Proceedings of the Third International Scientic Symposium on Tea and Human Health: Role of Flavonoids in the Diet

Overview of Dietary Flavonoids: Nomenclature, Occurrence and Intake1

Gary R. Beecher2
Foods and Nutrition Consultant, Lothian, MD 20711
ABSTRACT Flavonoids and their polymers constitute a large class of food constituents, many of which alter metabolic processes and have a positive impact on health. Flavonoids are a subclass of polyphenols. They generally consist of two aromatic rings, each containing at least one hydroxyl, which are connected through a three-carbon bridge and become part of a six-member heterocyclic ring. The avonoids are further divided into subclasses based on the connection of an aromatic ring to the heterocyclic ring, as well as the oxidation state and functional groups of the heterocyclic ring. Within each subclass, individual compounds are characterized by specic hydroxylation and conjugation patterns. Many avonoids in foods also occur as large molecules (tannins). These include condensed tannins (proanthocyanidins), derived tannins and hydrolysable tannins. For proanthocyanidins, three subclasses (15 characterized) have been identied in foods. Monomers are connected through specic carbon-carbon and ether linkages to form polymers. Derived tannins are formed during food handling and processing, and found primarily in black and oolong teas. Flavonoids are widely distributed in nature, albeit not uniformly. As a result, specic groups of foods are often rich sources of one or more subclasses of these polyphenols. The polyphenolic structure of avonoids and tannins renders them quite sensitive to oxidative enzymes and cooking conditions. Scientists in several countries have estimated intakes of a few subclasses of avonoids from limited food composition databases. These observations suggest large differences in consumption, due in part to cultural and food preferences among populations of each country. J. Nutr. 133: 3248S3254S, 2003. KEY WORDS:

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avonoids

tannins

thearubigins

polyphenols

detary intake

Foods, because they are derived from biological systems, contain many compounds in addition to traditional nutrients (13). Many of these compounds have the capacity to alter enzymatic and chemical reactions, and therefore may impact human health both positively and negatively (4). These compounds have become known by names such as phytochemicals, phytonutrients, and nontraditional nutrients. One of the largest groups of these phytonutrients that may provide benecial health effects is the avonoids and their polymers. Over 60 years ago, extracts of foods presumably containing avonoids were shown by Szent-Gyorgy and his colleagues to have ben ecial biological properties (5). Although these early results were not corroborated, modulation of many biological systems by avonoids, tannins and other phytonutrients has been demonstrated by a plethora of investigators (6). Papers from this symposium update the current state of knowledge of tea
1 Presented as part of The Third International Scientic Symposium on Tea and Human Health: Role of Flavonoids in the Diet, given at the United States Department of Agriculture, September 23, 2002. This conference was sponsored by the American Cancer Society, American College of Nutrition, American Health Foundation, American Society for Nutritional Sciences, Food and Agriculture Organization, and the Linus Pauling Institute at Oregon State University and was supported by a grant from the Tea Council of the U.S.A. Guest editor for this symposium was Jeffrey Blumberg, PhD, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111. 2 To whom correspondence should be addressed. E-mail: gbeecher@earthlink.net.

avonoids on those biological actions related to chronic disease. This paper however, will review the nomenclature, occurrence in foods and intake of avonoids with emphasis on those prevalent in tea. Nomenclature Flavonoids are a subclass of the polyphenols, which are characterized as containing two or more aromatic rings, each bearing at least one aromatic hydroxyl and connected with a carbon bridge (7). For avonoids, this bridge consists of three carbons that combines with an oxygen and two carbons of one of the aromatic rings (A ring) to form a third 6-member ring [C ring (Fig. 1)]. In contrast, the lignans, another subclass of biologically active polyphenols, have a four-carbon bridge that leads to many different chemical structures in nature. The avonoids are further divided into subclasses based on the connection of the B ring to the C ring, as well as the oxidation state and functional groups of the C ring. Table 1 lists the subclasses of avonoids in ascending order of oxidation state along with the other signicant attributes that identify each subclass. Within each subclass, individual avonoids and isoavones are identied and characterized by hydroxylation and conjugation patterns of the B ring, as well as the conjugation patterns of hydroxyls on the A and C rings. Structures of avonoids common to foods have been widely published

0022-3166/03 $3.00 2003 American Society for Nutritional Sciences.

