Polyphenols: Food Sources and Bioavailability

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com
Polyphenols: food sources and bioavailability1,2

Claudine Manach, Augustin Scalbert, Christine Morand, Christian Rémésy, and Liliana Jiménez
ABSTRACT research are to establish evidence for the effects of polyphenol

Polyphenols are abundant micronutrients in our diet, and evidence consumption on health and to identify which of the hundreds of
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for their role in the prevention of degenerative diseases such as existing polyphenols are likely to provide the greatest protection
cancer and cardiovascular diseases is emerging. The health effects of in the context of preventive nutrition. If these objectives are to be
polyphenols depend on the amount consumed and on their bioavail- attained, it is first essential to determine the nature and distribu-
ability. In this article, the nature and contents of the various poly- tion of these compounds in our diet. Such knowledge will allow
phenols present in food sources and the influence of agricultural evaluation of polyphenol intake and enable epidemiologic anal-
practices and industrial processes are reviewed. Estimates of dietary ysis that will in turn provide an understanding of the relation
intakes are given for each class of polyphenols. The bioavailability between the intake of these substances and the risk of develop-
of polyphenols is also reviewed, with particular focus on intestinal ment of several diseases. Furthermore, not all polyphenols are
absorption and the influence of chemical structure (eg, glycosyla- absorbed with equal efficacy. They are extensively metabolized
tion, esterification, and polymerization), food matrix, and excretion by intestinal and hepatic enzymes and by the intestinal micro-
back into the intestinal lumen. Information on the role of microflora flora. Knowledge of the bioavailability and metabolism of the
in the catabolism of polyphenols and the production of some active various polyphenols is necessary to evaluate their biological
metabolites is presented. Mechanisms of intestinal and hepatic con- activity within target tissues. The types and distribution of poly-
jugation (methylation, glucuronidation, sulfation), plasma transport, phenols in foods and the bioavailability of polyphenols are the
and elimination in bile and urine are also described. Pharmacokinetic topics of the present review.
data for the various polyphenols are compared. Studies on the iden-
tification of circulating metabolites, cellular uptake, intracellular
metabolism with possible deconjugation, biological properties of the TYPES AND DISTRIBUTION OF POLYPHENOLS IN
conjugated metabolites, and specific accumulation in some target FOODS
tissues are discussed. Finally, bioavailability appears to differ Several thousand molecules having a polyphenol structure (ie,
greatly between the various polyphenols, and the most abundant several hydroxyl groups on aromatic rings) have been identified
polyphenols in our diet are not necessarily those that have the best in higher plants, and several hundred are found in edible plants.
bioavailability profile. A thorough knowledge of the bioavailability These molecules are secondary metabolites of plants and are
of the hundreds of dietary polyphenols will help us to identify those generally involved in defense against ultraviolet radiation or
that are most likely to exert protective health effects. Am J Clin aggression by pathogens. These compounds may be classified
Nutr 2004;79:727– 47. into different groups as a function of the number of phenol rings
that they contain and of the structural elements that bind these
KEY WORDS Polyphenols, flavonoids, phenolic acids, food rings to one another. Distinctions are thus made between the
sources, dietary intake, intestinal absorption, metabolism, bioavail- phenolic acids, flavonoids, stilbenes, and lignans (Figure 1). The
ability flavonoids, which share a common structure consisting of 2 ar-
omatic rings (A and B) that are bound together by 3 carbon atoms
that form an oxygenated heterocycle (ring C), may themselves be
INTRODUCTION divided into 6 subclasses as a function of the type of heterocycle
Over the past 10 y, researchers and food manufacturers have involved: flavonols, flavones, isoflavones, flavanones, antho-
become increasingly interested in polyphenols. The chief reason cyanidins, and flavanols (catechins and proanthocyanidins)
for this interest is the recognition of the antioxidant properties of (Figure 2). In addition to this diversity, polyphenols may be
polyphenols, their great abundance in our diet, and their probable associated with various carbohydrates and organic acids and with
role in the prevention of various diseases associated with oxida- one another.
tive stress, such as cancer and cardiovascular and neurodegen-
1
erative diseases (Scalbert A, Manach C, Morand C, Rémésy C, From the Unité des Maladies Métaboliques et Micronutriments, INRA,
Jiménez L. Crit Rev Food Sci Nutr, in press). Furthermore, poly- Saint-Genès Champanelle, France (CM, AS, CM, and CR), and Danone
Vitapole Research, Palaiseau cedex, France (LJ).
phenols, which constitute the active substances found in many 2
Address reprint requests to C Manach, Unité des Maladies Métaboliques
medicinal plants, modulate the activity of a wide range of en-
et Micronutriments, INRA, 63122 Saint-Genès Champanelle, France. E-
zymes and cell receptors (1). In this way, in addition to having mail: [email protected].
antioxidant properties, polyphenols have several other specific Received June 3, 2003.
biological actions that are as yet poorly understood. Two aims of Accepted for publication October 17, 2003.
Am J Clin Nutr 2004;79:727– 47. Printed in USA. © 2004 American Society for Clinical Nutrition 727
Licensed to Maryil MarcelaMartinez Mercado - [email protected]
728 MANACH ET AL

FIGURE 1. Chemical structures of polyphenols.
Phenolic acids
Two classes of phenolic acids can be distinguished: deriva-
tives of benzoic acid and derivatives of cinnamic acid (Figure 1).
The hydroxybenzoic acid content of edible plants is generally
very low, with the exception of certain red fruits, black radish,
and onions, which can have concentrations of several tens of
milligrams per kilogram fresh weight (2). Tea is an important
source of gallic acid: tea leaves may contain up to 4.5 g/kg fresh
wt (3). Furthermore, hydroxybenzoic acids are components of
complex structures such as hydrolyzable tannins (gallotannins in
mangoes and ellagitannins in red fruit such as strawberries, rasp-
berries, and blackberries) (4). Because these hydroxybenzoic FIGURE 2. Chemical structures of flavonoids.
acids, both free and esterified, are found in only a few plants eaten
by humans, they have not been extensively studied and are not
currently considered to be of great nutritional interest. trations generally decrease during the course of ripening, but
The hydroxycinnamic acids are more common than are the total quantities increase as the fruit increases in size.
hydroxybenzoic acids and consist chiefly of p-coumaric, caffeic, Ferulic acid is the most abundant phenolic acid found in cereal
ferulic, and sinapic acids. These acids are rarely found in the free grains, which constitute its main dietary source. The ferulic acid
form, except in processed food that has undergone freezing, content of wheat grain is 앒0.8 –2 g/kg dry wt, which may rep-
sterilization, or fermentation. The bound forms are glycosylated resent up to 90% of total polyphenols (28, 29). Ferulic acid is
derivatives or esters of quinic acid, shikimic acid, and tartaric found chiefly in the outer parts of the grain. The aleurone layer
acid. Caffeic and quinic acid combine to form chlorogenic acid, and the pericarp of wheat grain contain 98% of the total ferulic
which is found in many types of fruit and in high concentrations acid. The ferulic acid content of different wheat flours is thus
in coffee: a single cup may contain 70 –350 mg chlorogenic acid directly related to levels of sieving, and bran is the main source
(5). The types of fruit having the highest content (blueberries, of polyphenols (30). Rice and oat flours contain approximately the
kiwis, plums, cherries, apples) contain 0.5–2 g hydroxycinnamic same quantity of phenolic acids as wheat flour (63 mg/kg), although
acids/kg fresh wt (Table 1) (6). the content in maize flour is about 3 times as high (2). Ferulic acid is
Caffeic acid, both free and esterified, is generally the most found chiefly in the trans form, which is esterified to arabinoxylans
abundant phenolic acid and represents between 75% and 100% of and hemicelluloses in the aleurone and pericarp. Only 10% of ferulic
the total hydroxycinnamic acid content of most fruit. Hydroxy- acid is found in soluble free form in wheat bran (29). Several dimers
cinnamic acids are found in all parts of fruit, although the highest of ferulic acid are also found in cereals and form bridge structures
concentrations are seen in the outer parts of ripe fruit. Concen- between chains of hemicellulose.
POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 729

TABLE 1
Polyphenols in foods
Polyphenol content
Source (serving size) By wt or vol By serving

mg/kg fresh wt (or mg/L) mg/serving
Hydroxybenzoic acids (2, 6) Blackberry (100 g) 80–270 8–27
Protocatechuic acid Raspberry (100 g) 60–100 6–10
Gallic acid Black currant (100 g) 40–130 4–13
p-Hydroxybenzoic acid Strawberry (200 g) 20–90 4–18
Hydroxycinnamic acids (2, 5–7) Blueberry (100 g) 2000–2200 200–220
Caffeic acid Kiwi (100 g) 600–1000 60–100
Chlorogenic acid Cherry (200 g) 180–1150 36–230
Coumaric acid Plum (200 g) 140–1150 28–230
Ferulic acid Aubergine (200 g) 600–660 120–132

