucoronide andsulfate conjugates (Rijke et al., 2006). The pattern of conjuga-tion, glycosylation, or methylation can be very complex, canmodify the hydrophilicity of the molecule and its biologicalproperties, and can markedly increase the molecular weight ofthe flavonoid.

Flavonoids usually occur as glycosides in plants, reflectinga biological strategy (Passamonti et al., 2010); the effect ofglycosylation renders the flavonoid less reactive and more wa-ter soluble, increasing the polarity of the molecule, which isnecessary for storage in the plant cell vacuoles, decreasing atthe same time their propensity to interact with macromolecules(Corradini et al., 2011). However, flavan-3-ols (catechins andtheaflavins) are present in either free form or as gallic acid es-ters (e.g., in tea) (Holden et al., 2005). The glycosidic linkagesappear to be important for the absorption of flavonoids (Kren,2008; Kren and Martinkova, 2001).

Flavonoid glycosides are frequently acylated with aliphatic oraromatic acid molecules (Lin and Harnly, 2007). These deriva-tives are thermally labile and their isolation and further purifi-cation without partial degradation is difficult. The analysis offlavonoids and their conjugates (Rijke, 2005) is one of the mostimportant areas in the field of instrumental analytical methods,helping to solve varying problems in biological and medical sci-ences. MS techniques are the methods of choice in these researchareas, mainly the combination of chromatographic systems (CL,LC, or CE) with powerful detectors that enable the identifica-tion of simple compounds in complex mixtures (Steinmann andGanzera, 2011; Vukics and Guttman, 2010; Yang et al., 2009;Stobiecki and Kachlicki, 2006; Cuyckens and Claeys, 2004).

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COLOR AND PHOTOPROTECTIVE EFFECT OFFLAVONOIDS

Anthocyanins confer orange, red, magenta, violet, and bluecolors. Aurones and chalcones are yellow pigments, whileflavones and flavonols are colorless or very pale yellow, at leastto the human eye. Although flavonols and flavanones by them-selves do not have color, they modify coloration by complex-ation with anthocyanins and/or metallic ions (copigmentation)(Delgado-Vargas et al., 2000). The copigmentation mechanismis unique to the anthocyanin family. The resulting complexpalette of color is a key element in various aspects of plantreproduction (Shirley, 1996).

The coloration patterns of flowers attract insects to anthers(masculine organ) and pistils (feminine organs), and are thusinvolved in pollen development and germination (Simmonds,2003). It is well known that many species accumulate flavonoidsin these organs. The most common flavonoids in anthers are an-thocyanins, flavonols, and chalcones. Animals are attracted byfruit color and after consumption the seeds are dispersed throughexcrement. One of the most versatile classes of flavonoids, theanthocyanins, protect chloroplasts from photodegradation byabsorbing high-energy quanta, while scavenging free radicalsand reactive oxygen species (ROS) (Fraga, 2010; Sisa et al.,2010; Morganti, 2009; Gould and Lister, 2006). Flavonols pro-vide protection against the damaging effects of UV-B light, andare also involved in promoting the growth of pollen tubes downthe style to promote fertilization (Jaganath and Crozier, 2010).Isoflavonoids play important defense roles against pathogensand insect attacks and are key signal molecules in the formationof nitrogen-fixing root nodules in legumes. Isoflavones are alsoknown for their estrogenic activity (Vaya and Tamir, 2004) due totheir ability to bind to estrogen receptors and have received muchattention due to their putative role in the prevention of breastcancer and osteoporosis (Tarascou et al., 2010; Barnes, 2003).

In plants, flavonoids are relatively resistant to heat, oxygen,dryness, and moderate degrees of acidity but can be modifiedby light. Photostability of the flavonoid molecule depends onthe nature of the hydroxyl group attached to C-3 of the C ring.The absence or glycosylation of this hydroxyl group results inhigh photostability of the molecule (Sisa et al., 2010; Aherneand O’Brien, 2002).