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FIGURE 1 General structure and numbering pattern for common food avonoids. See Table 1 for unique linkages, unsaturation positions and functional groups of each avonoid subclass. For most food avonoids, R4 AH, R5AOH and R6AH. Exceptions include, biochanin A, R4 ACH3; formononetin, R4 ACH3, R5AR6AH; glycitein, R5AH, R6AOH; and hesperitin, R4 ACH3. Additional individual avonoids within each subclass are characterized by unique functional groups at R3, R3 , and R5 .

(10). The names of the prominent food avonoids within each avonoid subclass are also listed in Table 1. Most avonoids are present in nature as glycosides and other conjugates (avanols are an exception), which contribute to their complexity and the large number of individual molecules that have been identied ( 5000) (11). Many avonoids in foods are polymerized into large molecules, either by the plants themselves or as a result of food processing. These polymers are called tannins and were so named based on their function, i.e., precipitate proteins and some alkaloids convert animal hide to leather (12). There are several subclasses of tannins, three of which are important to foods and perhaps health [Table 2 (7)]. Condensed tannins or proanthocyanidins consist of monomeric units of avans linked through carbonOcarbon and ether linkages. Fifteen subclasses of proanthocyanidins have been identied (13), however, only three appear to be prominent in human foods of plant origin, procyanidins ([epi]catechin polymers), prodelephinidins ([epi]gallocatechin polymers) and propelargonidins ([epi]afselechin) polymers or their mixtures (14). In these tannins, the monomeric units are primarily linked through single 436 or 438 carbon-carbon bonds (B linkages), or through 438 carbon-carbon linkages and 237 ether bonds (A linkages). Other linkages also have been identied, but were isolated from nonfood plants or constitute minor compounds of foods such as cocoa (13). Tannins can range from dimers through large polymers and are

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TABLE 1
Flavonoid subclasses, their chemical characteristics, names of prominent food avonoids and typical food sources1
Flavonoid subclass Flavanol B-ring connection to C ring (position on C ring) 2 C-ring unsaturation None C-ring functional groups 3-Hydroxy ( ( ( ( ( ( Typical rich food sources3 Teas, red grapes and red wines

Prominent food avonoids2 )-Catechin (C) )-Gallocatechin (GC) )-Epicatechin (EC) )-Epigallocatechin (EGC) )-Epicatechin-3-gallate (ECG) )-Epigallocatechin-3-gallate (EGCG) Eriodictyol Hesperetin Naringenin Apigenin Luteolin Daidzein Genistein Glycitein Biochanin A Formononentin Isorhamnetin Kaempferol Myricetin Quercetin Cyanidin Delphinidin Malvidin Pelargonidin Petunidin Peonidin

3-O-gallate Flavanones Flavones Isoavones 2 2 3 None 2-3 Double bond 2-3 Double bond 4-Oxo 4-Oxo 4-Oxo

Citrus foods Green leafy spices, e.g., Parsley Soybeans, soy foods and legumes

Flavonols

2-3 Double bond

3-Hydroxy, 4-Oxo 3-Hydroxy

Nearly ubiquitous in foods, e.g., Quercetin Red, purple and blue berries

Anthocyanidins

1-2, 3-4 Double bonds

1 See Figure 1 for general avonoid structure and numbering pattern. 2 Flavonoids in highest concentration in foods and those reported in the USDA Database for the Flavonoid Content of Selected Foods and in the

USDA-Iowa State University Database on the Isoavone Content of Foods (8,9). Total amount in food of each avonoid reported as either aglycone or gallate form. 3 Data in USDA avonoid databases (8) used as source of information.

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TABLE 2
Tannin subclasses common to foods1
Subclass name Condensed tannins (proanthocyanidins) Characteristics2 Oligomers and polymers of avanols, also may contain gallates In foods, primarily linked by 436 or 438 COC bonds (B linkages) or 438 COC bond and 237 ether bond (A linkage) Acid catalyzed depolymerization of interior monomers converted to corresponding anthocyanidins; hence polymers named proanthocyanidins Examples: 1) (epi)catechin monomers3cyanidin therefore named procyanidins, 2) (epi)gallocatechin monomers3delephinidin therefore named prodelphinidins Compounds formed during processing of plant material and absent, or nearly so, in healthy, intact tissue Denitive structures often unknown and trivial names given as a result of isolation procedure or plant source. Example: Thearubigins, a heterogeneous mixture of relatively large molecular weight compounds formed during production of oolong and black teas Systematic naming applied to elucidated and well-dened structures Examples: 1) Theaavin avanol derived benztropolone (EC EGC), 2) Theaavin-3,3 -digallate avanol derived benztropolone (ECG EGCG) Esters of gallic acid (gallotannins) or ellagic acid (ellagitannins) and a nonaromatic polyol (sugar, quinic acid, etc.) Gallo- and ellagitannins may be further linked by COC and COOOC bonds to form dimers, trimers, etc.