Sinapic acid Apple (200 g) 50–600 10–120
Pear (200 g) 15–600 3–120
Chicory (200 g) 200–500 40–100
Artichoke (100 g) 450 45
Potato (200 g) 100–190 20–38
Corn flour (75 g) 310 23
Flour: wheat, rice, oat (75 g) 70–90 5–7
Cider (200 mL) 10–500 2–100
Coffee (200 mL) 350–1750 70–350
Anthocyanins (8–10) Aubergine (200 g) 7500 1500
Cyanidin Blackberry (100 g) 1000–4000 100–400
Pelargonidin Black currant (100 g) 1300–4000 130–400
Peonidin Blueberry (100 g) 250–5000 25–500
Delphinidin Black grape (200 g) 300–7500 60–1500
Malvidin Cherry (200 g) 350–4500 70–900
Rhubarb (100 g) 2000 200
Strawberry (200 g) 150–750 30–150
Red wine (100 mL) 200–350 20–35
Plum (200 g) 20–250 4–50
Red cabbage (200 g) 250 50
Flavonols (11–18) Yellow onion (100 g) 350–1200 35–120
Quercetin Curly kale (200 g) 300–600 60–120
Kaempferol Leek (200 g) 30–225 6–45
Myricetin Cherry tomato (200 g) 15–200 3–40
Broccoli (200 g) 40–100 8–20
Blueberry (100 g) 30–160 3–16
Black currant (100 g) 30–70 3–7
Apricot (200 g) 25–50 5–10
Apple (200 g) 20–40 4–8
Beans, green or white (200 g) 10–50 2–10
Black grape (200 g) 15–40 3–8
Tomato (200 g) 2–15 0.4–3.0
Black tea infusion (200 mL) 30–45 6–9
Green tea infusion (200 mL) 20–35 4–7
Red wine (100 mL) 2–30 0.2–3
Flavones (11–12, 14, 18) Parsley (5 g) 240–1850 1.2–9.2
Apigenin Celery (200 g) 20–140 4–28
Luteolin Capsicum pepper (100 g) 5–10 0.5–1
Flavanones (19–21) Orange juice (200 mL) 215–685 40–140
Hesperetin Grapefruit juice (200 mL) 100–650 20–130
Naringenin Lemon juice (200 mL) 50–300 10–60
Eriodictyol
Isoflavones (22–25) Soy flour (75 g) 800–1800 60–135
Daidzein Soybeans, boiled (200 g) 200–900 40–180
Genistein Miso (100 g) 250–900 25–90
Glycitein Tofu (100 g) 80–700 8–70
Tempeh (100 g) 430–530 43–53
Soy milk (200 mL) 30–175 6–35
Monomeric flavanols (6, 17, 26, 27) Chocolate (50 g) 460–610 23–30
Catechin Beans (200 g) 350–550 70–110
Epicatechin Apricot (200 g) 100–250 20–50
Cherry (200 g) 50–220 10–44
Grape (200 g) 30–175 6–35
Peach (200 g) 50–140 10–28
Blackberry (100 g) 130 13
Apple (200 g) 20–120 4–24
Green tea (200 mL) 100–800 20–160
Black tea (200 mL) 60–500 12–100
Red wine (100 mL) 80–300 8–30
Cider (200 mL) 40 8
730 MANACH ET AL
Flavonoids production of soya milk (36). The fermentation carried out during
Flavonols are the most ubiquitous flavonoids in foods, and the the manufacturing of certain foods, such as miso and tempeh, results
main representatives are quercetin and kaempferol. They are in the hydrolysis of glycosides to aglycones. The aglycones are
generally present at relatively low concentrations of 앒15– highly resistant to heat. The isoflavone content of soya and its man-
30 mg/kg fresh wt. The richest sources are onions (up to 1.2 g/kg ufactured products varies greatly as a function of geographic zone,
fresh wt), curly kale, leeks, broccoli, and blueberries (Table 1). growing conditions, and processing. Soybeans contain between 580
Red wine and tea also contain up to 45 mg flavonols/L. These and 3800 mg isoflavones/kg fresh wt, and soymilk contains between
30 and 175 mg/L (25, 37).
compounds are present in glycosylated forms. The associated
Flavanols exist in both the monomer form (catechins) and the
sugar moiety is very often glucose or rhamnose, but other sugars
polymer form (proanthocyanidins). Catechins are found in many
may also be involved (eg, galactose, arabinose, xylose, glucu-
types of fruit (apricots, which contain 250 mg/kg fresh wt, are the
ronic acid). Fruit often contains between 5 and 10 different fla-
richest source; Table 1). They are also present in red wine (up to
vonol glycosides (6). These flavonols accumulate in the outer
300 mg/L), but green tea and chocolate are by far the richest
and aerial tissues (skin and leaves) because their biosynthesis is
sources. An infusion of green tea contains up to 200 mg catechins

stimulated by light. Marked differences in concentration exist
(38). Black tea contains fewer monomer flavanols, which are
between pieces of fruit on the same tree and even between dif-
oxidized during “fermentation” (heating) of tea leaves to more
ferent sides of a single piece of fruit, depending on exposure to
complex condensed polyphenols known as theaflavins (dimers)
sunlight (31). Similarly, in leafy vegetables such as lettuce and
and thearubigins (polymers). Catechin and epicatechin are the
cabbage, the glycoside concentration is 욷10 times as high in the
main flavanols in fruit, whereas gallocatechin, epigallocatechin,
green outer leaves as in the inner light-colored leaves (14). This
and epigallocatechin gallate are found in certain seeds of legu-
phenomenon also accounts for the higher flavonol content of minous plants, in grapes, and more importantly in tea (27, 39). In
cherry tomatoes than of standard tomatoes, because they have contrast to other classes of flavonoids, flavanols are not glyco-
different proportions of skin to whole fruit. sylated in foods. The tea epicatechins are remarkably stable when
Flavones are much less common than flavonols in fruit and exposed to heat as long as the pH is acidic: only 앒15% of these
vegetables. Flavones consist chiefly of glycosides of luteolin and substances are degraded after 7 h in boiling water at pH 5 (40).
apigenin. The only important edible sources of flavones identi- Proanthocyanidins, which are also known as condensed tan-
fied to date are parsley and celery (Table 1). Cereals such as nins, are dimers, oligomers, and polymers of catechins that are
millet and wheat contain C-glycosides of flavones (32–34). The bound together by links between C4 and C8 (or C6). Their mean
skin of citrus fruit contains large quantities of polymethoxylated degree of polymerization in foods has rarely been determined. In
flavones: tangeretin, nobiletin, and sinensetin (up to 6.5 g/L of cider apples, the mean degree of polymerization ranges from 4 to
essential oil of mandarin) (2). These polymethoxylated flavones 11 (41). Through the formation of complexes with salivary pro-
are the most hydrophobic flavonoids. teins, condensed tannins are responsible for the astringent char-
In human foods, flavanones are found in tomatoes and certain acter of fruit (grapes, peaches, kakis, apples, pears, berries, etc) and
aromatic plants such as mint, but they are present in high con- beverages (wine, cider, tea, beer, etc) and for the bitterness of choc-
centrations only in citrus fruit. The main aglycones are naringe- olate (42). This astringency changes over the course of maturation
nin in grapefruit, hesperetin in oranges, and eriodictyol in lem- and often disappears when the fruit reaches ripeness; this change has
ons. Flavanones are generally glycosylated by a disaccharide at been well explained in the kaki fruit by polymerization reactions
position 7: either a neohesperidose, which imparts a bitter taste with acetaldehyde (43). Such polymerization of tannins probably
(such as to naringin in grapefruit), or a rutinose, which is flavor- accounts for the apparent reduction in tannin content that is com-
less. Orange juice contains between 200 and 600 mg hesperi- monly seen during the ripening of many types of fruit. It is difficult
din/L and 15– 85 mg narirutin/L, and a single glass of orange to estimate the proanthocyanidin content of foods because proan-
juice may contain between 40 and 140 mg flavanone glycosides thocyanidins have a wide range of structures and molecular weights.
(20). Because the solid parts of citrus fruit, particularly the albedo The only available data concern dimers and trimers, which are as
(the white spongy portion) and the membranes separating the abundant as the catechins themselves (26).
segments, have a very high flavanone content, the whole fruit Anthocyanins are pigments dissolved in the vacuolar sap of the
may contain up to 5 times as much as a glass of orange juice. epidermal tissues of flowers and fruit, to which they impart a
Isoflavones are flavonoids with structural similarities to estro- pink, red, blue, or purple color (9). They exist in different chem-
gens. Although they are not steroids, they have hydroxyl groups in ical forms, both colored and uncolored, according to pH. Al-
positions 7 and 4' in a configuration analogous to that of the hy- though they are highly unstable in the aglycone form (anthocya-
droxyls in the estradiol molecule. This confers pseudohormonal nidins), while they are in plants, they are resistant to light, pH,
properties on them, including the ability to bind to estrogen recep- and oxidation conditions that are likely to degrade them. Degra-
tors, and they are consequently classified as phytoestrogens. Isofla- dation is prevented by glycosylation, generally with a glucose at
vones are found almost exclusively in leguminous plants. Soya and position 3, and esterification with various organic acids (citric
its processed products are the main source of isoflavones in the and malic acids) and phenolic acids. In addition, anthocyanins
human diet. They contain 3 main molecules: genistein, daidzein, and are stabilized by the formation of complexes with other fla-
glycitein, generally in a concentration ratio of 1:1:0.2. These isoflavonoids (copigmentation). In the human diet, anthocyanins are
vones are found in 4 forms: aglycone, 7-O-glucoside, 6⬙-O-acetyl- found in red wine, certain varieties of cereals, and certain leafy
7-O-glucoside, and 6⬙-O-malonyl-7-O-glucoside (35). The 6⬙-O- and root vegetables (aubergines, cabbage, beans, onions, rad-
malonylglucoside derivatives have an unpleasant, bitter, and ishes), but they are most abundant in fruit. Cyanidin is the most
astringent taste. They are sensitive to heat and are often hydrolyzed common anthocyanidin in foods. Food contents are generally
to glycosides during the course of industrial processing, as in the proportional to color intensity and reach values up to 2– 4 g/kg

fresh wt in blackcurrants or blackberries (Table 1). These values wt and may be as high as 10 g/kg in certain varieties of cider
increase as the fruit ripens. Anthocyanins are found mainly in the apples (41, 51).
skin, except for certain types of red fruit, in which they also occur For many plant products, the polyphenol composition is much
in the flesh (cherries and strawberries). Wine contains 앒200 – less known, knowledge is often limited to one or a few varieties,
350 mg anthocyanins/L, and these anthocyanins are transformed and data sometimes do not concern the edible parts. Some foods,
into various complex structures as the wine ages (10, 44). particularly some exotic types of fruit and some cereals, have not
been analyzed yet. Furthermore, numerous factors other than
Lignans variety may affect the polyphenol content of plants; these factors
Lignans are formed of 2 phenylpropane units (Figure 1). The include ripeness at the time of harvest, environmental factors,
richest dietary source is linseed, which contains secoisolaricir- processing, and storage.
esinol (up to 3.7 g/kg dry wt) and low quantities of matairesinol. Environmental factors have a major effect on polyphenol con-
Other cereals, grains, fruit, and certain vegetables also contain tent. These factors may be pedoclimatic (soil type, sun exposure,
traces of these same lignans, but concentrations in linseed are rainfall) or agronomic (culture in greenhouses or fields, biolog-
앒1000 times as high as concentrations in these other food ical culture, hydroponic culture, fruit yield per tree, etc). Expo-

