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*
Laboratoire des Maladies Métaboliques et Micronutriments, INRA, 63122 Saint-Genès-Champanelle, France and
Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, U.K.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONNature of dietary polyphenolsPolyphenol content in food...Bioavailability of polyphenolsChemical and biochemical factors...ConclusionsREFERENCES |
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KEY WORDS: • polyphenol • phenolic acid • flavonoid • flavonoid glycoside • dietary intake • bioavailability • gut absorption • metabolism • colonic microflora • glucosidase • antioxidant
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONNature of dietary polyphenolsPolyphenol content in food...Bioavailability of polyphenolsChemical and biochemical factors...ConclusionsREFERENCES |
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). It may also prevent stroke (Ness and Powles 1997
), whereas wine consumption might prevent coronary heart
disease (Criqui and Ringel 1994
, Renaud and De Lorgeril 1992
). The consumption of tea may protect against
cancers (Yang and Wang 1993
) and coronary heart diseases
(Tijburg et al. 1997
), and that of soy may protect
against breast cancer and osteoporosis (Adlercreutz and Mazur 1997
). A second reason is linked to the fundamental chemical
nature of polyphenols. Polyphenols are reducing agents, and together
with other dietary reducing agents, such as vitamin C, vitamin E and
carotenoids, they protect the body’s tissues against oxidative stress.
Commonly referred to as antioxidants, they may prevent various diseases
associated with oxidative stress, such as cancers, cardiovascular
diseases, inflammation and others. Last, polyphenols are the most
abundant antioxidants in our diets.
However, the considerable diversity of their structures makes them
different from other antioxidants. Several thousands of natural
polyphenols have been identified in plants, many of them in plant foods
(Shahidi and Naczk 1995
), although only a more limited
number are at significant levels in most human diets. The chemical
structure of polyphenols will affect their biological properties:
bioavailability, antioxidant activity, specific interactions with cell
receptors and enzymes and other properties. To understand their impact
on human health, it is essential to know the nature of the main
polyphenols ingested, their dietary origin, the amounts consumed in
different diets, their bioavailability and the factors controlling
their bioavailability. These aspects are discussed in this review.
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Nature of dietary polyphenols |
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TOPABSTRACTINTRODUCTIONNature of dietary polyphenolsPolyphenol content in food...Bioavailability of polyphenolsChemical and biochemical factors...ConclusionsREFERENCES |
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).
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). Caffeic acid is also
found in the form of esters. The most frequently encountered caffeoyl
ester is chlorogenic acid, which is present in many fruits and
vegetables and in coffee. One cup of instant coffee (200 ml) contains
50–150 mg of chlorogenic acid (Clifford 1999
). Other
phenolic acid derivatives are hydrolyzable tannins. Phenolic acids are
esterified to a polyol, usually glucose. The phenolic acids are either
gallic acid in gallotannins (mango fruit) or other phenolic acids
derived from the oxidation of galloyl residues in ellagitannins
(blackberry, raspberry, strawberry, wine and brandy aged in oak
barrels) (Fig. 1)
(Clifford and Scalbert 2000
). Their
occurrence is much more limited than that of condensed tannins. Flavonoids are the most abundant polyphenols in our diets. They can be divided into several classes according to the degree of oxidation of the oxygen heterocycle: flavones, flavonols, isoflavones, anthocyanins, flavanols, proanthocyanidins and flavanones.
The occurrence of some of these flavonoids is restricted to a few
foodstuffs. The main source of isoflavones is soy, which contains ~1
mg of genistein and daidzein/g dry bean (Reinli and Block 1996
). These two isoflavones have received considerable
attention due to their estrogenic properties and their suggested role
in the prevention of breast cancer and osteoporosis (Adlercreutz and Mazur 1997
). Citrus fruits are the main food source of
flavanones. The most widely consumed is hesperidin from oranges
(125–250 mg/L of juice) (Rousseff et al. 1987
).
Other flavonoid types are common to various food sources. Quercetin,
the main flavonol in our diet, is present in many fruits and vegetables
as well as in beverages. It is particularly abundant in onions (0.3
mg/g fresh weight) (Hertog et al. 1992
) and tea (10–25
mg/L) (Hertog et al. 1993a
), which represent the main
sources of flavonols in the Dutch diet (Hertog et al. 1993b
). Flavones are less common and were identified in sweet
red pepper (luteolin) and celery (apigenin) (Hertog et al. 1992
). The main flavanols are catechins. They are very abundant
in tea. Young shoots contain 200–340 mg of catechin, gallocatechin and
their galloylated derivatives/g of dry leaves (Hara et al. 1995
). An infusion of green tea contains 1 g/L catechins
(Lee et al. 1995
). In black tea, their content is
reduced to about half this value due to their oxidation into more
complex polyphenols during fermentation (Ding et al. 1992
). Other sources are red wine (270 mg/L) (Frankel et al. 1995
) and chocolate (Arts et al. 1999
).
Proanthocyanidins are polymeric flavanols. They are present in plants
as complex mixtures of polymers with an average degree of
polymerization between 4 and 11. They are responsible for the
astringency of food and are usually present in association with
flavanol catechins. Common sources are fruits such as apple, pear and
grape, beverages such as red wine and tea, as well as chocolate
(Santos-Buelga and Scalbert 2000
). Anthocyanins are
pigments of red fruits such as cherries, plums, strawberries,
raspberries, blackberries, grapes, red currants and black currants.
Their contents vary from 0.15 (strawberries) to 4.5 mg/g (cherries) in
fresh fruit (Clifford 1996
). The average content in red
wines is 26 mg/L (Frankel et al. 1995
).
Stilbenes are not widespread in food plants. Nevertheless, one of them,
resveratrol, which was revealed during the screening of medicinal
plants, has recently received great attention for its anticarcinogenic
properties (Jang et al. 1997
) and presence in wine.
However, its very low concentration in wine (0.3–2 mg/L in red wines)
(Frankel et al. 1995
) makes the attribution of
protective effects to this molecule unlikely.
Lignans have been identified in human plasma and urine
(Adlercreutz and Mazur 1997
). Their dietary origin is
established, but their precursor in food is still unknown. The only
foods that contain considerable quantities of lignans are flaxseed and
flaxseed oil (Axelson et al. 1982
). When fed to humans
or animals, they are metabolized by the gut microflora into the
"mammalian lignans." Lignans are recognized as phytoestrogens due
to their estrogen agonist and antagonist properties.
Other dietary polyphenols are not well-defined chemical entities
and result from the oxidative polymerization of flavonoids and phenolic
acids. This may occur during ripening or food processing (grinding,
fermentation, storage, cooking and other processes). These
ill-defined phenolic compounds are the main polyphenols in black
tea and wine, particularly aged wine (Santos-Buelga and Scalbert 2000
).
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Polyphenol content in food and dietary intake |
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TOPABSTRACTINTRODUCTIONNature of dietary polyphenolsPolyphenol content in food...Bioavailability of polyphenolsChemical and biochemical factors...ConclusionsREFERENCES |
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The structural diversity of polyphenols makes the estimation of their
content in food difficult. Their average content in some food servings
is given in Table 1
. Values are only indicative because they vary widely according to
varieties: by a factor of 1:4 for flavonoids and phenolic acids in
apple (Amiot et al. 1992
, Hammerstone et al. 2000
) and in the same proportions for quercetin in yellow and
red onions (Tsushida and Svzuki 1996
). The white
varieties of onions are devoid of flavonols.