BIOLOGICAL ACTIVITIES OF FLAVONOIDSFlavonoids possess a wide range of biological activi-

ties (Egert and Rimbach, 2011; Stoclet and Schini-Kerth,2011; Buer et al., 2010; Liu et al., 2010; Pan et al.,2010; Forester and Waterhouse, 2009; Serrano, 2007;Havsteen, 2002) including antioxidant, antibacterial, anti-inflammatory, anti-allergic, antitumor, antithombotic, proapop-totic, and vasodilatory action. The wide spectrum of functionsexplains why recently a number of reviews on the propertiesof flavonoids have been published (Table 3). Many of them areactive principles of medical plants and exhibit pharmacological

TABLE 3Structural differences among flavonoid classes (Nichenametla

et al., 2006)

Flavonoid class

Carbon involved indouble bond on C

ringFunctional groups on

C ring

Flavanols — 3-hydroxy,3-o-gallate

Flavonols 2nd and 3rd 3-hydroxy, 4-oxFlavones 2nd and 3rd 4-oxoFlavanones — 4-oxoAnthocyanidins 1st and 2nd 3rd

and 4th3-hydroxy

effects (Tapsell et al., 2006; Havsteen, 2002). The health-promoting effects of flavonoids may relate to interactionswith key enzymes, signaling cascades involving cytokines andtranscription factors, or antioxidant systems (Buer et al., 2010).Many flavonoids in particular are also able to modulate theactivity of key human enzymes such as tyrosine kinases (Parrand Bolwell, 2000). The major active nutraceutical ingredientsin plants are flavonoids (Lobo et al., 2010; Lin and Weng, 2006;Shahidi and Naczk, 2006). Nutraceutical is a term coined in1979 by Stephen DeFelice (Ahmad et al., 2011). It is defined“as a food or parts of food that provide medical or healthbenefits, including the prevention and treatment of disease.”Subsequently, several other terms such as medical food, func-tional food, and nutritional supplements were used. The termfunctional food was used for the first time in Japan in the 1980s(Herrero et al., 2005). The work of Espin et al. (2007) may beconsulted in order to appreciate the significance of these terms.

Flavonoids are not synthesized in animal cells, thus theirdetection in animal tissues is indicative of plant ingestion.Once ingested, flavonoids undergo extensive metabolism in thesmall and large intestines, in the liver, and in cells, resultingin very different forms in the body to those found in foods(Spencer, 2009). The chemical diversity, size, three-dimensionalshape, and physical and biochemical properties of flavonoidsallow them to interact with targets in different subcellular lo-cations to influence biological activity in plants, animal, andmicrobes (Buer et al., 2010; Peer and Murphy, 2007; Taylor andGrotewold, 2005).

Flavonoids appear to have played a major role in success-ful medical treatments in ancient times and their use has con-tinued up to now (Gutteridge and Halliwell, 2010; Havsteen,2002). The first observation concerning their biological activi-ties was made by Rusznyak and Szent-Giorgi (1936); the termvitamin P was proposed for flavonoids, although it was later dis-missed. Williams and Grayer (2004) have stated: “Flavonoidscontinue to capture the interest of scientists from many differentdisciplines because of their structural diversity, biological and

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ecological significance (e.g. the colored pigments in manyflower petals), and health promoting and anti-cancer proper-ties.” Unlike traditional vitamins, flavonoids are not essential forshort-term well-being. Nevertheless, modest long-term intakemay exhibit potential health benefits (Jaganatah and Crozier,2010).

However, the responsible natural chemicals seldom work in-dependently (Lila, 2009). Flavonoid subclasses are simultane-ously present in foods or food products of plant origin, thusmaking it difficult to ascertain which family is responsible for agiven potential biological effect (Pascual-Teresa et al., 2010). Acomplex interplay among the various components accounts forthe pharmacological effects of functional foods, nature-derivedsupplements, and pharmaceuticals, as they modulate biologicalprocesses in human metabolism (Lila, 2009).

DIETARY SOURCESFlavonols are the most widespread of the flavonoids in

plant food. Flavones, unlike flavonols, they are not widely dis-tributed, and as a consequence their dietary is very low. Flavan-3-ols represent the most common flavonoid consumed in theAmerican and, most probably, the Western diet and are regardedas functional ingredients in various beverages, whole and pro-cessed foods, herbal remedies, and supplements (Jaganatah andCrozier, 2010). Their presence in food affects quality parame-

ters such as astringency, bitterness, sourness, sweetness, salivaryviscosity, aroma, and color formation.