sources (45). Lignans are metabolized to enterodiol and en- sure to light has a considerable effect on most flavonoids. The
terolactone by the intestinal microflora. The low quantities of degree of ripeness considerably affects the concentrations and
secoisolariciresinol and matairesinol that are ingested as part of proportions of the various polyphenols (6). In general, phenolic
our normal diet do not account for the concentrations of the acid concentrations decrease during ripening, whereas anthocy-
metabolites enterodiol and enterolactone that are classically anin concentrations increase. Many polyphenols, especially phe-
measured in plasma and urine. Thus, there are undoubtedly other nolic acids, are directly involved in the response of plants to
lignans of plant origin that are precursors of enterodiol and en- different types of stress: they contribute to healing by lignifica-
terolactone and that have not yet been identified (46). Thompson tion of damaged areas, they possess antimicrobial properties, and
et al (47) used an in vitro technique involving the fermentation of their concentrations may increase after infection (2, 6, 52). Al-
foods by human colonic microflora to quantitatively evaluate though very few studies directly addressed this issue, the poly-
precursors of enterodiol and enterolactone. They confirmed that phenol content of vegetables produced by organic or sustainable
oleaginous seeds (linseed) are the richest source and identified agriculture is certainly higher than that of vegetables grown
algae, leguminous plants (lentils), cereals (triticale and wheat), without stress, such as those grown in conventional or hydro-
vegetables (garlic, asparagus, carrots), and fruit (pears, prunes) ponic conditions. This was shown recently in strawberries,
as minor sources. blackberries, and corn (53). With the current state of knowledge,
it is extremely difficult to determine for each family of plant
Stilbenes products the key variables that are responsible for the variability
in the content of each polyphenol and the relative weight of those
Stilbenes are found in only low quantities in the human diet. variables. A huge amount of analysis would be required to obtain
One of these, resveratrol, for which anticarcinogenic effects have this information. For example, determination of the p-coumaric
been shown during screening of medicinal plants and which has acid content of 쏜500 red wines showed that genetic factors were
been extensively studied, is found in low quantities in wine more important than was exposure to light or climate (54).
(0.3–7 mg aglycones/L and 15 mg glycosides/L in red wine) Storage may also affect the content of polyphenols that are easily
(48 –50). However, because resveratrol is found in such small oxidized. Oxidation reactions result in the formation of more or less
quantities in the diet, any protective effect of this molecule is polymerized substances, which lead to changes in the quality of
unlikely at normal nutritional intakes. foods, particularly in color and organoleptic characteristics. Such
changes may be beneficial (as is the case with black tea) or harmful
(browning of fruit) to consumer acceptability. Storage of wheat flour
VARIABILITY OF POLYPHENOL CONTENT OF FOODS results in marked loss of phenolic acids (28). After 6 mo of storage,
Fruit and beverages such as tea and red wine constitute the flours contained the same phenolic acids in qualitative terms, but
main sources of polyphenols. Certain polyphenols such as quer- their concentrations were 70% lower. Cold storage, in contrast, did
cetin are found in all plant products (fruit, vegetables, cereals, not affect the content of polyphenols in apples (55, 56), pears (57),
leguminous plants, fruit juices, tea, wine, infusions, etc), whereas or onions (58). At 25 °C, storage of apple juice for 9 mo results in
others are specific to particular foods (flavanones in citrus fruit, a 60% loss of quercetin and a total loss of procyanidins, despite
isoflavones in soya, phloridzin in apples). In most cases, foods the fact that polyphenols are more stable in fruit juices than is vita-
contain complex mixtures of polyphenols, which are often min C (59, 60).
poorly characterized. Apples, for example, contain flavanol Methods of culinary preparation also have a marked effect on
monomers (epicatechin mainly) or oligomers (procyanidin B2 the polyphenol content of foods. For example, simple peeling of
mainly), chlorogenic acid and small quantities of other hydroxy- fruit and vegetables can eliminate a significant portion of poly-
cinnamic acids, 2 glycosides of phloretin, several quercetin gly- phenols because these substances are often present in higher
cosides, and anthocyanins such as cyanidin 3-galactoside in the concentrations in the outer parts than in the inner parts. Cooking
skin of certain red varieties. Apples are one of the rare types of may also have a major effect. Onions and tomatoes lose between
food for which fairly precise data on polyphenol composition are 75% and 80% of their initial quercetin content after boiling for
available. Differences in polyphenol composition between vari- 15 min, 65% after cooking in a microwave oven, and 30% after
eties of apples have notably been studied. The polyphenol pro- frying (18). Steam cooking of vegetables, which avoids leaching,
files of all varieties of apples are practically identical, but con- is preferable. Potatoes contain up to 190 mg chlorogenic acid/kg,
centrations may range from 0.1 to 5 g total polyphenols/kg fresh mainly in the skin (61). Extensive loss occurs during cooking,
732 MANACH ET AL
and no remaining phenolic acids were found in French fries or fruit is practically the sole source of flavanones, ingestion of
freeze-dried mashed potatoes (54). these substances is probably greater in regions where these fruits
Industrial food processing also affects polyphenol content. As are produced, such as southern Europe. Anthocyanin consump-
with fruit peeling, dehulling of legume seeds and decortication tion was studied only in Finland, where high amounts of berries
and bolting of cereals can result in a loss of some polyphenols. are eaten, and was found to be 82 mg/d on average, although
Grinding of plant tissues may lead to oxidative degradation of some intakes exceeded 200 mg/d (72).
polyphenols as a result of cellular decompartmentation and con- Consumption of soya in the Asian countries is 앒10 –35 g/d,
tact between cytoplasmic polyphenol oxidase and phenolic sub- which is equivalent to a mean intake of 25– 40 mg isoflavones/d,
strates present in the vacuoles. Polyphenols are then transformed with a maximum intake of 100 mg/d (23, 73, 74). Americans and
into brown pigments that are polymerized to different degrees. Europeans, who eat little soya, consume only a few milligrams of
This unwanted process can occur, for example, during the pro- isoflavones per day. Nevertheless, the incorporation of growing
cess of making jam or compote from fruit. Production of fruit quantities of soya extracts into manufactured food products
juice often involves clarification or stabilization steps specifi- could result in an increase in isoflavone intake. Women under-
cally aimed at removing certain flavonoids responsible for dis- going phytoestrogen replacement therapy for menopause con-

coloration and haze formation. Manufactured fruit juices thus sume between 30 and 70 mg isoflavones/d in the form of soya
have low flavonoid content. The pectinolytic enzymes used dur- extract capsules (75).
ing such processing also hydrolyze the esters of hydroxycin- In Spain the total consumption of catechins and proanthocya-
namic acid (62). Conversely, maceration operations facilitate nidin dimers and trimers has been estimated at 18 –31 mg/d, and
diffusion of polyphenols in juice, as occurs during vinification of the main sources are apples, pears, grapes, and red wine (76).
red wine. This maceration accounts for the fact that the polyphe- Consumption of monomer flavonols in Holland is significantly
nol content of red wines is 10 times as high as that of white wines higher (50 mg/d), and the principal sources are tea, chocolate,
(63) and is also higher than that of grape juice (64). apples, and pears (27). Ingestion of more highly polymerized
Because of the wide range of existing polyphenols and the proanthocyanidins could be as high as several hundred milli-
considerable number of factors that can modify their concentra- grams per day as previously suggested (42), but there are still no
tion in foods, no reference food-composition tables (as they exist reliable data.
for other micronutrients such as vitamins) have yet been drawn Consumption of hydroxycinnamic acids may vary highly ac-
up. Only partial data for certain polyphenols, such as flavonols cording to coffee consumption. Some persons who drink several
and flavones, catechins, and isoflavones, have been published on cups per day may ingest as much as 500 – 800 mg hydroxycin-
the basis of direct food analysis (11, 27) or bibliographic com- namic acids/d, whereas subjects who do not drink coffee and who
pilations (37, 65). Since March 2003, a database in which the also eat small quantities of fruit and vegetables do not ingest
flavonoid contents of 225 selected foods were compiled from 97 쏜25 mg/d (54). A German study estimated daily consumption of
bibliographic sources has been available on the US Department hydroxycinnamic acids and hydroxybenzoic acids at 211 and
of Agriculture website (66). A comprehensive composition table 11 mg/d, respectively. Caffeic acid intake alone was 206 mg/d,
for polyphenols is essential; it should allow daily polyphenol and the principal sources were coffee (which provides 92% of
consumption to be calculated from dietary questionnaires. Poly- caffeic acid) and fruit and fruit juices combined (source of 59%
phenol intake could then be correlated with the incidence of of p-coumaric acid) (65).
certain diseases or early markers for these diseases in epidemi- Various authors have noted a high variability in polyphenol
ologic studies, which would permit investigations of the protec- intake. Intake of phenolic acids ranged from 6 to 987 mg/d in
tive role of these micronutrients. Germany (65). The mean consumption of flavonols and flavones
in the Dutch population was 23 mg/d; values at the 10th and 90th
percentiles were 4 and 46 mg/d, respectively; and some subjects
DIETARY INTAKE OF POLYPHENOLS consumed up to 100 mg/d (69). The main reason for these vari-
Only partial information is available on the quantities of poly- ations is individual food preferences. When polyphenol content
phenols that are consumed daily throughout the world. These is expressed as the amount provided by a food serving, as in Table
data have been obtained through analysis of the main aglycones 1, the consumption of one particular food, such as berries for
(after hydrolysis of their glycosides and esters) in the foods most anthocyanins or coffee for hydroxycinnamic acids, clearly ap-
widely consumed by humans. pears to be capable of markedly changing the total polyphenol
In 1976 Kuhnau (8) calculated that dietary flavonoid intake in intake. If mean values are required, the addition of the intakes of
the United States was 앒1 g/d and consisted of the following: 16% flavonols, flavanones, flavanols (monomers, dimers, and tri-
flavonols, flavones, and flavanones; 17% anthocyanins; 20% mers), and isoflavones gives a total daily consumption of 100 –
catechins; and 45% “biflavones.” Although these figures were 150 mg in Western populations, to which must be added the
obtained under poorly detailed conditions, they continue to serve considerably variable intake of hydroxycinnamic acids, antho-
as reference data. Certain studies have subsequently provided cyanins, and proanthocyanidins. Finally, the total polyphenol
more precise individual data concerning the intake of various intake probably commonly reaches 1 g/d in people who eat sev-
classes of polyphenols. Flavonols have been more extensively eral servings of fruit and vegetables per day. Note that it is really
studied. Consumption of these substances has been estimated at difficult to follow a diet totally free of polyphenols. Because
앒20 –25 mg/d in the United States, Denmark, and Holland (67– polyphenol intake is difficult to evaluate by using dietary ques-
69). In Italy, consumption ranged from 5 to 125 mg/d, and the tionnaires, biomarkers for polyphenol exposure would be very
mean value was 35 mg/d (70). The intake of flavanones is similar useful. A few studies have tried to correlate flavonol, flavanone,
to or possibly higher than that of flavonols, with a mean con- and isoflavone intakes with plasma concentrations or urinary
sumption of 28.3 mg hesperetin/d in Finland (71). Because citrus excretion of metabolites (77– 82), but we are not yet able to