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). Similarly, polyphenols in wheat
grain are principally contained in the outer layers (aleurone cells,
seed coat) and are lost during the refining of flour (Shahidi and Naczk 1995
). Conversely, pressing may result in the
solubilization of phenolic compounds in juices otherwise present in the
unconsumed parts of the fruit. This is the case of phloridzin from
apples, which is confined to its skin and especially to the
pips (Spanos and Wrolstad 1992
).
For a number of reasons, including structural diversity, lack of
standardized analytical methods and variation of content in a
particular foodstuff, it is extremely difficult to estimate the average
daily intake of polyphenols. Most authors refer to the data published
>25 y ago (Kühnau 1976
). A daily intake of 1 g of total phenols was reported, but the methods used to obtain this
result were not detailed. In Table 1
, we present the content of various
classes of polyphenols in some foods and beverages commonly consumed in
Western diets.
Two different approaches were used to estimate polyphenols:
i) specific compounds such as chlorogenic acid in potato or
coffee, quercetin in onions or catechins in tea were estimated
individually by chromatographic techniques or ii) total
phenols were estimated by reduction of the Folin-Ciocalteu
reagent (Scalbert 1992
). Values obtained by the first
method are usually lower than those estimated by the Folin assay (Table 1)
. One reason is that some polyphenols in a given food source may
escape determination by chromatography. These can be unknown compounds,
compounds present as traces that were not considered in the
characterization of food sources or compounds that are not resolved by
chromatography, such as proanthocyanidin polymers and oxidized
polyphenols (Santos-Buelga and Scalbert 2000
) as in
apple, wine, tea or beer.
A second reason is that other reducing agents may be present in food.
Ascorbic acid also reduces the Folin reagent (1 mg is equivalent to
0.70 mg catechin often used as a standard in this assay)
(Singleton and Rossi 1965
). For example, the ascorbic
acid content of potato, tomato, onion, apple and orange juice (17, 24,
8, 12 and 54 mg/100 g fresh weight, respectively) (Souci et al. 1986
) would account for 40 and 46% of the estimated total
phenols in potato and tomato but for only 6 and 4% in
polyphenol-rich onion and apple.
It has been claimed on the basis of the Folin assay, that vegetables
(dry legumes included) provide 218 mg of total phenols/d in an average
U.S. diet (Vinson et al. 1998
). Due to the contribution
of ascorbic acid to the Folin values, the actual value should be lower.
No similar survey of total phenol content in fruits has been published.
Fruits are usually richer in polyphenols than vegetables, with total
phenol contents as high as 1–2 g/100 g fresh weight for some fruits,
such as plum and persimmon (Macheix et al. 1990
). They
often contain high amounts of proanthocyanidins (apple, plum, grape and
persimmon) and anthocyanins (cherry and other red fruits) not commonly
found in vegetables (with the exception of eggplant and dry legumes)
(Clifford 1996
, Santos-Buelga and Scalbert 2000
). The consumption of cereal products contributes to the
phenolic acid intake only when whole grains are used for their
manufacture. Chocolate is also very rich in polyphenols, and a minor
consumption of chocolate may significantly contribute to total
polyphenol intake and more particularly to the catechin (Arts et al. 1999
) and proanthocyanidin intake.
A major source of polyphenols is beverages (red wine, coffee, tea and
fruit juices). For those regularly consuming wine, coffee or tea, these
beverages will likely be the major source of polyphenols. Orange juice
is not as rich in polyphenols. Vitamin C (50 mg/100 ml) (Souci et al. 1986
) accounts for ~40% of the estimated total
phenols, with the remaining fraction corresponding to flavanones. Beer
and chocolate drinks also provide proanthocyanidins. A total phenol
content in beer of 500-1000 mg/L was measured (Leupold and Drawert 1981
), but part of this may be in fact derived from
Maillard products (Maillard and Berset 1995
).
The total polyphenol intake can be calculated from the polyphenol
contents in food and food consumption tables. Kühnau (1976)
determined a flavonoid intake in the United States of
~1 g/d, but no details were given on the methods used to determine
this figure. A person who would consume in 1 d the different
servings of foodstuffs and beverages shown in Table 1
would effectively
ingest >1 g of flavonoids and phenolic acids, regardless of the method
of polyphenol estimation used (chromatography or Folin colorimetric
assay).
Some general trends regarding the main sources of polyphenols and main
polyphenols consumed can be deduced from the data presented in Table 1
:
contribution to polyphenol intake is shared more or less equally by
food and beverages. Phenolic acids account for approximately one third
of the total phenols, and flavonoids account for two thirds. This
proportion will largely depend on the consumption of coffee
(Clifford 1999
). Heavy coffee drinkers will likely
consume more phenolic acids than flavonoids. The proportion of the
different flavonoids will also largely vary according to the foodstuffs
consumed. For persons consuming fruits or beverages such as red wine,
tea, chocolate or beer, the most abundant flavonoids will be flavanols
(catechins plus proanthocyanidins), anthocyanins and their oxidation
products (Clifford 1996
, Santos-Buelga and Scalbert 2000
). It is anticipated that taken together, they
will account for more than two thirds of the total polyphenol dietary
intake.
It appears that polyphenol intake depends to a large extent on dietary
habits and preferences. This concerns not only the consumption of
polyphenols as a whole or that of the different classes of polyphenols
but also that of each individual phenolic compound. This has been
clearly shown for quercetin, for which differences in consumption of 3
and 34 mg/d have been reported for the 10th and 90th percentiles of a
Dutch cohort (Hertog et al. 1993b
).
The evaluation of polyphenol dietary intake still lacks precision. Most
of the data on polyphenol content in food originate from scattered
sources. A more comprehensive and thorough survey of the occurrence in
food of the various types of polyphenols must be undertaken using
well-standardized methods. So far, this has been done for
flavonols, flavones (Hertog et al. 1992
and 1993b
) and
isoflavones (Reinli and Block 1996
). The intake of
flavonols (largely quercetin) and flavones by the Dutch population has
been established as 21 and 2 mg/d, respectively (Hertog et al. 1993b
). For isoflavones, an average dietary intake of 30–40
mg/d was determined for the Japanese (Kimira et al. 1998
, Wakai et al. 1999
). The consumption in
Western countries is significantly lower due to the limited consumption
of soy products (Kirk et al. 1999
).
It thus appears that the intake of flavonols, flavones and isoflavones is relatively low compared with that of phenolic acids and other flavonoids, such as proanthocyanidins, anthocyanins and oxidized polyphenols. The consumption of compounds such as quercetin and genistein does not exceed 2–4% of the total polyphenol dietary intake in Western diets. They have been the most largely studied phenolic compounds in human nutrition due to their particular biological activities. However, attention should also be paid to the other phenolic compounds that also contribute to the prevention of oxidative stress and that may have some, still ignored, more specific biological activities.