Red wines and berries are typically rich in anthocyanins(Birse, 2007; Kuskoski et al., 2006; Zimman, Waterhouse andKennedy, 2004; Kuskoski et al., 2003). Quercetin, the mostcommon flavonol, is abundant in onions, broccoli, and lettuce.Tea leaves, coffee beans, and red wine are rich in flavanols.Leguminous species (soybeans) are rich in isoflavone, whichhave a very limited distribution in the plant kingdom. Cit-rus fruits are rich in flavanones, while tropical plants are alsorich in flavonoids (Passamonti et al., 2010; Liu et al., 2008;Manach and Donovan, 2004). Flavonols and flavones occurin food usually as glycosides. Of the major flavonoid classes,flavonols predominate in fruits in which a variety of glycosideshave been identified, whereas in vegetables quercetin glyco-sides predominate. Flavones are much less common than fla-vanols in fruit and vegetables. The only important edible sourcesof flavones identified to date are parsley and celery (Manachand Donovan, 2004). Flavanones are exclusively found in citrusfruits. Dietary sources of flavonoids are compiled in Table 4.

FLAVONOID DATABASEThe principal weakness in most epidemiological studies in

this area lies in the food composition database on flavonoids usedbecause data on flavonoid composition are scarce (Zamora-Ros

TABLE 4Dietary sources of flavonoids

Flavonoidsubclass Prominent food flavonoids Typical rich food sources

Anthocyanins CyanidinDelphynidin

Bilberries, black and red currants, blueberries, cherries,chokecherries, grapes, strawberries, pomegranates

Chalcones Cinnamon methylhydroxychalcone Apples, pears, strawberries, tomatoes, cinnamonFlavanols Catechin

EpigallocatechinEpigallicatechingallate

Apples, blueberries, grapes, onions, lettuce, red wine, tea,chocolate, apricots, sour cherries, grape juice, mint

Flavanonols Taxifolin or dihydroquercetinAromaderin or dihydrokaempherol

Grapes, red onion, acai palm

Flavanones HesperetinNaringeninEriodiclyol

Citrus fruits and juices, peppermint

Flavonols QuercetineKaempferolMyricetin

Apples, beans, blueberries, buckwheat, cranberries, endive,leeks, broccoli, lettuce, onions, olives, peppers, tomatoes

Flavones ApigeninLuteolin

Citrus fruits, celery, parsley, spinach, rutin, olives, artichokes

Isoflavones GenisteinDaidzeinGlyatein

Soybeans, grape seed/skin, chick-peas, black beans, green peas

Xanthones Mangostin Mangoes, mangosteens, bark of pear, apples, cherries

Sources: Ignat et al., 2011; Han et al., 2007; Naczh and Shadidi, 2006; Manach et al., 2004; Beecher, 2003; Aherne and O’Brien, 2002; Duthieet al., 2000; Rice-Evans et al., 2000.

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et al., 2010). However, there has been increasing interest at theinternational level in assessing the quality of data in food com-position databases (Castanheira et al., 2009; Reinivuo et al.,2009). Integrated databases of flavonoids for nutrition research,containing information on structural, biological, and physico-chemical properties, have been constructed in order to assistchemical and biological research (Kinoshita et al., 2005, 2006).The USDA (United States Department of Agriculture) has main-tained tables of food composition for over 120 years, sincethe pioneering work of Atwater and Woods (Atwater, 1895).The USDA databases are the most complete, updated, and useddatabases in the estimation of flavonoid intake (Zamora-Roset al., 2010; Haytowiz et al., 2009). The USDA Special InterestDatabase for flavonoid content of selected foods contains 26of the most abundant compounds within five predominant sub-classes of flavonoids: flavonols, flavones, flavanones, flavan-3-ols, and anthocyanidins (Holden et al., 2005). The Nutrient DataLaboratory (NDL) of USDA conducted a validation study ofthe USDA Data Quality Evaluation System (DQES) (Bhagwatet al., 2009). The quality of the Brazilian National FlavonoidDatabas has also been evaluated following the indications ofUSDA-DQES (Menezes et al., 2011). There is no doubt that thecombination of databases could provide a very powerful toolfor the design and interpretation of clinical and epidemiologicalstudies in the future (Kay, 2010).