propose a reliable measurement in urine or plasma samples that hydrolysis in the stomach and thus arrive intact in the duodenum
could reflect the long-term intake of the various polyphenols. (87). Only aglycones and some glucosides can be absorbed in the
small intestine, whereas polyphenols linked to a rhamnose moi-
ety must reach the colon and be hydrolyzed by rhamnosidases of
BIOAVAILABILITY OF POLYPHENOLS
the microflora before absorption (88, 89). The same probably
It is important to realize that the polyphenols that are the most applies to polyphenols linked to arabinose or xylose, although
common in the human diet are not necessarily the most active this question has not been specifically studied. Because absorp-
within the body, either because they have a lower intrinsic action occurs less readily in the colon than in the small intestine
tivity or because they are poorly absorbed from the intestine, because of a smaller exchange area and a lower density of trans-
highly metabolized, or rapidly eliminated. In addition, the me- port systems, as a general rule, glycosides with rhamnose are
tabolites that are found in blood and target organs and that result absorbed less rapidly and less efficiently than are aglycones and
from digestive or hepatic activity may differ from the native glucosides. This has been clearly shown in humans for quercetin
substances in terms of biological activity. Extensive knowledge glycosides: maximum absorption occurs 0.5– 0.7 h after inges-
of the bioavailability of polyphenols is thus essential if their tion of quercetin 4'-glucoside and 6 –9 h after ingestion of the

health effects are to be understood. same quantity of rutin (quercetin-3␤-rutinoside). The bioavail-
Metabolism of polyphenols occurs via a common pathway ability of rutin is only 15–20% of that of quercetin 4'-glucoside
(83). The aglycones can be absorbed from the small intestine. (90, 91). Similarly, absorption of quercetin is more rapid and
However, most polyphenols are present in food in the form of efficient after ingestion of onions, which are rich in glucosides,
esters, glycosides, or polymers that cannot be absorbed in their than after ingestion of apples containing both glucosides and
native form. These substances must be hydrolyzed by intestinal various other glycosides (92). In the case of quercetin glucosides,
enzymes or by the colonic microflora before they can be ab- absorption occurs in the small intestine, and the efficiency of
sorbed. When the flora is involved, the efficiency of absorption absorption is higher than that for the aglycone itself (93, 94). The
is often reduced because the flora also degrades the aglycones underlying mechanism by which glucosylation facilitates quer-
that it releases and produces various simple aromatic acids in the cetin absorption has been partly elucidated. Hollman et al sug-
process. During the course of absorption, polyphenols are con- gested that glucosides could be transported into enterocytes by
jugated in the small intestine and later in the liver. This process the sodium-dependent glucose transporter SGLT1 (93). They
mainly includes methylation, sulfation, and glucuronidation. could then be hydrolyzed inside the cells by a cytosolic
This is a metabolic detoxication process common to many xe- ␤-glucosidase (95). Another pathway involves the lactase phlo-
nobiotics that restricts their potential toxic effects and facilitates ridzine hydrolase, a glucosidase of the brush border membrane of
their biliary and urinary elimination by increasing their hydro- the small intestine that catalyzes extracellular hydrolysis of some
philicity. The conjugation mechanisms are highly efficient, and glucosides, which is followed by diffusion of the aglycone across
aglycones are generally either absent in blood or present in low the brush border (96). Both enzymes are probably involved, but
concentrations after consumption of nutritional doses. Circulat- their relative contribution for the various glucosides remains to
ing polyphenols are conjugated derivatives that are extensively be clarified. Quercetin 3-glucoside, which is not a substrate for
bound to albumin. Polyphenols are able to penetrate tissues, cytosolic ␤-glucosidase, is certainly absorbed after hydrolysis by
particularly those in which they are metabolized, but their ability lactase phloridzine hydrolase, at least in rats, whereas hydrolysis
to accumulate within specific target tissues needs to be further of quercetin 4'-glucoside seems to involve both pathways (97,
investigated. Polyphenols and their derivatives are eliminated 98). In humans, whatever the mechanism of deglucosylation, the
chiefly in urine and bile. Polyphenols are secreted via the biliary kinetics of plasma concentrations are similar after ingestion of
route into the duodenum, where they are subjected to the action quercetin 3-glucoside or quercetin 4'-glucoside (99). Isoflavone
of bacterial enzymes, especially ␤-glucuronidase, in the distal glycosides present in soya products can also be deglycosylated
segments of the intestine, after which they may be reabsorbed. by ␤-glucosidases from the human small intestine (95, 96). How-
This enterohepatic recycling may lead to a longer presence of ever, the effect of glucosylation on absorption is less clear for
polyphenols within the body. isoflavones than for quercetin. Aglycones present in fermented
soya products were shown to be better absorbed than were the
Intestinal absorption and metabolism glucosides ingested from soybeans (100). However, a dose or
Much about the intestinal mechanisms of the gastrointestinal matrix effect may explain the difference in absorption observed
absorption of polyphenols remains unknown. Most polyphenols in this first study. Setchell et al (101) showed that when pure
are probably too hydrophilic to penetrate the gut wall by passive daidzein, genistein, or their corresponding 7-glucosides were
diffusion, but the membrane carriers that could be involved in administered orally to healthy volunteers, a tendency toward
polyphenol absorption have not been identified. To date, the greater bioavailability was observed with the glucosides, as mea-
unique active transport mechanism that has been described is a sured from the area under the curve of the plasma concentrations:
Naѿ-dependent saturable transport mechanism involved in cin- 2.94, 4.54, 4.52, and 4.95 ␮g · h/mL for daidzein, genistein,
namic and ferulic acid absorption in the rat jejunum (84). daidzin, and genistin, respectively. However, in another human
In foods, all flavonoids except flavanols are found in glyco- study, peak plasma concentrations were markedly higher after
sylated forms, and glycosylation influences absorption. The fate aglycone ingestion than after glucoside ingestion, and this effect
of glycosides in the stomach is not clear. Experiments using was observed with low or high single doses and after long-term
surgically treated rats in which absorption was restricted to the intakes (102). In addition, hydrolysis of isoflavone glycosides
stomach showed that absorption at the gastric level is possible for into aglycones in a soy drink did not change the bioavailability of
some flavonoids, such as quercetin and daidzein, but not for their the isoflavones in humans (103). No data are available for other
glycosides (85, 86). Most of the glycosides probably resist acid polyphenols in humans, but note that in rats, no enhancement of
734 MANACH ET AL
absorption was observed with glucosylation of naringenin and compounds are rapidly absorbed from the small intestine and are
phlorizin (104, 105). Furthermore, diglucosylation of the lignan conjugated and, in particular, glucuronidated in the same way
secoisolariciresinol decreases its absorption (106). that flavonoids are (54, 121). However these compounds are
Glycosylation does not influence the nature of the circulating naturally esterified in plant products, and this impairs their ab-
metabolites. Intact glycosides of quercetin, daidzein, and sorption. Human tissues (intestinal mucosa, liver) and biological
genistein were not recovered in plasma or urine after ingestion as fluids (plasma, gastric juice, duodenal fluid) do not possess es-
pure compounds or from complex food (107–110). For fla- terases capable of hydrolyzing chlorogenic acid to release caffeic
vanones, only trace amounts of glycosides have been detected in acid (122–124). This has also been observed in rats (125, 126).
human urine, corresponding to 0.02% of the administered dose of Only the colonic microflora would be capable of carrying out this
naringin (111). But a very high dose (500 mg) of the pure com- hydrolysis, and some of the bacterial strains involved have been
pound was administered in this study, and some metabolic pro- identified (127). Consequently, as observed for flavonoid gly-
cesses may have been saturated by this nonnutritional intake. cosides that must be hydrolyzed by the microflora, the efficiency
Anthocyanins constitute an exception, because intact glycosides of absorption of phenolic acids is markedly reduced when they
are the major circulating forms. The explanation for this may lie