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Bioavailability of polyphenols |
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TOPABSTRACTINTRODUCTIONNature of dietary polyphenolsPolyphenol content in food...Bioavailability of polyphenolsChemical and biochemical factors...ConclusionsREFERENCES |
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, van het Hof et al. 1997
), red wine
(Duthie et al. 1998
, Fuhrman et al. 1995
,
Maxwell et al. 1994
, Serafini et al. 1998
, Whitehead et al. 1995
) or black currant
and apple juice (Young et al. 1999
). More direct
evidence on the bioavailability of a few phenolic compounds has been
obtained by measuring their concentrations in plasma and urine after
the ingestion of either pure compounds or of foodstuffs with known
content of the compound of interest.
The chemical structure of polyphenols determines their rate and extent
of intestinal absorption and the nature of the metabolites circulating
in the plasma. The few bioavailability studies in humans show that the
quantities of polyphenols found intact in urine vary from one phenolic
compound to another (Table 2
). They are particularly low for quercetin and rutin, a glycoside of
quercetin (0.3–1.4%), but reach higher values for catechins in green
tea, isoflavones in soy, flavanones in citrus fruits or anthocyanidins
in red wine (3–26%). Interindividual variations have also been
observed: 5–57% of the naringin consumed with grapefruit juice is
found in urine according to the individual (Fuhr and Kummert 1995
).
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). Absorption level of rutin, a rhamnoglucoside of
quercetin, was one half to one third that of quercetin glucoside and
required deglycosylation by the intestinal microflora before absorption
through the colon barrier (Hollman et al. 1997
).
The same bioavailability studies (Table 2)
have also shown that the
concentrations of intact flavonoids in human plasma rarely exceed 1
µM when the quantities of polyphenols ingested do not exceed those
commonly ingested with our diets. These maximum concentrations are most
often reached 1–2 h after ingestion (Aziz et al. 1998
,
Balant et al. 1979
, Hollman et al. 1996
,
Kivits et al. 1997
, Lee et al. 1995
,
Unno et al. 1996
), except for polyphenols, which are
absorbed only after partial degradation by the colon microflora. With
regard to rutin, the maximum concentration of quercetin in the plasma
is reached 9 h after ingestion (Hollman et al. 1997
). For most flavonoids absorbed in the small intestine, the
plasma concentration then rapidly decreases (elimination half-life
period of 1–2 h). This fast excretion is facilitated by the
conjugation of the aglycone to sulfate and glucuronide groups (see
later). The elimination half-life period for quercetin is much
higher (24 h) (Hollman et al. 1997
). This slow
elimination of quercetin is possibly explained by its particularly high
affinity for plasma albumin (Dangles et al. 2000
,
Manach et al. 1995
).
The maintenance of a high concentration in plasma thus requires a
repeated ingestion of the polyphenols over time, as has been observed
with volunteers consuming tea every 2 h (van het Hof et al. 1999
). However, the half-life of metabolites formed in the
colonic microflora is longer due to the long residence time of
polyphenols in the colon. More than 2 d are needed for the
phytoestrogen metabolites equol (Lu et al. 1995
),
enterodiol and enterolactone (Nesbitt et al. 1999
) to
reach the baseline concentrations in plasma and urine after the
consumption of soy milk and flaxseed, respectively.
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Chemical and biochemical factors affecting polyphenol bioavailability |
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TOPABSTRACTINTRODUCTIONNature of dietary polyphenolsPolyphenol content in food...Bioavailability of polyphenolsChemical and biochemical factors...ConclusionsREFERENCES |
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Gut absorption.
Flavonoid glycosides. Certain classes of polyphenols, such
as flavonols, isoflavones, flavones and anthocyanins, are usually
glycosylated. The linked sugar is often glucose or rhamnose but can
also be galactose, arabinose, xylose, glucuronic acid or other sugars
(Harborne 1994
). The number of sugars is most commonly
one but can be two or three, and there are several possible positions
of substitution on the polyphenol. The sugars can be further
substituted, for example, with a malonic acid group. The glycosylation
influences chemical, physical and biological properties of the
polyphenol. For example, partition coefficients measure the relative
affinity of a compound for aqueous and organic phases and are important
in determining whether a compound will passively diffuse across a
biological membrane and how they might partition in a cell. The
flavonol quercetin has a partition coefficient (log octanol/water) of
1.2 ± 0.1, whereas for a glycoside,
quercetin-3-O-rhamnoglucoside, the value is lower (0.37
± 0.06), showing greater hydrophilicity (Brown et al. 1998
).
For glycosylated polyphenols, the predicted effect of the attached moiety on passive diffusion across biological membranes suggests that removal of the hydrophilic moiety will usually be necessary for passive diffusion across the small intestine brush border to occur. Therefore, the first step of metabolism should be removal of the sugar by enzymes (glycosidases). Glycosidase activities can occur in the food itself (endogenous or added during processing) or in the cells of the gastrointestinal mucosa or can be secreted by the colon microflora.
Nonenzymatic deglycosylation in the human body, such as in the acid
conditions of the stomach, does not occur (Gee et al. 1998
). The absorption of polyphenols should therefore be
controlled by enzyme specificity and distribution. Human cells express
some ß-glucosidases, but the expression pattern is tissue specific
and often regulated during development. Polyphenols with attached
glucose (or possibly arabinose or xylose) are potential substrates for
endogenous human enzymes. Attached rhamnose is not a substrate for
human ß-glucosidases and so is only cleaved by colon microflora
-rhamnosidases.
Table 3
shows the activity of cell-free extracts from human and rat
intestine and from human liver on various polyphenol glycosides. In
humans, there is no hydrolysis of rhamnosides, suggesting that
rhamnosides are not metabolized or absorbed in these tissues. In marked
contrast, there is hydrolysis of rhamnosides in rat tissues, albeit to
a small extent. This difference is important to note when interpreting
uptake and metabolism data. Furthermore, the human small intestine
cell-free extract hydrolyzes quercetin-3-O-glucoside,
whereas the liver does not. This is ascribed to the presence of lactase
phlorizin hydrolase
(LPH),3
a ß-glucosidase, on the outside of the brush border membrane
(Day et al. 2000
). Importantly, activity of this enzyme
does not require prior absorption of the polyphenol glycoside into the
small intestine epithelial cells. The activity of the liver extracts
and of some of the small intestine is due to cytosolic ß-glucosidase
(CBG), a soluble enzyme found in many tissues. The CBG purified from
pig liver exhibited the same specificity as predicted from these
studies on human tissue (Lambert et al. 1999
) (i.e., no
activity on quercetin-3-O-glucoside).
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). However, the half-life of
each compound was similar (20–30 h) and much longer than the
half-life of commonly administered drugs. A longer half-life is
generally predicted to be the reason that some drugs exhibit a greater
efficacy than others with a shorter clearance time.
Acylated flavonoids. Flavanols such as (-)-epicatechin are
often acylated, especially by gallic acid. Galloyl substitutions result
in only a small change in the partition coefficients of flavanols and
do not influence the bioavailability of polyphenols as dramatically as
glycosylation. Flavanols appear to pass through biological membranes
and to be absorbed without deconjugation or hydrolysis. There is some
evidence for degalloylation of the flavanol (-)-epigallocatechin
gallate in saliva in humans (Yang et al. 1999
). However,
in humans given green tea, plasma levels of epigallocatechin and
epigallocatechin gallate were 0.2–2% of the ingested amount (2–3
cups of tea) depending on the human subjects but showed no difference
between galloylated and nongalloylated polyphenols (Nakagawa et al. 1997
).