Derived tannins

FIGURE 2 General structure for theaavins. Specic compounds are as follows: theaavin, R1AR2AH; theaavin-3-gallate, R1Agallate, R2AH; theaavin-3 -gallate, R1AH, R2Agallate; and theaavin-3,3 digallate, R1AR2Agallate. Downloaded from jn.nutrition.org by guest on July 28, 2011

Hydrolyzable tannins

derived tannins (Table 2). The complexity and molecular size of these compounds has made denitive elucidation of their structures difcult (19). Nontheless, thearubigins are in relatively high concentrations in most black and oolong teas (Table 3) and may be important in the health related properties of these foods (20 22). Another class of common food tannins is the hydrolysable tannins, which consist of gallic acid or ellagic acid to which a nonaromatic polyol, such as a sugar or quinic acid, is esteried TABLE 3
Transformation and losses of avonoids during tea processing1
Content of prepared teas Total avonols2 Total avan3-ols3 mg/100 mL Green, brewed Green, brewed, decaffeinated Black, brewed Black, brewed, decaffeinated Black, instant Black, ready-to-drink Oolong, brewed 5.2 4.8 3.9 4.4 1.4 2.3 2.7 132.1 55.8 34.3 2.7 2.0 2.1 51.6 1.1 8.8 73.4 49.0 23.7 25.5 NA5 Thearubigins4

1 Modied from Clifford (7). 2 See Table 1 for abbreviations of avanols.

found in a wide variety of foods, e.g., apples, berries, chocolate, red wines and nuts (1517). A second class of food tannins is the derived tannins (7). These complex compounds are formed primarily under oxidative enzymatic and atmospheric conditions during the manipulation of plants and subsequent processing into foods, e.g., oolong and black teas, red wines and coffee. Because of the complexity of the compounds of this class of tannins, strict chemical nomenclature has been difcult and often trivial names have been assigned as a consequence. Clifford (7) has proposed a series of naming rules for many dimers of derived tannins. Of importance to oolong and black teas are the avanol-derived theaavins. The unique feature of the theaavins is the benztropolone ring, a seven-member ring, which is formed by the oxidation of the B ring of either (-)-epigallocatechin or (-)-epigallocatechin-3-gallate, loss of CO2 and simultaneous merger with the B ring of a second molecule of (-)-epicatechin or (-)-epicatechin-3-gallate (Fig. 2). As a result, four possible compounds are formed, all of which have been separated by HPLC methods (18) and tabulated in at least one database (8). Subjecting foods containing avanols to conditions that favor formation of theaavins also results in a heterogenous group of high-molecular-weight (110 kDa) compounds loosely termed thearubigins. Thearubigins are also members of

Tea description

1 Data from USDA Database for the Flavonoid Content of Selected Foods (8). These data are presented for illustrative purposes only; statistical comparisons are not appropriate as the values have been combined from several types of experiments. 2 Summation of concentrations of kaempferol, myricetin and quercetin. Data are presented as aglycones of avonols. In most teas, quercetin is the prominent avonol. 3 Summation of concentrations of ( )-catechin, ( )-epicatechin, ( )-epicatechin-3-gallate, ( )-epigallocatechin, ( )-epigallocatechin3-gallate and ( )-gallocatechin. Data are presented as aglycones of avan-3-ols. In those teas with substantial total avan-3-ol concentrations ( 30 mg/mL), ( )-epigallocatechin-3-gallate is the most abundant avanol. 4 Thearubigin content expressed on basis of gallic acid. 5 Thearubigin content not analyzed.