are present in the esterified form rather than in the free form (123,
in the instability of these molecules in the aglycone form or in a
125, 128). In patients who have undergone colonic ablation,
specific mechanism of absorption or metabolism for anthocya-
caffeic acid was much better absorbed than was chlorogenic acid:
nins. Passamonti et al (112) have proposed that glycosides of
11% and 0.3% of the ingested doses were excreted in urine,
anthocyanins may be transported by bilitranslocase at the gastric
level, bacause they have been shown to be good ligands for this respectively (123). Similarly, when chlorogenic acid was given
carrier. They could also be directly converted into glucuronides by gavage to rats, no intact compound was detected in plasma in
by a UDP glucose dehydrogenase as suggested by Wu et al (113). the following 6 h, and the maximum concentrations of metabo-
Proanthocyanidins differ from most other plant polyphenols lites obtained after administration of caffeic acid in the same
because of their polymeric nature and high molecular weight. conditions were 100-fold those of the metabolites (various glu-
This particular feature should limit their absorption through the curonidated or sulfated derivatives of caffeic and ferulic acids)
gut barrier, and oligomers larger than trimers are unlikely to be obtained after chlorogenic acid administration (125). Surpris-
absorbed in the small intestine in their native forms. In vitro ingly, the plasma concentrations were maximal only 30 min after
experiments using single layers of Caco-2 cells as a model of gavage, which may seem inconsistent with hydrolysis of chlo-
absorption in the small intestine showed that only the dimers and rogenic acid in the cecum. The same observation was made in a
trimers of flavanols are able to cross the intestinal epithelium human study. When volunteers ingested coffee containing high
(114). Procyanidin B2 is very poorly absorbed in rats, whereas amounts of esterified phenolic acids but no free caffeic acid, the
procyanidin B3 is not absorbed (115, 116). The possibility that peak plasma concentration of caffeic acid was observed only 1 h
procyanidin oligomers are hydrolyzed to mixtures of flavanol after ingestion of the coffee (129). In this study, the alkaline
monomers and dimers in acidic conditions was suggested by hydrolysis of coffee showed that chlorogenic acid represented
Spencer et al from in vitro experiments (117). However, purified only 30% of the bound caffeic acid. Thus, a possible explanation
procyanidin dimer B3, as well as grapeseed proanthocyanidins is that other forms of caffeic acid present in coffee may have been
having a higher degree of polymerization, are not degraded to hydrolyzed in the upper part of the gut. Furthermore, the modes
more readily absorbable monomers in rats (116). The stability of of administration used in both studies, ie, direct stomach intuba-
proanthocyanidins was investigated in humans by regular anal- tion in the rat study and ingestion of coffee alone by fasted
ysis of gastric juice sampled with a gastric probe after ingestion volunteers in the second study, might allow a rapid transit to the
of a proanthocyanidin-rich cocoa beverage (118). This study colon and explain the rapid kinetics of appearance of plasma
confirmed that proanthocyanidins are not degraded in the acidic metabolites. However, these 2 studies raise doubt about the total
conditions of the stomach in vivo. A minor absorption of some inability of the tissues to hydrolyze esterified phenolic acids.
procyanidin dimers seems possible in humans. The procyanidin In addition to being esterified to simple acids, hydroxycin-
dimer B2 was detected in the plasma of volunteers after ingestion
namic acids may be bound to polysaccharides in plant cell walls;
of a cocoa beverage; however, the maximal plasma concentra-
the main example of this is esterification of ferulic acid to arabi-
tion that was reached 2 h after ingestion was much lower than that
noxylans in the outer husks of cereals. Although free ferulic acid
reached after a roughly equivalent intake of epicatechin (0.04
is reported to be rapidly and efficiently absorbed (up to 25%)
compared with 6.0 ␮mol/L) (119). Proanthocyanidins, which are
among the most abundant dietary polyphenols, are very poorly from tomatoes in humans (130), its absorption after ingestion of
absorbed and may exert only local activity in the gastrointestinal cereals is expected to be much lower because of this esterifica-
tract or activity mediated by phenolic acids produced through tion. Ferulic acid metabolites recovered in the urine of rats rep-
microbial degradation. Their local action may nevertheless be resent only 3% of the ingested dose when ferulic acid is provided
important because the intestine is particularly exposed to oxidiz- as wheat bran, whereas the metabolites represent 50% of the dose
ing agents and may be affected by inflammation and numerous when ferulic acid is provided as a pure compound (131). Another
diseases such as cancer (120). Polyphenol concentrations in the study showed that feruloyl esterases are present throughout the
colon can reach several hundred micromoles per liter (83), and entire gastrointestinal tract, particularly in the intestinal mucosa,
together with a few carotenoids, polyphenols constitute the only and that some of the ester bonds between ferulic acid and poly-
dietary antioxidants present in the colon, because vitamins C and saccharides in cell walls may thus be hydrolyzed in the small
E are absorbed in the upper segments of the intestine. intestine (126). However, the role of feruloyl esterases seems to
Despite the scarcity of studies performed on the bioavailability be very limited, and absorption occurs mainly in the colon after
of hydroxycinnamic acids, when ingested in the free form, these hydrolysis by enzymes of bacterial origin. Xylanases degrade the

parietal polymers to small, soluble feruloyl oligosaccharides, acids (8, 142). Aglycones are split by the opening of the hetero-
and then esterases release free ferulic acid. Note that diferulic cycle at different points depending on their chemical structure:
acids from cereal brans have been shown to be absorbed in rats flavonols mainly produce hydroxyphenylacetic acids, flavones
(132). and flavanones mainly produce hydroxyphenylpropionic acids,
The effects of the food matrix on the bioavailability of poly- and flavanols mainly produce phenylvalerolactones and hy-
phenols have not been examined in much detail. Direct interac- droxyphenylpropionic acids. These acids are further metabo-
tions between polyphenols and some components of food, such lized to derivatives of benzoic acid. The microbial metabolites
as binding to proteins and polysaccharides, can occur, and these are absorbed and conjugated with glycine, glucuronic acid, or
interactions may affect absorption. Furthermore, more indirect sulfate. The cleavage and metabolic pathways are well estab-
effects of the diet on various parameters of gut physiology (pH, lished in animals, and the influence of chemical structure on
intestinal fermentations, biliary excretion, transit time, etc) may degradation is known. For example, the absence of a free hy-
have consequences on the absorption of polyphenols. Enzymes droxyl in position 5, 7, or 4' protects the compound from cleavage
and carriers involved in polyphenol absorption and metabolism (143). However, data are still limited in humans, so it is possible
may also be induced or inhibited by the presence of some mi- that new microbial metabolites will be identified. Interindividual

cronutrients or xenobiotics. Interactions with milk proteins were variations and the influence of the microflora composition and of
considered first because Serafini et al (133) reported that addition the usual diet on microbial metabolite production have to be
of milk to black tea abolished the increase in antioxidant potential evaluated. Recent studies have shown that plasma concentrations
that was observed when tea was consumed without milk. How- and urinary excretion of microbial metabolites in humans can be
ever, subsequent studies showed that addition of milk to black or higher than those of tissular metabolites, especially for polyphe-
green tea had no effect on the bioavailability of catechins, quer- nols such as wine polyphenols that are not easily absorbed (128,
cetin, or kaempferol in humans (134, 135). Some investigators 144, 145). Thus, the identification and quantification of micro-
have speculated that the presence of alcohol in red wine could bial metabolites constitute an important field of research. Some
improve the intestinal absorption of polyphenols by increasing microbial metabolites may have a physiologic effect; for exam-
their solubility. Ethanol was shown to enhance the absorption of ple, hydroxyphenylacetic acids have been suggested to inhibit
quercetin in rats, but only when present at a concentration too platelet aggregation (146). Besides, among the wide array of
high to be attained in the diet (쏜30%, by vol) (136). In humans, aromatic acids with low molecular weight, some may be used as
plasma concentrations of catechin metabolites were similar after biomarkers for polyphenol intake. An association between poly-
consumption of red wine or dealcoholized red wine (137). Yet, phenol intake and the amount of excreted hippuric acid was
20% more catechin metabolites were excreted in urine after red found after consumption of black tea or a crude extract from
wine intake than after dealcoholized red wine intake, which in- Equisenum arvense (147, 148). However, hippuric acid is not a
dicates a possible role of ethanol in enhancing the rate of poly- degradation product of catechin and can be derived from sources
phenol elimination, perhaps by a diuretic effect (138). On the other than polyphenols, such as quinic acid and the aromatic
other hand, tartaric acid, which is a major organic acid in wine, amino acids; thus, it is not a suitable biomarker of polyphenol
was shown to enhance the absorption of catechin in rats (139). intake (144). 3-Hydroxyhippuric acid may be a more valid
Existing data do not suggest a marked effect of the various diet biomarker (124).
components on polyphenol bioavailability. The absorption of Specific active metabolites are produced by the colonic mi-
quercetin, catechin, and resveratrol in humans was recently croflora. This is the case with lignans from linseed, which are
shown to be broadly equivalent when these polyphenols were metabolized to enterolactone and enterodiol, which have agonis-
administered in 3 different matrices: white wine, grape juice, and tic or antagonistic effects on estrogens (149, 150). Similarly,
vegetable juice (140). According to Hendrich (141), neither the equol produced from soya daidzein appears to have phytoestro-
background diet or type of soy food nor the presence of 40 g genic properties equivalent to or even greater than those of the
wheat fiber significantly alters the apparent absorption of isofla- original isoflavone (151, 152). There is a great interindividual
vones. However, more studies are needed, especially on dietary variability in the capacity to produce equol. Only 30-40% of the
fiber. Dietary fiber is generally associated with polyphenols in occidental people excrete significant quantities of equol after
plant foods and stimulates intestinal fermentation, which could consumption of isoflavones, and these persons are called “equol
influence the production of particular microbial metabolites. Ad- producers” (152, 153). The corresponding percentage among
ministration of polyphenols without a food matrix could mark- Asian populations is unknown, but a recent study suggested that
edly affect their bioavailability. With regard to flavonols, much the percentage in Japanese men could be as high as 60% (154).
higher plasma concentrations were achieved when quercetin glu- The ability or inability of persons to produce equol seems to
cosides were administered to fasted volunteers in the form of a remain the same for at least several years (152, 155). The com-
water-alcohol solution (up to 5 ␮mol/L) (99) than when an equiv- position of the intestinal flora plays a major role. Inoculation of
alent quantity was ingested with foods such as onions, apples, or germ-free rats with human flora from equol producers confers on
a complex meal (0.3– 0.75 nmol/L) (92, 107). This suggests that these rats the capacity to produce this metabolite, whereas col-
the consumption of any food may limit polyphenol absorption onization with flora from non– equol producers leaves the rats
and that high plasma concentrations would be obtained only if incapable of producing equol (156). Equol is not recovered in
supplements were taken separately from meals. plasma from infants who are fed soy-based formulas, which
suggests that the bacteria responsible for its production are not
The role of the colonic microflora developed in the first months of life (157). Three strains of
Polyphenols that are not absorbed in the small intestine reach bacteria are reportedly able to convert pure daidzein to equol in
the colon. The microflora hydrolyzes glycosides into aglycones vitro: Streptococcus intermedius ssp., Ruminococcus productus
and extensively metabolizes the aglycones into various aromatic spp., and Bacteroides ovatus spp. (158). The possibility of con-
736 MANACH ET AL
verting nonproducers to producers by food must be investigated. lapping substrate specificities and different tissue distribution
Equol producers tend to consume less fat and more carbohydrates (174). The subfamily of UDP-glucuronosyltransferases called
as percentages of energy than do non– equol producers (159, UGT1A that is localized in the intestine probably plays a major
160). Consumption of dietary fiber has been suspected to affect role in the first-pass metabolism of polyphenols. These isoen-
equol production by favoring the growth of certain bacterial zymes have a wide polymorphic expression pattern that could
species. However, supplementation with 16 g wheat bran/d did result in a high interindividual variability in polyphenol glucu-
not increase equol production in young women (159). In mice, ronidation. The active isoenzymes of the 1A class seem to differ
equol production increased with the addition of fructooligosac- according to the polyphenol considered (173, 175). In vitro glu-
charides in the diet (161). But this result needs to be confirmed in curonidation of quercetin, luteolin, or isorhamnetin by rat or
humans because of obvious interspecies differences, which are human microsomes in the intestine and the liver showed that,
shown by the fact that rats are constitutive equol producers. The even if the nature of the glucuronides formed is constant, the
effect of adaptation of the intestinal flora to the consumption of proportion of the various metabolites varies widely depending on
isoflavones is not clear. Lu et al (162) observed an increase in the species and organ (173, 176, 177). The highest rate of con-
equol production after 1 mo of isoflavone consumption. Some jugation is observed at the 7-position, and the 5-position does not