Phenolic acid esters. Hydroxycinnamates such as ferulic acid
and caffeic acid are also commonly esterified to sugars, organic acids
and lipids. As an example, chlorogenic acid is caffeic acid ester
linked to quinic acid, and this compound is found at very high levels
in coffee (Clifford 1999
). These ester-linked
substitutions have a marked effect on the chemical, physical and
biological properties of the polyphenols. There are no esterases in
human tissues able to release caffeic acid from chlorogenic acid
(Plumb et al. 1999
). In agreement with this, rat small
intestine takes up only a very small amount of chlorogenic acid and
does not metabolize it (Spencer et al. 1999
).
Consequently, the only significant site for chlorogenic acid metabolism
is the colonic microflora. Similarly, ferulic or other hydroxycinnamic
acids bound to plant cell walls are also not released by mammalian
endogenous enzymes but require release by enzymes such as xylanases and
esterases of the colonic microflora (Kroon et al. 1996
).
Ellagitannins are also hydrolyzed. Ellagic acid was found in
urine and lungs of mice fed raspberry and pomegranate ellagitannins
(Boukharta et al. 1992
). However, it is not certain
whether this results from acid hydrolysis in the stomach or from the
action of the gut microflora (Daniel et al. 1991
).
Proanthocyanidins. The absorption of polyphenols also
depends on the molecular weight. Because of their large molecular
weight, proanthocyanidin polymers are likely not as easily absorbed in
the small intestine. Evidence showing the absorption of
proanthocyanidins through the gut barrier is still scarce
(Santos-Buelga and Scalbert 2000
). Experiments on the in
vitro absorption through a cell monolayer derived from the human
intestinal cell line Caco-2 showed that radiolabeled procyanidin dimer
and trimer were absorbed in contrast to procyanidin polymers having an
average degree of polymerization of 7 (Déprez 1999
). The dimer and the trimer were absorbed to a similar
extent as (+)-catechin. This must be confirmed with in vivo studies.
Deconjugation and reconjugation reactions in metabolism.
After hydrolysis of a polyphenol derivative to the free aglycone,
polyphenols are conjugated by methylation, sulfation, glucuronidation
or a combination. The steps are controlled by the specificity and
distribution of the enzymes that catalyze the reactions. The pathway
followed is common to drug metabolism, and much of the information
available on the metabolism of polyphenols derives from comparisons
with drug metabolism. The formation of conjugates can dramatically
alter the biological properties of the circulating metabolites.
However, there are significant differences between the administration
of drugs (usually in hundreds of milligrams in one concentrated dose)
and the consumption of dietary polyphenols (usually <100 mg in a
diluted dose). These differences imply that drugs can readily saturate
the metabolic pathways that rely on the supply of cofactors such as
UDP-glucuronic acid. Consequently, unconjugated drugs are often
found in the blood. On the other hand, polyphenols in food would not be
expected to saturate the metabolic pathways, and hence the circulating
species would be expected to be conjugated. When food polyphenols are
administered at pharmacological doses, they are found in the free form
in the blood (Hackett et al. 1983
). After the intake of
a large dose (2 g) of (+)-catechin, free (+)-catechin was detected in
the plasma after 30 min. After 2 h, traces of methyl-catechin
were detected, and after 8 h, 40% of the urinary catechin was
methylated, sulfated and glucuronidated. However, after the consumption
of a few milligrams of (+)-catechin, normally present in
(reconstituted) red wine, all of the circulating catechin was
conjugated and no free polyphenol was detected (Bell et al. 2000
). The dose will also determine the primary site of
metabolism. Large doses are metabolized primarily in the liver. Small
doses may be metabolized by the intestinal mucosa, with the liver
playing a secondary role to further modify the polyphenol conjugates
from the small intestine. For example, in rats, after an oral
administration of 10 mg (-)-epicatechin, the polyphenol was first
glucuronidated during intestinal absorption, followed by hepatic
sulfation and methylation, with possible further methylation in the
kidneys before excretion (Piskula and Terao 1998
). This
implies that the intestine is an important site for metabolism of
food-derived polyphenols.
Most bioavailability studies on polyphenols have measured total
polyphenols in blood after treatment with deconjugating enzymes.
However, in studies using rats or isolated rat intestine as models,
attempts to measure some conjugates have been made. In these studies,
most polyphenol glycosides are first deglycosylated and then converted
to glucuronides or sulfates with or without methylation as has been
shown for phloridzin (Mizuma and Awazu 1998
),
luteolin-7-O-glucoside (Shimoi et al. 1998
),
quercetin glycosides (Crespy et al. 1999
),
kaempferol-3-O-glucoside (Spencer et al. 1999
), genistin and daidzin (Piskula et al. 1999
). A very limited number of human studies have been carried
out in which the nature of the conjugates has been established, but
studies on quercetin and kaempferol (Erlund et al. 1999
,
Watson and Oliveira 1999
) and naringin
(naringenin-7-rhamnoglucoside) (Furuta and Kasuya 1997
)
are in support of the animal data.
However, there are some exceptions to the
deconjugation-reconjugation sequence. After feeding red fruit
anthocyanins, cyanidin-3-glucoside and cyanidin-3,5-diglucoside,
glucosides were found in human plasma (Miyazawa et al. 1999
). Quercetin-3-O-rhamnoglucoside was detected in
the plasma of volunteers fed tomatoes (Mauri et al. 1999
). There is some evidence that flavonoids from parsley are
absorbed by the rat stomach without deglycosylation (Pforte et al. 1999
). Glycosides of flavonols in onions, such as
quercetin-4'-O-glucoside and
quercetin-3'-O-methyl-4'-O-glucoside, may be
found in the plasma of volunteers with a peak of absorption of 0.5–4 h
(Aziz et al. 1998
). In a study using the isolated rat
intestine and several flavonoids and flavonoid glycosides, only
quercetin-3-O-glucoside was not fully deglycosylated and
glucuronidated, because some unchanged glycoside passed across the rat
small intestine (Spencer et al. 1999
). The
interpretation of these data is complicated by analytical difficulties
in measuring polyphenol metabolites in plasma. The existence of
glycosides in plasma needs to be clarified, because their fate within
our body should substantially differ from that of aglycones. Glucosides
would be slowly deconjugated by liver ß-glucosidases, provided that
the glucoside could enter hepatocytes. Rutinosides would be difficult
to metabolize, because there are no human -rhamnosidases and this
activity occurs only in the colon as a product of microflora. This
would mean that quercetin-3-O-rhamnoglucoside, once
absorbed, could have a long half-life.
The data available on polyphenol bioavailability are still limited
compared with that available for other components of the diet or for
drugs. Nevertheless, there is now enough information to develop a
working hypothesis which allows the prediction of uptake of polyphenols
from the diet. This hypothesis is shown in Figure 2
and facilitates the future design of experiments to test polyphenol
uptake. The model is based on data from human interventions in vivo
together with knowledge gained from enzyme specificity studies and,
when human data are missing, from animal models.
|
The metabolic steps in polyphenol metabolism are shown in Figure 3
. The individual reactions are catalyzed by enzymes, some of which show
genetic polymorphisms and are also inducible by diet. The levels and
sites of expression in human tissues determine the metabolic fate and
the pharmacokinetics of ingested polyphenols. The conjugating enzymes
have been intensely studied owing to their role in drug metabolism. The
distribution, inducibility and polymorphisms are summarized below for
each enzyme. It is important to take these factors into account in the
interpretation of future human intervention studies.
|
,
Lamarco and Glew 1986
). For example, a high specificity
was shown toward ß-glucose residues on steroids such as estradiol by
rabbit ß-glucosidase (Mellor and Layne 1971
, 1974
).