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(7). Although this class of tannins was named for the ease of cleavage of the ester linkage, several other linkages may occur (COC, COOOC) to form dimers and higher complexes, which have varying degrees of resistance to chemical breakdown (23). Although hydrolysable tannins are widespread in some plant foods, e.g., grapes and wines, and contribute important organoleptic qualities, they have received little attention in terms of their impact on human health. Flavonoid content of foods Although avonoids are widely distributed in nature and in foods, they lack uniform distribution throughout the plant kingdom. Table 4 lists the avonoid and tannin content of selected foods on an mg/serving basis. In general these data show that a serving of teas, fruits (apples, blueberries), dark chocolate and red wine are moderate to high in avonoid and/or tannin content. However, a serving of broccoli or selected fruit juices (cranberry and orange) provides relatively low levels of these phytonutrients. More important than the total avonoid/tannin content of foods per se, may be the content of avonoid and tannin subclasses. As an example, soy and soy-based foods, e.g., tofu, are unique sources of isoavones (Table 4), which appear to have unique health-related biological properties. Similarly, although cranberries contain only moderate levels of proanthocyanidins, these tannins have a substantial proportion of unique molecular structures (A linkages) (25), which may contribute to their bacterial antiadhesion activity (26,27). However, cocoa contains primarily B linkages and appears to be effective against several biomarkers of cardiovascular disease (28,29). Black and oolong teas have high contents of derived tannins (theaavins, thearubigins, etc.), which may contribute to the health-promoting benets of these beverages (Table 3). Food processing. Two aspects of food processing are pertinent for discussion relative to avonoids: 1) transformation during processing and 2) losses during processing and cooking. Relative to transformation, black and oolong teas are the foods that undergo the largest change of avan-3-ols during their production. The most dramatic changes are the reduction of avan-3-ols levels with a concomitant increase in the concentration of thearubigins (Table 3; compare brewed green tea with brewed black tea and brewed oolong tea). In contrast, total avonols remain relatively low and constant during conversion of green tea leaves into black or oolong tea (Table 3), and theaavins concentrations increases only slightly (data not shown). As outlined above, these changes are due to the oxidative processes that occur during production of black and oolong tea, in which avan-3-ols are converted primarily into thearubigins and, to a much lesser extent, into theaavins. The data in Table 3 do not permit the assessment of the stoichiometry of these conversions, however, due to the complexity of these reactions it is reasonable to assume that some of the avan-3-ols are converted to products other than compounds measured as theaavins and thearubigins. Several other processes common to the production of commercial teas also alter their avonoid content. Decaffeination and manipulations employed in the preparation of instant and ready-to-drink teas all appear to decrease either avanol levels (Table 3; decaffeinated green tea) or both concentrations of avanols and thearubigins (Table 3; black teas). It is important to point out that some of the uctuations in avonoid content among different teas may be due to blends of different teas relative to type, area of production and cost. The avonoid content of leaf tissue is very sensitive to environmental conditions such as amount of light energy and pollutants (30).

TABLE 4
Flavonoid and tannin content of selected foods1
Food Apple, with peel Flavan-3-ols Flavonols Proanthocyanidins Blueberries Anthocyanidins Flavan-3-ols Flavonols Proanthocyanidins Broccoli, raw Flavan-3-ols Flavonols Proanthocyanidins Chocolate, dark Flavan-3-ols Proanthocyanidins Chocolate, milk Flavan-3-ols Proanthocyanidins Cranberry juice cocktail Flavan-3-ols Flavonols Proanthocyanidins Orange juice Flavanones Flavonols Proanthocyanidins Tofu Isoavones Tea, black, brewed Flavan-3-ols Flavonols Thearubigins Tea, green, brewed Flavan-3-ols Flavonols Thearubigins Wine, red Anthocyanidins Flavan-3-ols Flavonols Proanthocyanidins Wine, white Flavan-3-ols Proanthocyanidins mg/serving Reference

13 6 147 82 1 3 131 0 3 ND3 24 165 6 88 1 3 42 28 1 ND3 334 6 10 116 304 12 3 9405 1020 10 77103 235 23

8 8 15 8 8 8 2 8 8 14 8 15 8 2 Downloaded from jn.nutrition.org by guest on July 28, 2011 8 8 16 8 8 14 9 8 8 8 8 8 8 24 24 24 24 24 24

1 Foods selected for representativeness of food type and source of avaonids. Data for monomeric avonoids presented as aglycones, for thearubigins as gallic acid equivalents, and for proanthocyanidins as representative oligomers. 2 Data presented by Gu, L., Kelm, M. A., Hammerstone, J. F., Holden, J., Haytowitz, D. B., Beecher, G. & Prior, R. L. Development of a database of procyanidin prole and content in foods, 5th International Food Composition Database Conference, June 30 July 2, 2003, Washington, DC. 3 Not detected with current routine methods of analysis. 4 Mean of several types of tofu (9). 5 Ranges of values encompass wines aged for varying periods of time. Most foods have highly variable avonoid and/or tannin content due to varietal, environmental and other inuences.