DIETARY INTAKEConsiderable effort has been made to establish optimal hu-

man dietary consumption levels for flavonoids based on theirpharmacodynamic effects and to determine flavonoid contentin assorted dietary sources (Chun et al., 2007). The flavonoidcontent in food ranges from 10 to 104 mg/kg of fresh weight(Manach and Donovan, 2004). Reliable values for flavonoids infoods are needed to test the possible relationships of flavonoidswith cardiovascular diseases and cancer risk reduction, and toadopt potential policies related to these phytochemicals. TheWorld Health Organization recommends a daily intake of at least400 g of fruits and vegetables, together with physical activity,to prevent cardiovascular diseases, certain cancers, obesity, anddiabetes (World Health Organization, 2004).

Flavonoids are the most common and the largest plantpolyphenolics obtained from the everyday plant-source diet(Chun et al., 2007), and their daily intake, depending on diet,can range from several hundred mg up to 1–2 g (Pan et al.,2010; Holden et al., 2005; Vries et al., 1997). The U.S. pub-lic consumes as much as 250 mg of flavonoids per person perday (Manach and Donovan, 2004) in a variety of forms (fruits,vegetables, nuts, drinks, spices, and vitamin and mineral sup-plements). Intake was estimated at 189.7 ± 11.2 mg, by usingUSDA databases in the framework of the 1992–2002 NationalHealth and Nutrition Examination Survey (NHANES), with tea,citrus fruit juices, wine, and citrus fruits being the major dietarysources (Chun et al., 2007). Depending on food choice, thiscould be even much higher.

The daily intake of food flavonoids in a group of 45 femaleFlemish dietitians, determined by using a semi-quantitative foodfrequency questionnaire, was 166.0 ± 146.6 mg/d, 203.0 ±243.2 mg/d, and 158.3 ± 151.8 mg/d, respectively, dependingon the method (Mullie et al., 2008). The estimated ingestion bythe Brazilian population ranged from 60 to 106 mg/day (Arabbiet al., 2004). Estimated dietary flavonoid consumption of theAustralian population was 351 mg per person per day, of which75% were flavan-3-ols (Johannot and Somerset, 2006). Tea wasthe major dietary flavonoid source in Australia.

Great differences in flavonoid intake and food sourceswere observed between a large Mediterranean cohort andnon-Mediterranean populations (U.S. and Finland as non-Mediterranean countries) (Zamora-Ros et al., 2010). The meanintake for a Spanish population was 313 mg/day (Zamora-Roset al., 2010). Estimated per capita daily flavonoid intake is 182mg and 177 mg for the UK and Ireland, respectively (Bekingand Vieira, 2011). Flavonoids are among the major antioxidantconstituents of our diet. The daily intake is almost at the samelevel as the sum of other antioxidants, including carotene,vitamin C, and vitamin E.

CONCLUDING REMARKSThe strict relationship between diet and health has been

known since ancient times, and recent studies demonstratedthe relevance of many food components in modulating health(Gutteridge and Halliwell, 2010; Vitaglioni et al., 2004,Havsteen, 2002). The amount and the type of ingested fats,the intake of dietary fiber (Palafox-Carlos et al., 2011), and theconsumption of antioxidant compounds have been correlated tovarious chronic degenerative diseases (Hervert-Hernandez andGoni, 2011; Crozier et al., 2010; Ramos, 2008; Nichenametlaet al., 2006).

The explosion of knowledge and interest in polyphenol chem-istry in recent decades (i.e., Table 1) attests to its vast potentialfor practical applications in various fields and for simply gaininga better understanding of the chemistry of life (Ellestad, 2006). Atremendous increase in the number of scientific publications onpolyphenols has happened over past 20 years (Quideau et al.,2011). The regular consumption of fruits, seeds, vegetables,and derived foodstuffs and beverages in which polyphenols arepresent in substantial quantities has been claimed to be benefi-cial for human health, and plant polyphenols nowadays enjoyever-increasing recognition not only by the scientific communitybut also, and most remarkably, by the general public (Quideauet al., 2011).

Moreover, free radicals are known to take part in lipid per-oxidation in foods, which is responsible for rancid odors andflavors, which decrease nutritional quality (Leopoldini et al.,2011; Liu, 2010; Shahidi and Zhong, 2010; Scherer and Godoy,2009; Hounsome et al., 2008). Natural antioxidants have highantioxidant activity and are used in many food applications(Sidani and Makris, 2011; Shoji, 2007). Phenolic compounds,which are widely distributed, have the ability to scavenge free

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radicals by single-electron transfer. The so-called antioxidantproperty has become the trademark of polyphenols in recent ex-ploitation by the agro-food, cosmetic, and parapharmaceuticalindustries (although antioxidation is not a property limited topolyphenols) (Quideau et al., 2011).