LPH (EC 3.2.1.108) is found only in the small intestine. The
physiological substrates of this mixed function ß-glycosidase are
glucosylceramides and lactosylceramides (in milk fat globules)
(Leese and Semenza 1973
). Lactose is also a substrate,
and hydrolysis by LPH is required before absorption. Five percent of
Europeans and 90% of Africans and Asians have LPH deficiency in
adulthood. (Anonymous 1991
). LPH has recently been
suggested to play an important role in metabolism of polyphenol
glucosides, because it catalyzes the hydrolysis of a wide range of
polyphenol glucosides, including quercetin-3-O-glucoside,
which is not a substrate for CBG (Day et al. 2000
).
After deconjugation, polyphenols are conjugated (Fig. 3)
.
Catechol-O-methyltransferase (COMT; EC 2.1.1.6) plays a
crucial role in the metabolism of dopamine. There is a common
functional genetic polymorphism in the COMT gene, which results in a
threefold to fourfold difference in COMT enzyme activity in humans
(Tiihonen et al. 1999
). This enzyme methylates
polyphenols and occurs in a wide range of tissues. The specificity for
polyphenols will determine which hydroxyl groups on the polyphenol ring
are methylated. However, cytochrome P450 demethylates flavonols at the
4' position and not at the 3' position; therefore, specificity of
methylation of quercetin could be defined by specificity of
demethylation by cytochrome P450, not methylation by COMT
(Nielsen et al. 1998
).
UDP glucuronosyl transferase (UDPGT, UGT; EC 2.4.1.17) catalyzes the
conjugation of polyphenols to glucuronic acid. It is situated in the
endoplasmic reticulum and exists as a large family of related enzymes.
Glucuronidation of polyphenols is predominantly by the UGT1A family,
which occurs in intestine, liver and kidney. UGT1A1, -1A3, -1A4, -1A6
and -1A9 are found in human liver; UGT1A1, -1A3, -1A4, -1A6, -1A8, -1A9
and -1A10 are expressed in human colon; and kidney is high in UGT1A9.
Human gastric epithelium expressed UGT1A7 and -1A10, but UGT1A1 shows
polymorphism and is expressed only in 29% of samples. Of all tissues,
liver has the greatest capacity for glucuronidation (Mojarrabi and MacKenzie 1998
, Strassburg et al. 1998
, 1999
). In Gilbert’s syndrome patients, glucuronidation is
reduced to 35% of normal (mild unconjugated hyperbilirubinemia); this
is found in 5% of the population. Drugs, alcohol and smoking induce
UGT1A, which creates latent Gilbert’s syndrome patients. Furthermore,
diet affects the levels of UGT (Bu-Abbas et al. 1995
,
Burchell et al. 1995
). Clearly, glucuronidation is
modified by environment, diet and genetic polymorphisms, which could
explain interindividual differences observed in the glucuronidation of
catechin (Yang et al. 1998
). The effect of
glucuronidation at exact locations on most polyphenols is not known.
The biological activities of metabolites is an important area for
further research.
Phenol sulfotransferases (P-PST, SULT; EC 2.8.2.1) are a small group of
cytosolic enzymes that are widely distributed. The endogenous substrate
are iodothyronines, although other substrates include 4-nitrophenol,
phenols and hydroxyarylamines (Coughtrie et al. 1998
). Several forms have been described. For example, SULT1A1
is high in liver, whereas SULT1A3, with a high activity on catechol
groups found in many polyphenols, is high in colon. Generally,
sulfotransferases are not induced by diet, xenobiotics or environment
(Burchell et al. 1995
). Some sulfotransferases are
inhibited by polyphenols. Quercetin inhibited human SULT1A1 with a
noncompetitive Ki value of 0.10 µM,
which was three to four orders of magnitude more potent than its
inhibition of other human sulfotransferases (Walle et al. 1995
). Dealcoholized red wine (2000-fold dilution) or a
10,000-fold dilution of strong coffee inhibited SULT1A1 by 50%
(Burchell and Coughtrie 1997
). There is no specific
genetic disease associated with sulfotransferase deficiency, although
there is extreme variation within the human population.
N-Acetyl transferase catalyzes acetylation of amines but is
unimportant for polyphenol metabolism. Some glutathione transferases,
cytochrome P450s and epoxide hydrolases show genetic polymorphisms but
generally are thought to play a minor role in polyphenol metabolism
(Wormhoudt et al. 1999
).
Metabolism by the gut microflora.
Polyphenols that are not absorbed in the stomach or small bowel will be
carried to the colon (Fig. 4
). In addition, polyphenols that are absorbed, metabolized in the liver
and excreted in the bile or directly from the enterocyte back to the
small intestine will also reach the colon but in a different chemical
form, such as a glucuronide (Fig. 4)
. The colon contains
~1012 microorganisms/cm3
and has enormous catalytic and hydrolytic potential. Deconjugation
reactions readily occur. For example,
quercetin-3-O-rhamnoglucoside and
quercetin-3-O-rhamnoside are not hydrolyzed by endogenous
human enzymes but are readily hydrolyzed by gut microflora to quercetin
by organisms such as Bacteroides distasonis
(-rhamnosidase and ß-glucosidase), B. uniformis
(ß-glucosidase) and B. ovatus (ß-glucosidase)
(Bokkenheuser et al. 1987
). Enterococcus
casseliflavus utilizes the sugar moiety of
quercetin-3-O-glucoside to give formate, acetate and lactate
but does not further metabolize the aglycone.
Quercetin-3-O-glucoside is transformed to
3,4-dihydroxyphenylacetic acid, acetate and butyrate by
Eubacterium ramulus from the human colon. The number of
bacteria able to use quercetin-3-O-glucoside was estimated
to be 107 to 109/g dry mass
(Schneider et al. 1999
).
|
). In rats, 33–44% of the dose of labeled catechin was
excreted in the bile as glucuronide conjugates, but other metabolites
[m- and p-hydroxyphenylpropionic acid,
-(3-hydroxyphenyl)-
-valerolactone and
-(3,4-dihydroxyphenyl)--valerolactone] were from gut microflora
metabolism (Das and Griffiths 1969
). A procyanidin
polymer was also shown to be degraded by a human colonic microflora
grown in vitro and anaerobically into low-molecular-weight phenolic
acids that might well be absorbed in vivo through the colon
(Déprez et al. 2000
). Bioavailability and plasma antioxidant capacity.
Plasma concentrations of the intact parent polyphenols in plasma are
often low (Table 2)
and do not account on their own for the increase in
the antioxidant capacity of the plasma. Metabolites also contribute to
increase this antioxidant capacity. Polyphenols can be partially
O-methylated in the liver: ~20% of catechin present in
plasma 1 h after consumption of red wine was
O-methylated (Donovan et al. 1999
), and
quercetin was partially methylated in humans consuming a
quercetin-rich meal (Manach et al. 1998
). Microbial
metabolites formed in the colon are also important. Equol may be three
to four times more abundant in plasma than the parent isoflavones
(Cassidy et al. 1994
). Many of the aromatic acids formed
in the colon still bear free phenolic groups and retain part of the
reducing capacity of the parent molecule.