Thus, as teas are blended based on organoleptic and visual factors, avonoid levels also may be altered. Flavonoids also are susceptible to other food processing and food handling procedures. For example, storage of onions results in the loss of 25 to 33% of the quercetin during the 1st 12 d, but only small losses thereafter (31). When cooked in

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water, those foods having a high surface area or ruptured cell walls results in a substantial reduction in the levels of avonoids (32,33). These losses may be explained by the solubility of the avonoids in water (a polar solvent) and the ease with which they can escape the cellular compartment of vegetables. In contrast, quercetin conjugates of onion are quite stable to high temperatures (100C) with only a small amount degraded at temperatures of hot vegetable oil (31). These observations suggest that during food processing, enzymatic transformations are more important relative to changes in avonoid content than the cooking process per se. Flavonoid databases. The association between ingestion of a class or classes of micronutrients and health promotion is often demonstrated through epidemiological studies. Such studies require databases of the food content of each member of the class(es) of phytonutrients of interest. For avonoids, several countries have assembled databases of values for those compounds assumed to be rich in their respective food supply (Table 5). Information in several of the databases is available on the Internet (see Literature Cited for web address). The lack of data for a subclass of avonoids within a country suggests several possibilities including 1) low consumption of foods containing that subclass(es), 2) analytical technology is not available, and 3) cost-benet analysis has failed to raise the avonoid subclass consumption-health promotion association to a sufciently high priority. However, because of the apparent avonoid-health benet relationship, several countries are developing or expanding avonoid and tannin food composition databases.

Flavonoid consumption Scientists have calculated avonoid intakes of individuals for several countries (Table 5). Consumption of total avonoids ranges from about 20 mg/d (United States, Denmark, Finland) to 70 mg/d (Holland). These values are considerably lower than earlier estimates (several hundred mg/d), which were based on limited analyses of only a few foods (43,44). Also contributing to the disagreement of consumption data may be the lack of comprehensive food composition data for one or more avonoid subclasses (and all of the tannin subclasses) in the countries listed in Table 5. From a health perspective, the consumption of selected subclasses of avonoids may be more important than total avonoid intake. Intakes of both avones and avonols were determined for the ve countries listed in Table 5. In that regard, consumption of avonoids in these two subclasses is lowest in Finland ( 4 mg/d) and generally similar for the populations studied in Denmark, Japan, Holland and United States (16 32 mg/d). The similarity of intakes for occupants of these four developed countries is remarkable considering the wide divergence of populations and cultural habits. Only two countries calculated intakes of avanones, those avonoids common to citrus foods (Denmark and Finland). Both countries have similar intakes of 714 mg/d (Denmark) and 20 mg/d (Finland) (Table 5). Similarly, scientists have calculated intakes of avan-3-ols only for the Dutch, and isoavones for populations of three countries (Table 5). Although limited, these values provide estimates of avonoid intakes primarily

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TABLE 5
Estimates of avonoid consumption in several countries1
Country Population Flavonoids evaluated Intake2 mg/d Denmark Danish Household Consumption Survey (dietary history)3 3 Flavanones 1 Flavone 2 Flavonols Total 3 Flavanones 2 Flavones 4 Flavonols Total 2 Flavones 3 Flavonols 6 Flavan-3-ols 4 Isoavones Total 1 Flavone 4 Flavonols 2 Isoavones Total 2 Flavones 3 Flavonols 4 Isoavones 2 Isoavones Total 714 12 1530 2346 20 1 4 24 23 50 1 73 1 16 47 63 1 2022 1 12 2034 34 Reference

Finland

Finnish Mobile Clinic Health Examination Survey-10,054 subset (dietary history)

35

Holland

Dutch National Food Consumption Survey (dietary history) Prospect-EPIC (FFQ)

36 37 38 39

Japan

115 Women (dietary history)

United States

US Health Professionals (FFQ) Framingham Offspring Study (FFQ) 1095 Asian-American women (dietary history)

40 41 42

1 The intake data in this table are representative values only and not intended to be an extensive review. Studies were generally selected based on a large number of subjects and/or a substantial number of subclasses of avonoids evaluated. 2 Intake data are based on aglycone form of each avonoid. 3 Comment in parentheses indicates tool used to collect food intake information. FFQ, food frequency questionnaire.