Recently discovered properties of phenolic compounds havebeen exploited for cosmetics, pharmaceuticals, nutritional sup-plements, and functional foods (Ahmad et al., 2011; Lobo et al.,2010; Corneli, 2009; Morganti, 2009). The food industry haslaunched numerous functional products, the health functional-ity of which is closely connected with their polyphenol content,which is usually higher than its content in traditional products(Valls et al., 2009).

Flavonoids can be subdivided into a number of classes:chalcones, dihydrochalcones, aurons, flavones, flavonols, dihy-droflavonols, flavanones, flavanols (catechins), flavandioles orleucoanthocyanidins, anthocyanidins (its glycoside is called an-thocyanin), and isoflavonones (Andersen and Markham, 2006;Grotewold, 2006b). Recent advances in genomics, proteomics,and metabolomics provide new approaches to defining the roleof flavonoids in plant development and to exploring their poten-tial application in agriculture and medicine (Woo et al., 2005).Protection against oxidative diseases, ability to modulate the ac-tivity of various enzymes, and interactions with specific recep-tors are among the most significant health benefits of flavonoids(Jaganatah and Crozier, 2010; Fraga, 2010; Daayf and Lattanzio,2008; Grotewold, 2006b; Prior et al., 2006; Shahidi and Naczk,2006).

Food composition databases are essential for epidemiolog-ical research, public health, nutrition and education, clinicalpractice, and the food industry (Williamson, 2005), and manynational food composition databases exist, the USDA databasebeing the most complete in terms of the estimation of flavanoidintake (Haytowitz et al., 2009).

Anthocyanins are one of the flavonoid groups that have beenmost widely studied in recent decades (Valls et al., 2009). Antho-cyanins usually contain a single glucoside unit, but many antho-cyanins contain two, three, or more sugars attached at multiplepositions, or occurring as oligosacaride side chains. Intensityand type of the color of anthocyanins is affected by the numberof hydroxyl and methoxyl groups: if more hydroxyl groups, thenthe color goes toward a more bluish shade; if more methoxylgroups, then redness is increased (He and Giusti, 2010; Giustiand Jing, 2008; Heredia et al., 1998). In spite of the increas-ingly large number of structures they are derived from, onlyabout 30 different anthocyanidins, almost 94% of the new an-thocyanins discovered are in fact based on only the six commonanthocyanidins: pelargonidin, cyanidin, delphinidin, peonidin,petunidin, and malvidin (Jin and Giusti, 2011; Andersen andJordhein, 2006).

A point of note is that antocyanins are readily distinguishedfrom other flavonoids as they undergo rearrangements inresponse to pH (Crozier et al., 2010). The uniqueness ofanthocyanin antioxidants critically depends on their ability

for electron delocalization and to form resonating structuresfollowing changes in pH, which does not take place in otherpopular antioxidants (Zafra-Stone et al, 2007; Prior and Wu,2006). The topics of anthocyanidin equilibrium forms, biosyn-thesis, and molecular biology, and anthocyanin localization inplant cells have seen important progress in recent years (Gouldet al., 2009; Andersen, 2008).

The purpose of this review, which intends to reflect the in-terdisciplinary nature of the research in this prolific area, is toserve as a useful introduction to the study of analysis and an-tioxidant capacity of anthocyanin pigments, taking into accountthe general aspects of the topic and considerations concerningpolyphenols and flavonoids. The following topics will be thesubject of future reports: (i) early history, chemical structure,color, and intake of anthocyanins; (ii) the extraction, analysis,and antioxidant power of anthocianin pigments; and (iii) thebioavailability, biological activity, methods used for measuringthe antioxidants of anthocyanin, and the influence of antho-cyanins in the antioxidant activity of red wines.

ACKNOWLEDGMENTSThis work was supported by the Junta de Andalucıa (Spain)

through grant excellence research project P06-FQM-02029, forwhich the authors are grateful. Thanks are due to Professor AnaTroncoso Gonzalez for helping in the discussion and writing ofthis article.

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