Measurement of the total antioxidant capacity of plasma after the
consumption of polyphenol-rich food allows a comparison of their
contribution to the total plasma antioxidant capacity with that of
ascorbic acid, the other main aqueous soluble dietary antioxidant found
in our diets. The consumption of 300 ml of red wine (containing ~500
mg of polyphenols; Table 1
) was reported to induce an increase of the
plasma antioxidant capacity similar to that of 1 g of ascorbic
acid (Whitehead et al. 1995
). The plasma concentration
of ascorbic acid after the consumption of 1 g of vitamin C is 75
µM (Levine et al. 1996
). Taking into account the
relative reducing power of ascorbic acid and gallic acid (used as a
polyphenol standard) (Singleton and Rossi 1965
), the
concentration of total polyphenols in plasma after the ingestion of 500
mg of polyphenols would be 50 µM. Similar conclusions were reached by
Duthie et al. (1998)
, who observed, using the Folin
assay, an increase in the plasma polyphenol concentration of 15 µM
after the consumption of one third of this quantity of red wine (100
ml). This concentration of 50 µM after ingestion of ~500 mg of red
wine polyphenols is on average 10 times higher than the peak
concentration of the parent flavonoids (recalculated from the data of
Table 2
for an intake of 500 mg). This suggests that the metabolites
formed in our tissues or by the colon microflora significantly
contribute to the antioxidant capacity.
The polyphenol concentration in the gut should be much higher than in the plasma. For example, the dilution of 500 mg of polyphenols with the digestive bolus in the colon would give a local concentration of 3 mM. Such a high local concentration in the colon might contribute to anticarcinogenic effects.
|
Conclusions |
|---|
|
TOPABSTRACTINTRODUCTIONNature of dietary polyphenolsPolyphenol content in food...Bioavailability of polyphenolsChemical and biochemical factors...ConclusionsREFERENCES |
|---|
The intestinal absorption of polyphenols can be high. However, the plasma concentration of any individual molecule rarely exceeds 1 µM after the consumption of 10–100 mg of a single compound. Measurement of the plasma antioxidant capacity suggests that more phenolic compounds are present, largely in the form of unknown metabolites, produced either in our tissues or by the colonic microflora. It will be important to learn more about these metabolites, particularly because of their potent biological activity. Biologists should focus less on the parent compounds as they are ingested and more on the biological activities of the metabolites present in our tissues, and in particular on the conjugated analogues.
We need to better assess the role of the microflora in the bioavailability of polyphenols and to determine the proportions of the plasma phenolic metabolites absorbed by the small intestine or by the colon after transformation by the microflora. Changes in the composition of the colonic microflora could explain the large interindividual variations in bioavailability. Bioavailability is also largely influenced by the structure of polyphenols. We have just begun to understand the reason why some flavonol glycosides are better absorbed than their aglycones, but very little is known on the influence of other structural parameters.
Better knowledge of the consumption and bioavailability of dietary polyphenols will be essential in the future to properly evaluate their role in the prevention of diseases. After the consumption of a given source of polyphenols or of a given diet, we should be able to evaluate the contribution to the prevention of oxidative stress with regard to other dietary antioxidants. We should also be able to predict the tissue levels of specific metabolites that may bind to specific receptors and trigger the responses beneficial for our health. This should lead to some dietary recommendations that are optimized for particular population groups and to the design of new food products that will satisfy future needs.
|
FOOTNOTES |
|---|
2 To whom reprint requests should be addressed.
3 Abbreviations used: LPH, lactase phlorizin hydrolase; CBG, ß-glucosidase; COMT, catechol-O-methyltransferase; SULT, phenol sulfotransferases; UGT, UDP glucuronosyl transferase.
|
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|---|
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TOPABSTRACTINTRODUCTIONNature of dietary polyphenolsPolyphenol content in food...Bioavailability of polyphenolsChemical and biochemical factors...ConclusionsREFERENCES |
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M. A. Lila, G. G. Yousef, Y. Jiang, and C. M. Weaver Sorting Out Bioactivity in Flavonoid Mixtures J. Nutr., May 1, 2005; 135(5): 1231 - 1235. [Abstract] [Full Text] [PDF]
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W. Watjen, G. Michels, B. Steffan, P. Niering, Y. Chovolou, A. Kampkotter, Q.-H. Tran-Thi, P. Proksch, and R. Kahl Low Concentrations of Flavonoids Are Protective in Rat H4IIE Cells Whereas High Concentrations Cause DNA Damage and Apoptosis J. Nutr., March 1, 2005; 135(3): 525 - 531. [Abstract] [Full Text] [PDF]
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A. Scalbert, I. T Johnson, and M. Saltmarsh Polyphenols: antioxidants and beyond Am. J. Clinical Nutrition, January 1, 2005; 81(1): 215S - 217S. [Abstract] [Full Text] [PDF]
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G. Williamson and C. Manach Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies Am. J. Clinical Nutrition, January 1, 2005; 81(1): 243S - 255S. [Abstract] [Full Text] [PDF]
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B. Halliwell, J. Rafter, and A. Jenner Health promotion by flavonoids, tocopherols, tocotrienols, and other phenols: direct or indirect effects? Antioxidant or not? Am. J. Clinical Nutrition, January 1, 2005; 81(1): 268S - 276S. [Abstract] [Full Text] [PDF]
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J. O Moskaug, H. Carlsen, M. C. Myhrstad, and R. Blomhoff Polyphenols and glutathione synthesis regulation Am. J. Clinical Nutrition, January 1, 2005; 81(1): 277S - 283S. [Abstract] [Full Text] [PDF]
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L. I Mennen, R. Walker, C. Bennetau-Pelissero, and A. Scalbert Risks and safety of polyphenol consumption Am. J. Clinical Nutrition, January 1, 2005; 81(1): 326S - 329S. [Abstract] [Full Text] [PDF]
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 E. Bagli, M. Stefaniotou, L. Morbidelli, M. Ziche, K. Psillas, C. Murphy, and T. Fotsis Luteolin Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis; Inhibition of Endothelial Cell Survival and Proliferation by Targeting Phosphatidylinositol 3'-Kinase Activity Cancer Res., November 1, 2004; 64(21): 7936 - 7946. [Abstract] [Full Text] [PDF]