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from tea (50 mg/d avan-3-ols) and soy foods ( 1 47 mg/d isoavones). Cultural dietary habits often dictate which foods are consumed and, in turn, the subclass(es) and amount of avonoids that are ingested. For example, soy and soy foods are highly consumed in Japan and as a result, isoavone consumption has been assessed and found to be higher than intakes of other avonoid subclasses (Table 5). Cultural habits remain strong in terms of consumption of soy foods; Asians who have migrated to the U.S. still retain a relatively modest intake of isoavones compared with residents of Japan and nonAsian residents of the U.S. (Table 5). Similarly, avan-3-ol consumption has been determined in large populations in Holland because of the popularity of tea as a beverage in this country (37,45). The intake data (Table 5) reect that these avonoids are the most highly consumed subclass of those investigated in Holland. As food composition databases for food avonoids and tannins are more fully developed, the completeness, accuracy and precision of the consumption data for these polyphenols also will improve. DISCUSSION Foods have many components other than traditional nutrients, e.g., protein, amino acids, vitamins, minerals, etc., many of which have been associated with biological activities consistent with reduced risk of several chronic diseases and other maladies (13). Two groups of these food components include avonoids and tannins, which are large classes of polyphenols. Unlike traditional nutrients whose absence in the diet causes deciency diseases, removal of avonoids and tannins from diets fails to induce such abnormalities and is the primary reason these food components have not been classied as a vitamin(s) in the United States (46). In the case of traditional nutrients, dietary adequacy is established through manipulation of diets and menus using biomarkers and symptoms of the disease as endpoints. However, for chronic diseases, because of the long period (often decades) required for manifestation of symptoms and the lack of adequate animal models, epidemiologic studies have been a primary tool for making associations between consumption of food components and incidence of the disease (47). Such studies require extensive databases of values for the avonoid and tannin content of foods consumed by the population of interest. Unlike traditional nutrients, for which such databases were developed after the nutrient was classied as essential, accurate and extensive food composition databases are needed to improve the accuracy and precision of the prediction of relationships between consumption of these nonessential nutrients and incidence of chronic disease(s). In many countries, teas provide rich dietary sources of avan-3-ols, avonols and derived tannins, yet databases of values for some of these components (derived trannins) are weak at best and in most cases nonexistent. Analysis of avonoids and tannins of foods is difcult and time consuming (10,18). Relative to the derived tannins of teas, only recently has an analytical approach been agreed upon (48), and limited data generated employing this procedure (8). Improvement and completion of data in food composition databases for those teas commonly consumed in each country will provide the tools necessary to accurately assess the role of tea in the reduction of chronic disease risk and maintenance of health. LITERATURE CITED
1. Beecher, G. R. (1999) Phytonutrients role in metabolism: effects on resistance to degenerative processes. Nutr. Rev. 9 (Part II): S3S6.

2. Hines, E. 1999 New nutritive substances: beyond the ABCs. Food Quality 6: 39 43. 3. Rhodes, M. & Price, K. R. (1999) Phytochemicals: classication and occurrence. In: Encyclopedia of Human Nutrition (Sadler, M. J., Strain, J. J. & Caballero, B., eds.), pp. 1539 1549. Academic Press/Harcourt Brace & Company Publishers, New York, NY. 4. Thompson, L. U. (1993) Potential health benets and problems associated with antinutrients in foods. Food Res. Intnl. 26: 131149. 5. Berg, P. A. & Daniel, P. T. (1988) Effects of avonoid compounds on the immune response. In: Plant Flavonoids in Biology and Medicine II: Biochemical, Cellular, and Medicinal Properties (Cody, V., Middleton, E., Jr., Harborne, J. B. & Beretz, A., eds.), pp. 157171. Alan R. Liss, Inc., New York, NY. 6. Middleton, E., Jr. & Kandaswami, C. (1993) The impact of plant avonoids on mammalian biology: implications for immunity, inammation and cancer. In: The Flavonoids. Advances in Research since 1986 (Harborne, J. 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