non-equol-producing women even acquired the ability to pro- appear to be a site for glucuronidation. For most flavonoids, a
duce equol after consuming soymilk for 2 wk (153). But Lampe significant proportion of the glucuronides that are formed in the
et al (163) did not observe any effect on equol production of a intestinal mucosa are secreted back to the gut lumen, which
1-mo adaptation in comparison with a 4-d supplementation. A reduces net absorption (178, 179). The transporter multiresistant
more comprehensive knowledge of the factors that may influ- protein 2 (MRP2) or the P-glycoprotein may be involved in this
ence equol production is all the more essential because Setchell efflux (180, 181). The proportion of glucuronides that are se-
et al (152) convincingly proposed that equol producers might creted toward the mucosal side depends markedly on the struc-
gain more benefits from soya consumption than would nonpro- ture of the polyphenol (0 –52% of the initial dose) (182). Intes-
ducers. tinal excretion of glucuronides does not occur with catechin and
ferulic acid, which indicates that this is not a mechanism of
Conjugation and nature of metabolites elimination for all polyphenols (131, 168, 182).
Once absorbed, polyphenols are subjected to 3 main types of The metabolic fate in the liver of the conjugates that are pro-
conjugation: methylation, sulfation, and glucuronidation. duced in the intestine is not yet clear. After penetration into
Catechol-O-methyl transferase catalyzes the transfer of a methyl HepG2 cells, quercetin 7-glucuronide and quercetin 3-O-
group from S-adenosyl-L-methionine to polyphenols having an glucuronide undergo 2 types of metabolism: methylation of the
o-diphenolic (catechol) moiety. Such a reaction is well known for catechol and deglucuronidation followed by 3'-sulfation (183).
quercetin, catechin, caffeic acid, and luteolin, and Wu et al (113) However, in the same conditions, quercetin 4'-glucuronide is not
recently showed for the first time the methylation of cyanidin to metabolized. This could result from a lower rate of penetration
peonidin in humans. The methylation generally occurs predom- into the cells or a lower affinity of the metabolizing enzymes for
inantly in the 3' position of the polyphenol, but a minor propor- this substrate. A complex set of conjugating enzymes and carrier
tion of 4'-O-methylated product is also formed. Note that a sub- systems is probably involved in the regulation of uptake and the
stantial amount of 4'-methylepigallocatechin was detected in production and release of the various polyphenol metabolites by
human plasma after ingestion of tea (164, 165). Catechol-O- the hepatocytes, as shown for other conjugates (184, 185). The
methyl transferase is present in a wide range of tissues. Its ac- activity of these enzymes and carrier systems may depend on the
tivity is highest in the liver and the kidneys (166, 167) although nature of the polyphenol and may be influenced by genetic poly-
significant methylation was reported for catechin in the small morphisms that lead to important interindividual differences in
intestine of rats (168). Sulfotransferases catalyze the transfer of the capacity to metabolize polyphenols.
a sulfate moiety from 3'-phosphoadenosine-5'-phosphosulfate to The relative importance of the 3 types of conjugation (meth-
a hydroxyl group on various substrates (steroids, bile acids, poly- ylation, sulfation, and glucuronidation) appears to vary accord-
phenols, etc). Neither the isoforms that are specifically involved ing to the nature of the substrate and the dose ingested. Sulfation
in the conjugation of polyphenols nor the positions of sulfation is generally a higher-affinity, lower-capacity pathway than is
for the various polyphenols have yet been clearly identified, but glucuronidation, so that when the ingested dose increases, a shift
sulfation clearly occurs mainly in the liver (166, 169). UDP- from sulfation toward glucuronidation occurs (186). The balance
glucuronosyltransferases are membrane-bound enzymes that are between sulfation and glucuronidation of polyphenols also
located in the endoplasmic reticulum in many tissues and that seems to be affected by species, sex, and food deprivation (187).
catalyze the transfer of a glucuronic acid from UDP-glucuronic Moreover, inhibition of methylation by a specific inhibitor shifts
acid to steroids, bile acids, polyphenols, and thousands of dietary metabolism of quercetin glucuronides toward sulfation in
constituents and xenobiotics. The presence of glucuronidated HepG2 cells (183). Regardless of the respective contributions of
metabolites in the mesenteric or portal blood after perfusion of methylation, sulfation, and glucuronidation, in general, the ca-
polyphenols in the small intestine of rats shows that glucuronida- pacity for conjugation is high. The concentration of free aglycone
tion of polyphenols first occurs in the enterocytes before further is usually very low in plasma after the intake of a nutritional dose,
conjugation in the liver (170 –172). This is probably the case in except for tea catechins (up to 77% for epigallocatechin gallate)
humans as well, because in humans the in vitro glucuronidation (164). Saturation of the conjugation processes has been observed
of quercetin and luteolin by microsomes from the intestine is in rats administered high doses and rats given an acute supply of
markedly higher than that by microsomes from the liver (173). polyphenols by gavage (166, 170). Competitive inhibition of
About 15 isoforms of UDP-glucuronosyltransferases have been conjugation could also occur in the presence of various polyphe-
identified in humans, and these isoforms have broad and over- nols and xenobiotics in the intestine, but it has never been studied.

In these conditions, significant amounts of free aglycones could nols is unclear. Does the bound ligand have some biological
circulate in blood, probably with biological effects different from activity, or does the polyphenol have to be in the free form to be
those of conjugated metabolites. active? Dangles et al (195) showed that the catechol moiety of
Identification of circulating metabolites has been undertaken albumin-bound quercetin remains accessible to oxidizing agents
for only a few polyphenols. This identification must include not such as periodate. If this key structural element of quercetin is
only the nature and number of the conjugating groups but also the also accessible to free radicals, this suggests that quercetin could
positions of these groups on the polyphenol structure because exert its antioxidant activity even when it is bound to albumin.
these positions can affect the biological properties of the However, the biological properties of polyphenols are certainly
conjugates (176). After consumption of onions containing not limited only to their antioxidant capacity; thus, binding to
glucosides of quercetin, the major circulating compounds in albumin may have a considerable effect.
human plasma were identified as quercetin 3-O-glucuronide, The partitioning of polyphenols and their metabolites between
3'-O-methylquercetin 3-O-glucuronide, and quercetin 3'-O- aqueous and lipid phases is largely in favor of the aqueous phase
sulfate (188). However, analysis by liquid chromatography– because of their hydrophilicity and binding to albumin. How-
tandem mass spectrometry of human plasma samples obtained ever, in some lipophilic membrane models, some polyphenols

in very similar conditions did not confirm the presence of penetrate the membrane to various extents (198 –202). Quercetin
sulfated quercetin (109). For other polyphenols, only scarce showed the deepest interaction, probably because of its ability to
data on the proportions of the various types of conjugates and assume a planar conformation (203). At physiologic pH, most
the percentages of free forms in plasma are available (101, polyphenols interact with the polar head groups of phospholipids
164, 175, 189 –192). The main circulating compounds are at the membrane surface via the formation of hydrogen bonds
generally glucuronides. that involve the hydroxyl groups of the polyphenols (204). A high
number of hydroxyl groups on the polyphenol structure and an
Plasma transport and partitioning into lipid structures increase in pH that leads to deprotonation of the hydroxyl groups
Polyphenol metabolites are not free in the blood. In vitro would thus enhance interactions between the polyphenols and
incubation of quercetin in normal human plasma showed that the membrane surface. This adsorption of polyphenols probably
quercetin is extensively bound to plasma proteins (99% for con- limits the access of aqueous oxidants to the membrane surface
centrations up to 15 ␮mol/L), whereas binding to VLDL is not and their initial attack on that surface.
significant (쏝0.5%) (193). Metabolites of quercetin are also LDL is made up of lipophilic structures that, once oxidized,
extensively bound to plasma proteins in the plasma of rats fed a participate in the etiology of atherosclerosis. Many studies have
quercetin-enriched diet (88). Albumin is the primary protein shown that various polyphenols have the ability to protect LDL
responsible for the binding. The affinity of polyphenols for al- from oxidation. However, a very small proportion of plasma
bumin varies according to their chemical structure. Kaempferol polyphenols are in fact associated with the LDL fraction after
and isorhamnetin, which differ from quercetin in the nature of the consumption of nutritional doses of these compounds (205, 206).
B-ring substitution, have an affinity for human serum albumin They are associated with lipoproteins only by ionic interactions
that is similar to that of quercetin (194). In contrast, substitution with charged residues on the surface of the particules. The low
of 3-OH markedly weakens binding to albumin, as shown for integration of polyphenols into LDL has been confirmed by in
rutin and isoquercitrin, the 3-O-glycosides of quercetin (195). vitro incubation experiments (207, 208). Protection probably
The effect of sulfation and glucuronidation is unknown, but it occurs at the interface between lipophilic and hydrophilic
probably depends highly on the position of substitution. Hy- phases. However, a recent study in which [3H]genistein was
droxycinnamic acids, especially ferulic and coumaric acids, have incubated in human plasma showed that genistein and its li-
a low affinity for bovine serum albumin but may have a different pophilic derivatives were incorporated into HDL and, to a lesser
affinity for albumin of human origin (196). No data are available extent, into LDL (209). These lipophilic derivatives could result
for the other polyphenols. It must be kept in mind that although from enzymatic esterification with fatty acids in plasma, as re-
the intrinsic affinity of circulating polyphenol conjugates for ported for estrogens, but further characterization of these deriv-
albumin may be much weaker than that of quercetin itself, the atives is needed.
physiologic concentration of serum albumin (앒0.6 mmol/L) is
probably large enough to allow their extensive binding. The Plasma concentrations
degree of binding to albumin may have consequences for the rate Plasma concentrations reached after polyphenol consumption
of clearance of metabolites and for their delivery to cells and vary highly according to the nature of the polyphenol and the
tissues. The conventional view is that cellular uptake is propor- food source. They are on the order of 0.3– 0.75 ␮mol/L after
tional to the unbound concentration of metabolites. Yet, varia- consumption of 80 –100 mg quercetin equivalent administered in
tions in local pH at specific sites may induce conformational the form of apples, onions, or meals rich in plant products (90, 92,
changes in albumin, which lead to dissociation of the ligand- 107). When ingested in the form of green tea (0.1– 0.7 ␮mol/L for
albumin complex. Conformational changes in albumin have an intake of 90 –150 mg), cocoa (0.25– 0.7 ␮mol/L for an intake
been shown to be induced by nonspecific interactions with var- of 70 –165 mg) (210 –213), or red wine (0.09 ␮mol/L for an
ious membranes (197). Whether such changes could facilitate the intake of 35 mg) (137), catechin and epicatechin are as effec-
cellular uptake of ligands such as polyphenol metabolites is un- tively absorbed as is quercetin. The maximum concentrations of
clear. However, incubations of quercetin in human whole blood hesperetin metabolites determined in plasma 5–7 h after con-
or in suspensions of erythrocytes in the absence of plasma pro- sumption of orange juice were 1.3–2.2 ␮mol/L for an intake of
teins suggests that binding to albumin could considerably de- 130 –220 mg (189, 214). Naringenin in grapefruit juice appears
crease the association of quercetin with these cells (193). The to be absorbed even better: a peak plasma concentration of
effect of albumin binding on the biological activity of polyphe- 6 ␮mol/L is obtained after ingestion of 200 mg. In contrast,
738 MANACH ET AL
plasma concentrations of anthocyanins are very low: peak con- zones of the brain: concentrations in the hypothalamus, hip-
centrations, which occur between 30 min and 2 h after consump- pocampus, and striatum were 10-fold those in the brainstem and
tion, are on the order of a few tens of nanomoles per liter for an cerebellum (228).
intake of 앒110 –200 mg anthocyanins (215–217). Similarly, the The nature of the tissular metabolites may be different from
intake of 앒25 mg secoisolariciresinol diglucoside in the form of that of blood metabolites because of the specific uptake or elim-
linseed produces only a slight increase (앒30 nmol/L) in plasma ination of some of the tissular metabolites or because of intra-
lignan concentrations, and this increase occurs gradually be- cellular metabolism. Youdim et al (236) showed that the uptake
tween 9 and 24 h (218). Isoflavones are certainly the best ab- of flavanone glucuronides by rat and mouse brain endothelial
sorbed flavonoids: plasma concentrations of 1.4 – 4 ␮mol/L are cultured cells is much lower than that of their corresponding
obtained between 6 and 8 h in adults who consume relatively low aglycones. In rats fed a genistein-supplemented diet, the fraction
quantities of soya derivatives supplying 앒50 mg isoflavones of genistein present in the aglycone form was much more im-
portant in several tissues than in blood. It accounted for 쏜50% of
(219 –221). This raises the question of the harmlessness of
the total genistein metabolites in mammary gland (237), uterus,
soymilk, which is consumed in large quantities by infants who
and ovary and 100% in the brain (231) and prostate (238),