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V. Noe, S. Penuelas, R. M. Lamuela-Raventos, J. Permanyer, C. J. Ciudad, and M. Izquierdo-Pulido Epicatechin and a Cocoa Polyphenolic Extract Modulate Gene Expression in Human Caco-2 Cells J. Nutr., October 1, 2004; 134(10): 2509 - 2516. [Abstract] [Full Text] [PDF]
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M. Dell'Agli, A. Busciala, and E. Bosisio Vascular effects of wine polyphenols Cardiovasc Res, September 1, 2004; 63(4): 593 - 602. [Abstract] [Full Text] [PDF]
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 L. M. Butler, W.-P. Koh, H.-P. Lee, M. C. Yu, and S. J. London Dietary Fiber and Reduced Cough with Phlegm: A Cohort Study in Singapore Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 279 - 287. [Abstract] [Full Text] [PDF]
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 G. Fassina, R. Vene, M. Morini, S. Minghelli, R. Benelli, D. M. Noonan, and A. Albini Mechanisms of Inhibition of Tumor Angiogenesis and Vascular Tumor Growth by Epigallocatechin-3-Gallate Clin. Cancer Res., July 15, 2004; 10(14): 4865 - 4873. [Abstract] [Full Text] [PDF]
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V. DE FREITAS, P. DA SILVA PORTO, M. ASSUNCAO, A. CADETE-LEITE, J. P. ANDRADE, and M. M. PAULA-BARBOSA FLAVONOIDS FROM GRAPE SEEDS PREVENT INCREASED ALCOHOL-INDUCED NEURONAL LIPOFUSCIN FORMATION Alcohol Alcohol., July 1, 2004; 39(4): 303 - 311. [Abstract] [Full Text] [PDF]
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 C. Gouedard, R. Barouki, and Y. Morel Dietary Polyphenols Increase Paraoxonase 1 Gene Expression by an Aryl Hydrocarbon Receptor-Dependent Mechanism Mol. Cell. Biol., June 15, 2004; 24(12): 5209 - 5222. [Abstract] [Full Text] [PDF]
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C.-Y. Chen, P. E. Milbury, H.-K. Kwak, F. W. Collins, P. Samuel, and J. B. Blumberg Avenanthramides and Phenolic Acids from Oats Are Bioavailable and Act Synergistically with Vitamin C to Enhance Hamster and Human LDL Resistance to Oxidation J. Nutr., June 1, 2004; 134(6): 1459 - 1466. [Abstract] [Full Text] [PDF]
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C. Manach, A. Scalbert, C. Morand, C. Remesy, and L. Jimenez Polyphenols: food sources and bioavailability Am. J. Clinical Nutrition, May 1, 2004; 79(5): 727 - 747. [Abstract] [Full Text] [PDF]
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D. S. Wheeler, J. D. Catravas, K. Odoms, A. Denenberg, V. Malhotra, and H. R. Wong Epigallocatechin-3-gallate, a Green Tea-Derived Polyphenol, Inhibits IL-1{beta}-Dependent Proinflammatory Signal Transduction in Cultured Respiratory Epithelial Cells J. Nutr., May 1, 2004; 134(5): 1039 - 1044. [Abstract] [Full Text] [PDF]
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V. Tyssandier, C. Feillet-Coudray, C. Caris-Veyrat, J.-C. Guilland, C. Coudray, S. Bureau, M. Reich, M.-J. Amiot-Carlin, C. Bouteloup-Demange, Y. Boirie, et al. Effect of Tomato Product Consumption on the Plasma Status of Antioxidant Microconstituents and on the Plasma Total Antioxidant Capacity in Healthy Subjects J. Am. Coll. Nutr., April 1, 2004; 23(2): 148 - 156. [Abstract] [Full Text] [PDF]
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G. Lopez-Lopez, L. Moreno, A. Cogolludo, M. Galisteo, M. Ibarra, J. Duarte, F. Lodi, J. Tamargo, and F. Perez-Vizcaino Nitric Oxide (NO) Scavenging and NO Protecting Effects of Quercetin and Their Biological Significance in Vascular Smooth Muscle Mol. Pharmacol., April 1, 2004; 65(4): 851 - 859. [Abstract] [Full Text]
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J. L Donovan Flavonoids and the risk of cardiovascular disease in women Am. J. Clinical Nutrition, March 1, 2004; 79(3): 522 - 523. [Full Text] [PDF]
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 D.-Y. Xie, L. A. Jackson, J. D. Cooper, D. Ferreira, and N. L. Paiva Molecular and Biochemical Analysis of Two cDNA Clones Encoding Dihydroflavonol-4-Reductase from Medicago truncatula Plant Physiology, March 1, 2004; 134(3): 979 - 994. [Abstract] [Full Text] [PDF]
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 H. Ralay Ranaivo, O. Rakotoarison, A. Tesse, C. Schott, A. Randriantsoa, A. Lobstein, and R. Andriantsitohaina Cedrelopsis grevei induced hypotension and improved endothelial vasodilatation through an increase of Cu/Zn SOD protein expression Am J Physiol Heart Circ Physiol, February 1, 2004; 286(2): H775 - H781. [Abstract] [Full Text] [PDF]
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J. R. Bacon, G. Williamson, R. C. Garner, G. Lappin, S. Langouet, and Y. Bao Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes Carcinogenesis, December 1, 2003; 24(12): 1903 - 1911. [Abstract] [Full Text] [PDF]
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H. Theobald, S.-E. Johansson, and P. Engfeldt INFLUENCE OF DIFFERENT TYPES OF ALCOHOLIC BEVERAGES ON SELF-REPORTED HEALTH STATUS Alcohol Alcohol., November 1, 2003; 38(6): 583 - 588. [Abstract] [Full Text] [PDF]
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J. Frank, T. Lundh, R. S. Parker, J. E. Swanson, B. Vessby, and A. Kamal-Eldin Dietary (+)-Catechin and BHT Markedly Increase {alpha}-Tocopherol Concentrations in Rats by a Tocopherol-{omega}-Hydroxylase-Independent Mechanism J. Nutr., October 1, 2003; 133(10): 3195 - 3199. [Abstract] [Full Text] [PDF]
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J. Blumberg Proceedings of the 3rd International Scientific Symposium on Tea and Human Health: Role of Flavonoids in the Diet. September 23, 2002. J. Nutr., October 1, 2003; 133(10): 3244S - 3318S. [Full Text] [PDF]
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G. R. Beecher Overview of Dietary Flavonoids: Nomenclature, Occurrence and Intake J. Nutr., October 1, 2003; 133(10): 3248S - 3254. [Abstract] [Full Text] [PDF]
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J. P. E. Spencer Metabolism of Tea Flavonoids in the Gastrointestinal Tract J. Nutr., October 1, 2003; 133(10): 3255S - 3261. [Abstract] [Full Text] [PDF]
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 M. A. Tawab, U. Bahr, M. Karas, M. Wurglics, and M. Schubert-Zsilavecz DEGRADATION OF GINSENOSIDES IN HUMANS AFTER ORAL ADMINISTRATION Drug Metab. Dispos., August 1, 2003; 31(8): 1065 - 1071. [Abstract] [Full Text] [PDF]
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H. Carlsen, M. C. W. Myhrstad, M. Thoresen, J. O. Moskaug, and R. Blomhoff Berry Intake Increases the Activity of the {gamma}-Glutamylcysteine Synthetase Promoter in Transgenic Reporter Mice J. Nutr., July 1, 2003; 133(7): 2137 - 2140. [Abstract] [Full Text] [PDF]
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I.-W. Peng and S.-M. Kuo Flavonoid Structure Affects the Inhibition of Lipid Peroxidation in Caco-2 Intestinal Cells at Physiological Concentrations J. Nutr., July 1, 2003; 133(7): 2184 - 2187. [Abstract] [Full Text] [PDF]
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K. J Murphy, A. K Chronopoulos, I. Singh, M. A Francis, H. Moriarty, M. J Pike, A. H Turner, N. J Mann, and A. J Sinclair Dietary flavanols and procyanidin oligomers from cocoa (Theobroma cacao) inhibit platelet function Am. J. Clinical Nutrition, June 1, 2003; 77(6): 1466 - 1473. [Abstract] [Full Text] [PDF]
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H.-Y. Kim, O.-H. Kim, and M.-K. Sung Effects of Phenol-Depleted and Phenol-Rich Diets on Blood Markers of Oxidative Stress, and Urinary Excretion of Quercetin and Kaempferol in Healthy Volunteers J. Am. Coll. Nutr., June 1, 2003; 22(3): 217 - 223. [Abstract] [Full Text] [PDF]
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M.-P. Gonthier, M.-A. Verny, C. Besson, C. Remesy, and A. Scalbert Chlorogenic Acid Bioavailability Largely Depends on Its Metabolism by the Gut Microflora in Rats J. Nutr., June 1, 2003; 133(6): 1853 - 1859. [Abstract] [Full Text] [PDF]
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O. Aprikian, V. Duclos, S. Guyot, C. Besson, C. Manach, A. Bernalier, C. Morand, C. Remesy, and C. Demigne Apple Pectin and a Polyphenol-Rich Apple Concentrate Are More Effective Together Than Separately on Cecal Fermentations and Plasma Lipids in Rats J. Nutr., June 1, 2003; 133(6): 1860 - 1865. [Abstract] [Full Text] [PDF]
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 M. Vanharanta, S. Voutilainen, T. H. Rissanen, H. Adlercreutz, and J. T. Salonen Risk of Cardiovascular Disease-Related and All-Cause Death According to Serum Concentrations of Enterolactone: Kuopio Ischaemic Heart Disease Risk Factor Study Arch Intern Med, May 12, 2003; 163(9): 1099 - 1104. [Abstract] [Full Text] [PDF]
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L. Y Rios, M.-P. Gonthier, C. Remesy, I. Mila, C. Lapierre, S. A Lazarus, G. Williamson, and A. Scalbert Chocolate intake increases urinary excretion of polyphenol-derived phenolic acids in healthy human subjects Am. J. Clinical Nutrition, April 1, 2003; 77(4): 912 - 918. [Abstract] [Full Text] [PDF]
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I. Naasani, F. Oh-hashi, T. Oh-hara, W. Y. Feng, J. Johnston, K. Chan, and T. Tsuruo Blocking Telomerase by Dietary Polyphenols Is a Major Mechanism for Limiting the Growth of Human Cancer Cells in Vitro and in Vivo Cancer Res., February 15, 2003; 63(4): 824 - 830. [Abstract] [Full Text] [PDF]
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M.-P. Gonthier, V. Cheynier, J. L. Donovan, C. Manach, C. Morand, I. Mila, C. Lapierre, C. Remesy, and A. Scalbert Microbial Aromatic Acid Metabolites Formed in the Gut Account for a Major Fraction of the Polyphenols Excreted in Urine of Rats Fed Red Wine Polyphenols J. Nutr., February 1, 2003; 133(2): 461 - 467. [Abstract] [Full Text] [PDF]
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D. J O'Byrne, S. Devaraj, S. M Grundy, and I. Jialal Comparison of the antioxidant effects of Concord grape juice flavonoids {alpha}-tocopherol on markers of oxidative stress in healthy adults Am. J. Clinical Nutrition, December 1, 2002; 76(6): 1367 - 1374. [Abstract] [Full Text] [PDF]
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D. Shanmuganayagam, M. R. Beahm, H. E. Osman, C. G. Krueger, J. D. Reed, and J. D. Folts Grape Seed and Grape Skin Extracts Elicit a Greater Antiplatelet Effect When Used in Combination than When Used Individually in Dogs and Humans J. Nutr., December 1, 2002; 132(12): 3592 - 3598. [Abstract] [Full Text] [PDF]
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L. Y Rios, R. N Bennett, S. A Lazarus, C. Remesy, A. Scalbert, and G. Williamson Cocoa procyanidins are stable during gastric transit in humans Am. J. Clinical Nutrition, November 1, 2002; 76(5): 1106 - 1110. [Abstract] [Full Text] [PDF]
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F. Perez-Vizcaino, M. Ibarra, A. L. Cogolludo, J. Duarte, F. Zaragoza-Arnaez, L. Moreno, G. Lopez-Lopez, and J. Tamargo Endothelium-Independent Vasodilator Effects of the Flavonoid Quercetin and Its Methylated Metabolites in Rat Conductance and Resistance Arteries J. Pharmacol. Exp. Ther., July 1, 2002; 302(1): 66 - 72. [Abstract] [Full Text] [PDF]
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 J. Song, O. Kwon, S. Chen, R. Daruwala, P. Eck, J. B. Park, and M. Levine Flavonoid Inhibition of Sodium-dependent Vitamin C Transporter 1 (SVCT1) and Glucose Transporter Isoform 2 (GLUT2), Intestinal Transporters for Vitamin C and Glucose J. Biol. Chem., May 3, 2002; 277(18): 15252 - 15260. [Abstract] [Full Text] [PDF]
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C. Adcocks, P. Collin, and D. J. Buttle Catechins from Green Tea (Camellia sinensis) Inhibit Bovine and Human Cartilage Proteoglycan and Type II Collagen Degradation In Vitro J. Nutr., March 1, 2002; 132(3): 341 - 346. [Abstract] [Full Text] [PDF]
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D. L. McKay and J. B. Blumberg The Role of Tea in Human Health: An Update J. Am. Coll. Nutr., February 1, 2002; 21(1): 1 - 13. [Abstract] [Full Text] [PDF]
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M. S. DuPont, R. N. Bennett, F. A. Mellon, and G. Williamson Polyphenols from Alcoholic Apple Cider Are Absorbed, Metabolized and Excreted by Humans J. Nutr., February 1, 2002; 132(2): 172 - 175. [Abstract] [Full Text] [PDF]
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K. Shimoi, N. Saka, R. Nozawa, M. Sato, I. Amano, T. Nakayama, and N. Kinae Deglucuronidation of a Flavonoid, Luteolin Monoglucuronide, during Inflammation Drug Metab. Dispos., December 1, 2001; 29(12): 1521 - 1524. [Abstract] [Full Text] [PDF]
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 J. H. Weisburger Chemopreventive Effects of Cocoa Polyphenols on Chronic Diseases Experimental Biology and Medicine, November 1, 2001; 226(10): 891 - 897. [Abstract] [Full Text] [PDF]
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A. L. A. Sesink, K. A. O'Leary, and P. C. H. Hollman Quercetin Glucuronides but Not Glucosides Are Present in Human Plasma after Consumption of Quercetin-3-Glucoside or Quercetin-4'-Glucoside J. Nutr., July 1, 2001; 131(7): 1938 - 1941. [Abstract] [Full Text] [PDF]
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J. L. Donovan, V. Crespy, C. Manach, C. Morand, C. Besson, A. Scalbert, and C. Rémésy Catechin Is Metabolized by Both the Small Intestine and Liver of Rats J. Nutr., June 1, 2001; 131(6): 1753 - 1757. [Abstract] [Full Text]
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S. Deprez, C. Brezillon, S. Rabot, C. Philippe, I. Mila, C. Lapierre, and A. Scalbert Polymeric Proanthocyanidins Are Catabolized by Human Colonic Microflora into Low-Molecular-Weight Phenolic Acids J. Nutr., November 1, 2000; 130(11): 2733 - 2738. [Abstract] [Full Text] [PDF]
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