are allergic to cow milk. In 4-mo-old infants, isoflavone intake
whereas it represented only 8% of the total plasma metabolites.
can reach 50 mg/d, which, when expressed relative to body
Only 2 studies reported data on polyphenol concentrations in
weight, is 5–10-fold the dose shown to exert a physiologic effect human tissues. The first study measured phytoestrogens in hu-
on the hormonal regulation of women’s menstrual cycles (222). man prostate tissue. Surprisingly, the study showed significantly
Plasma concentrations of genistein and daidzein in these infants lower prostatic concentrations of genistein in men with benign
can reach several micromoles per liter (223). prostatic hyperplasia than in those with a normal prostate,
whereas plasma genistein concentrations were higher in men
Tissue uptake with benign prostatic hyperplasia (239). In addition, concentra-
tions of enterodiol and enterolactone were higher in prostatic
Determination of the actual bioavailability of polyphenol me- tissue than in plasma, whereas the opposite was true for daidzein,
tabolites in tissues may be much more important than is knowl- genistein, and equol. In the other study, equol concentrations in
edge of their plasma concentrations. Data are still very scarce, women who ingested isoflavones were found to be higher in
even in animals. breast tissue than in serum, whereas genistein and daidzein were
When single doses of radiolabeled polyphenols (quercetin, more concentrated in serum than in breast tissue. Note that very
epigallocatechin gallate, quercetin 4'-glucoside, resveratrol) are high equol concentrations have been obtained in breast tissue,
given to rats or mice killed 1– 6 h later, radioactivity is mainly and these concentrations are equivalent to 6 ␮mol/L for an intake
recovered in blood and in tissues of the digestive system, such as the of 앒110 mg of its precursor, daidzein (240). These initial studies
stomach, intestine, and liver (224 –227). However, polyphenols show that plasma concentrations are not directly correlated with
have been detected by HPLC analysis in a wide range of tissues in concentrations in target tissues and that the distribution between
mice and rats, including brain (228, 229), endothelial cells (230), blood and tissues differs between the various polyphenols. This
heart, kidney, spleen, pancreas, prostate, uterus, ovary, mammary raises the question of whether plasma concentrations are accurate
gland, testes, bladder, bone, and skin (225, 231–233). The concen- biomarkers of exposure.
trations obtained in these tissues ranged from 30 to 3000 ng aglycone
Elimination
equivalents/g tissue depending on the dose administered and the
tissue considered. The time of tissue sampling may be of great Metabolites of polyphenols may follow 2 pathways of excre-
importance because we have no idea of the kinetics of penetration tion, ie, via the biliary or the urinary route. Large, extensively
and elimination of polyphenols in the tissues. conjugated metabolites are more likely to be eliminated in the
It is still difficult to say whether some polyphenols accumulate bile, whereas small conjugates such as monosulfates are prefer-
in specific target organs. A few studies seem to indicate that some entially excreted in urine. In laboratory animals, the relative
cells may readily incorporate polyphenols by specific mecha- magnitude of urinary and biliary excretion varies from one poly-
nisms. The endothelium is likely to be one of the primary sites of phenol to another (182). Biliary excretion seems to be a major
pathway for the elimination of genistein, epigallocatechin gal-
flavonoid action. Schramm et al (234) showed that a rapid,
late, and eriodictyol (170, 241). Biliary excretion of polyphenols
energy-dependent transport system is active in aortic endothelial
in humans may differ greatly from that in rats because of the
cells for the uptake of morin. This system may also transport
existence of the gall bladder in humans; however, this has never
other hydroxylated phenolic compounds. Microautoradiography
been examined. Intestinal bacteria possess ␤-glucuronidases that
of mice tissues after administration of radiolabeled epigallocat- are able to release free aglycones from conjugated metabolites
echin gallate or resveratrol indicated that radioactivity is un- secreted in bile. Aglycones can be reabsorbed, which results in
equally incorporated into the cells of organs (225, 227). Regional enterohepatic cycling. Pharmacokinetic studies in rats have
selectivity has also been observed in the prostate and the brain. shown a second maximum plasma concentration 앒7 h after
After 9 wk of feeding isoflavone aglycones to rats, accumulation genistein administration, which is consistent with enterohepatic
of isoflavones in the dorsolateral zone of the prostate was shown circulation (233). A second plasma peak was also observed in
to be 4-fold that in the ventral zone of this organ (235). Similarly, some human volunteers 10 –12 h after ingestion of hesperetin
after 28 d of oral administration of tangeretin, a polymethoxy- from orange juice or of isoflavones from soya (101, 189, 221).
lated flavone from Citrus, to rats, tangeretin concentrations in the Urinary excretion has often been determined in human studies.
brain were 6-fold those in other tissues (heart, lung, liver, kid- The total amount of metabolites excreted in urine is roughly
ney), and distribution of tangeretin was unequal in the various correlated with maximum plasma concentrations. It is quite high

for flavanones from citrus fruit (4 –30% of intake), especially for hydrophilic and can affect their site of action and their interac-
naringenin from grapefruit juice (111, 189, 214, 242, 243), and is tions with other antioxidants. Furthermore, their intrinsic reduc-
even higher for isoflavones: the percentages excreted are 16 – tive capacity may be changed. The antioxidant effect of conju-
66% for daidzein and 10 –24% for genistein (103, 192, 219, 221, gated derivatives of quercetin on copper ion–induced LDL
244). It may appear surprising that plasma concentrations of oxidation in vitro is about one-half that of the aglycone and is
genistein are generally higher than those of daidzein despite the dependent on the binding site of the glucuronic acid (107, 176,
higher urinary excretion of daidzein, but this can be explained by 258). Cren-Olive et al (259) also reported that the capacity of
the efficient biliary excretion of genistein. Urinary excretion 3'-O-methylcatechin and 4'-O-methylcatechin to protect LDL
percentages may be very low for other polyphenols, such as from in vitro oxidation is lower than that of catechin. However,
anthocyanins (0.005– 0.1% of intake) (113, 216, 217, 245, 246), an increase in the antioxidant capacity of plasma was observed
although Lapidot et al (247) reported elevated percentages of after the consumption of various polyphenol-rich foods, which
anthocyanin excretion (up to 5%) after red wine consumption. indirectly shows that at least some of the polyphenol metabolites
Low values could be indicative of pronounced biliary excretion retain antioxidant activity (212, 260 –264). Conjugation might
or extensive metabolism. Certain metabolites of anthocyanins enhance certain specific biological activities, as shown for some

may still be unidentified as a result of analytic difficulties with xenobiotics (265). Koga and Meydani (266) showed that plasma
these unstable compounds. Felgines et al (248) reported that the metabolites of catechin have an inhibitory effect on monocyte
major metabolites of pelargonidin 3-glucoside that are recovered adhesion to interleukin 1␤–stimulated human aortic endothelial
in human urine after strawberry intake are glucurono- and sul- cells, whereas catechin and metabolites of quercetin had no ef-
foconjugates of pelargonidin that are extensively degraded by fect. In another in vitro study, quercetin 3-O-glucuronide pre-
simple freezing of the urine samples. Urinary excretion of fla- vented vascular smooth muscle cell hypertrophy by angiotensin
vonols accounts for 0.3–1.4% of the ingested dose for quercetin II (267). However, conjugation seems instead to decrease the
and its glycosides (90, 92, 93) but reaches 3.6% when purified specific activities of polyphenols. The affinities for estrogenic
glucosides are given in hydroalcoholic solution to fasted volun- receptors of the aglycones of daidzein and genistein are 10- and
teers (99). Urinary recovery is 0.5– 6% for some tea catechins 40-fold, respectively, those of the respective glucuronides, but
(210, 249), 2–10% for red wine catechin (138), and up to 30% for the glucuronides still show weak estrogenic activity at physio-
cocoa epicatechin (190). For caffeic and ferulic acids, relative logic concentrations (268). Spencer et al (269) showed the in-
urinary excretion ranges from 5.9% to 27% (124, 130, 250) ability of 5- and 7-O-glucuronides of epicatechin to protect fi-
The exact half-lives of polyphenols in plasma have rarely been broblasts and neuronal cells from oxidative stress in vitro,
calculated with great precision but are on the order of 2 h for whereas epicatechin and methylepicatechin were protective.
compounds such as anthocyanins (217) and 2–3 h for flavanols Nevertheless, it is still difficult to draw any conclusions from the
(17, 164, 251, 252), except for epigallocatechin gallate, which is few existing studies regarding the effects of the type and position
eliminated more slowly probably because of higher biliary ex- of conjugation on the various potential activities of polyphenols.
cretion or greater complexing with plasma proteins, as described Polyphenol metabolites could also exert biological activities
for galloylated compounds (253, 254). The half-lives of isofla- after deconjugation at the cellular level. This possibility has been
vones and quercetin are on the order of 4 – 8 (25, 244, 255) and shown for sulfates and glucuronides of endogenous estrogens
11–28 (90, 92) h, respectively. This suggests that maintenance of (270, 271). Quercetin glucuronides were hydrolyzed by cell-free
high plasma concentrations of flavonoid metabolites could be extracts of human neutrophils, liver, and small intestine (272).
achieved with regular and frequent consumption of plant prod- However, the possibility of hydrolysis of flavonoid glucuronides
ucts. For instance, consumption of onions 3 times/d favors ac- inside cells has not been studied. We have seen above that the
cumulation of quercetin in plasma (256). For compounds, such as proportion of free aglycone in some tissues may be higher than
tea catechins, with rapid absorption and a short half-life, repeated that in blood, especially in the case of genistein in rats. This may
intakes must be very close together in time to obtain an accumu- be explained by specific uptake of the aglycone or intracellular
lation of metabolites in plasma (257); otherwise, plasma concen- deconjugation. This last hypothesis implies that anionic conju-
trations regularly fluctuate after repeated ingestions, and no final gates could be transported across plasma membranes via carrier
accumulation occurs (205). systems, as shown for other glucuronides (184, 273). Further-
more, ␤-glucuronidase is located in the lumen of the endoplasmic
Biological effects of polyphenol metabolites reticulum in various organs and would also have to be reached by
The biological activities of polyphenols have often been eval- polyphenol glucuronides. Note that carrier-mediated bidirec-
uated in vitro on pure enzymes, cultured cells, or isolated tissues tional transport across the membrane of the endoplasmic reticu-
by using polyphenol aglycones or some glycosides that are lum in rat hepatocytes has been described for other glucuronides,
present in food. Very little is known about the biological prop- such as estrogen glucuronides (274). Inside the endoplasmic
erties of the conjugated derivatives present in plasma or tissues reticulum, UDP-glucuronosyltransferases are present along with
because of the lack of precise identification and commercial ␤-glucuronidase. The respective Km values of these enzymes
standards. However, reflection on the antioxidative activity of toward flavonoids and their glucuronides seem to be in favor of
polyphenols suggests that the metabolism of polyphenols may glucuronidation rather than deglucuronidation at physiologic pH
have a considerable effect. For example, the hydrophobicity of values (176, 272). These results are not consistent enough to give
polyphenols is intermediate between that of vitamin C (highly a clear view of what occurs inside the cells, and additional studies
hydrophilic) and that of vitamin E (highly hydrophobic). Poly- are certainly needed. ␤-Glucuronidase is also present in the ly-
phenols are thus expected to act at water-lipid interfaces and may sosomes of various cells, from which it can be released in some
be involved in oxidation regeneration pathways with vitamins C particular situations such as oxidative stress. Its activity in-
and E. Glucuronidation and sulfation render polyphenols more creases in some physiopathologic states, such as inflammation,
740 MANACH ET AL
cancer, and AIDS (275, 276). Luteolin 7-O-glucuronide is hy- tified but are well absorbed. Intakes of monomeric flavonols,
drolyzed into aglycone by lysosomal ␤-glucuronidase released flavones, and flavanols are relatively low, and plasma concen-
from neutrophils after induction of inflammation and in the trations rarely exceed 1 ␮mol/L because of limited absorption
plasma of rats treated with lipopolysaccharide (277). In situ de- and rapid elimination. Flavanones and isoflavones are the fla-
conjugation of polyphenol metabolites might occur only in par- vonoids with the best bioavailability profiles, and plasma con-
ticular places, such as at inflammation sites or in tumors. Situa- centrations may reach 5 ␮mol/L. However, the distribution of
tions that decrease the pH would favor deglucuronidation these substances is restricted to citrus fruit and soya. Finally,
because the activity of ␤-glucuronidase is optimal at pH 4 –5 and hydroxycinnamic acids are found in a wide variety of foods, often
is reduced 9-fold at neutral pH (275). at high concentrations, but esterification decreases their intesti-
Polyphenols may also have an indirect effect on health because nal absorption. As a general rule, the metabolites of polyphenols
they are metabolized by the same pathways as various xenobi- are rapidly eliminated from plasma, which indicates that con-
otics or endogenous hormones. Flavonoids such as quercetin and sumption of plant products on a daily basis is necessary to main-
fisetin are better substrates for catechol-O-methyl transferase tain high concentrations of metabolites in the blood.
than are its endogenous substrates, catecholamines and catechol Recent studies have greatly increased our knowledge of the

estrogens. Deregulation of the O-methylation metabolism of plasma concentrations and urinary excretion of polyphenol me-
neurotransmitters and hormones in humans is an important risk tabolites in humans. However, values for these variables do not
factor for the development of some neurodegenerative diseases, seem to be well correlated with concentrations measured in tis-
cardiovascular diseases, and hormone-dependent cancers (278). sues. Available data, essentially those obtained from animal
Thus, if confirmed in humans, the potential competitive inhibi- studies, indicate that some polyphenol metabolites may accumu-
tion of the catechol-O-methyl transferase– catalyzed late in certain target tissues rather than just equilibrate between
O-methylation of endogenous catecholamines and catechol es- blood and tissues. The metabolites present may differ between
trogens by polyphenols with catechol groups may have a bene- tissues and plasma, and the nature of these metabolites needs to
ficial effect on these pathologies. Some polyphenols, such as be further elucidated. More animal studies are needed to inves-
quercetin and daidzein sulfoconjugates, are also efficient inhib- tigate intracellular metabolism and the accumulation of polyphe-
itors of sulfotransferases (279 –282) and thus may have an effect nol metabolites in specific organs. However, some important
on the function of thyroid hormones, steroids, and cat- differences may exist between animals and humans in some
echolamines (283). Whether UDP-glucuronosyltransferase is in- metabolic processes, especially the conjugation process.
duced or inhibited by polyphenols needs further investigation The notion of bioavailability integrates several variables, such
(284 –286). Interactions with drug transporters should also be as intestinal absorption, excretion of glucuronides toward the
considered (287). Isoflavones were shown to interact with trans- intestinal lumen, metabolism by the microflora, intestinal and
porters such as P-glycoprotein and canalicular multispecific or- hepatic metabolism, plasma kinetics, the nature of circulating
ganic anion transporter (288). Furthermore, some flavonoids metabolites, binding to albumin, cellular uptake, intracellular
could act as cytochrome P450 inhibitors and enhance drug bio- metabolism, accumulation in tissues, and biliary and urinary
availability. Increased concentrations of many drugs have been excretion. The difficulty lies in integrating all the information
shown with coadministrated grapefruit juice, and the effect was and relating the variables to health effects at the organ level.
attributed in part to inhibition of the intestinal cytochrome P450 These tasks are made all the more difficult because the relative
isoform 3A4 by naringenin (289). These data suggest that poly- weight of each variable may depend on the polyphenol consid-
phenols could affect the bioavailability of many carcinogens, ered. Some polyphenols may be less efficiently absorbed than are
other toxic chemicals, and therapeutic drugs by affecting the others but nevertheless reach equivalent plasma concentrations
activities of various enzymes involved in their own metabolism. because of lower secretion toward the intestinal lumen and lower
metabolism and elimination.
Better knowledge of bioavailability is essential for investigat-
CONCLUSION ing the health effects of polyphenols, whatever the approach
The many analytic studies of polyphenols in foods that have used. The fact that aglycones are not important metabolites in
been conducted to date provide a good indication of polyphenol blood because of extensive intestinal and hepatic conjugation has
distribution. Fruit and beverages such as tea, red wine, and coffee thus far been largely ignored, and many in vitro studies on the
constitute the principal sources of polyphenols, but vegetables, mechanisms of action of polyphenols continue to concentrate on
leguminous plants, and cereals are also good sources. Polyphenol aglycones or glycosides rather than on the identified metabolites,
concentrations in foods vary according to numerous genetic, often at concentrations that cannot realistically be attained in the
environmental, and technologic factors, some of which may be body. It is thus essential to confirm the effects observed with
controlled to optimize the polyphenol content of foods. The main aglycones through studies using physiologic concentrations of
tasks ahead are identifying the plant varieties that are the richest the metabolites actually found in the body. In addition, the ac-
in the polyphenols of interest, improving growing methods, and tivities of microbial metabolites must be examined in further
limiting losses during the course of industrial processing and studies to determine active structures, available concentrations,
domestic cooking. and potential modulation of the capacity of the microflora to
The health effects of polyphenols depend on both their respec- produce such metabolites. Clinical studies will be of great help in
tive intakes and their bioavailability, which can vary greatly. investigating the health effect of polyphenols, provided that
Although very abundant in our diet, proanthocyanidins are either markers of effects that are reliable and related to the prevention
very poorly absorbed or not absorbed at all, and their action is of diseases are available. Better knowledge of some variables of
thus restricted to the intestine. The same appears to be true for polyphenol bioavailability, such as the kinetics of absorption,
anthocyanins, unless some of their metabolites are not yet iden- accumulation, and elimination, will facilitate the design of such

studies. Besides, more precise data on the nature of the circulat- 20. Tomas-Barberan FA, Clifford MN. Flavanones, chalcones and dihy-
ing metabolites and on metabolism by the microflora can now be drochalcones—nature, occurence and dietary burden. J Sci Food Agric
2000;80:1073– 80.
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whether subjects are equol producers or non– equol producers naringin, heperidin, and neohesperidin in Citrus. J Agric Food Chem
seems particularly judicious in evaluating the health effects of 1987;35:1027–30.
soya isoflavone consumption. 22. Franke AA, Hankin JH, Yu MC, Maskarinec G, Low SH, Custer LJ.
Isoflavone levels in soy foods consumed by multiethnic populations in
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Polyphenols: food sources and bioavailability1,2

ABSTRACT research are to establish evidence for the effects of polyphenol

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POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 729

Source (serving size) By wt or vol By serving

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POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 731

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POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 737

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POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 739

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POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 741

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POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 743

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POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 745

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POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 747

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