Dossier: Polyphenols: diversity and bioavailability

Absorption and metabolism of polyphenols in the gut and impact

on health
Augustin Scalbert *, Christine Morand, Claudine Manach, Christian Rmsy
Laboratoire des maladies mtaboliques et micronutriments, INRA, 63122 Saint-Genes-Champanelle, France
Received 12 May 2002; accepted 14 May 2002
Abstract
Polyphenols are the most abundant antioxidants in the human diet. They show a considerable structural diversity, which largely inuences
their bioavailability. Phenolic acids like caffeic acid are easily absorbed through the gut barrier, whereas large molecular weight polyphenols
such as proanthocyanidins are very poorly absorbed. Once absorbed, polyphenols are conjugated to glucuronide, sulphate and methyl groups
in the gut mucosa and inner tissues. Non-conjugated polyphenols are virtually absent in plasma. Such reactions facilitate their excretion and
limit their potential toxicity. The polyphenols reaching the colon are extensively metabolised by the microora into a wide array of low
molecular weight phenolic acids. The biological properties of both conjugated derivatives and microbial metabolites have rarely been
examined. Their study will be essential to better assess the health effects of dietary polyphenols. Alternatively, some health effects of
polyphenols may not require their absorption through the gut barrier. Their role as iron chelators in the gut lumen is briey discussed.
2002 ditions scientiques et mdicales Elsevier SAS. All rights reserved.
Keywords: Polyphenols; Flavonoids; Bioavailability; Metabolism
1. Introduction
Polyphenols form a very complex group of molecules
present in most plants. Several thousand molecules have
been identied in various plant species, where they have
several important functions: they inhibit the development of
pathogens and decay microorganisms, and they provide
protection against UV radiation and oxidative stress. Tan-
nins deter herbivores from feeding on astringent fruits.
Phenolic compounds such as salicylic acid also serve as
signalling molecules, and lignins provide mechanical sup-
port [50,56].
Polyphenols are regular constituents of human food. The
different classes of polyphenols and some of the most
common compounds are shown in Table 1. The average
consumption of polyphenols with the diet is 1 g/d [39,57].
The main sources are fruits, beverages such as tea, coffee,
wine and fruit juices, chocolate and, to a lesser extent,
vegetables, cereals and legume seeds. Particular types of
polyphenols may be present in a large number of foods:
tannins give astringency or bitterness to different fruits,
wine, cider and tea, and anthocyanins give colour to red
fruits such as strawberry, blackcurrant and grape. On the
other hand, others such as isoavone phytoestrogens in soya
are restricted to a given food source.
Today, dietary polyphenols receive considerable interest
for their presumed role in the prevention of various dege-
nerative diseases such as cancers and cardiovascular dis-
eases. This presumed role is based on numerous animal
studies and some clinical and epidemiological studies.
These views are strengthened by the identication of
possible mechanisms of action. These mechanisms may be
generic or specic to a particular phenolic compound:
All polyphenols are reducing agents. As such, they may
scavenge free radicals, participate in the regeneration
of other antioxidants such as vitamin E and protect cell
constituents against oxidative damage. Their chemical
* Corresponding author.
E-mail address: scalbert@clermont.inra.fr (A. Scalbert).
Biomed Pharmacother 56 (2002) 276282
2002 ditions scientiques et mdicales Elsevier SAS. All rights reserved.
PII: S 0 7 5 3 - 3 3 2 2 ( 0 2 ) 0 0 2 0 5 - 6
structures inuence their redox potential, and different
in vitro tests have been developed to compare their
antioxidant capacity. Polyphenols with two vicinal
hydroxyl groups on an aromatic residue are better free
radical scavengers than polyphenols with a single
hydroxyl group per aromatic residue [36,53]. However,
the magnitude of these differences is much lower than
the differences in gut absorption. Therefore, it is
essential to evaluate the bioavailability of the different
polyphenols to explain their respective health effects.
Some polyphenols show specic effects. Isoavone
phytoestrogens, associated with a lower risk of
hormone-dependent diseases [1], have well-
documented pseudoestrogenic properties [40]. Biologi-
cal activities are often measured on cultured cells or
isolated tissues using polyphenol compounds in their
form present in food. However, polyphenols are exten-
sively metabolised both in tissues and by the colonic
microora (Fig. 1). It is thus necessary to identify their
metabolites and test their own biological properties.
We present here some data recently obtained on the
bioavailability of polyphenols. They are discussed in view
of their biological effects and site of action.
2. Absorption of polyphenols through the gut barrier
Indirect evidence of their absorption through the gut
barrier is the increase of the antioxidant capacity of the
plasma following the consumption of polyphenol-rich
foods. This has been observed for a wide array of foodstuffs
rich in polyphenols [26,46,60,65,68,69]. Recovery in urine
after ingestion of given amounts of a particular polyphenol
allows the comparison of the bioavailability of the different
molecules present in diets (Fig. 2). The few studies in
humans show that the quantities of polyphenols found intact
in urine vary from one phenolic compound to another [57].
Among avonoids, recovery is particularly low for querce-
tin and rutin, a glycoside of quercetin (0.31.4%), but
reaches higher values (327%) for catechins in green tea,
isoavones in soya, avanones in citrus fruits or anthocya-
nidins in red wine. The highest recovery values were
observed for caffeic acid (27%) [35] and the lowest for tea
theaavins (0.0006%) [48].
This low recovery in urine for some polyphenols is not
explained by chemical degradation in the gut. Several
phenolic compounds like caffeic acid and quercetin glyco-
sides were shown to be stable in gastric or intestinal juices
[27,30,49]. The stability of proanthocyanidins was followed
in man by regularly sampling the gastric juice with a gastric
probe after ingestion of proanthocyanidin-rich chocolate.
They were not degraded in the acidic conditions of the
stomach [54]. Another explanation could be that the
polyphenols not recovered in urine were excreted in the bile
[18]. The extent of biliary excretion of polyphenols has so
far not been assessed in man.
Table 1
Classication of dietary polyphenols according to their chemical structures
Class Examples
Flavonoids
Flavonols Quercetin, kaempferol, myricetin
Flavones Luteolin, apigenin
Isoavones Daidzein, genistein
Flavanones Hesperetin, naringenin
Flavanols
Catechins (monomers) Catechin, epicatechin, gallocatechin
Proanthocyanidins (polymers) Procyanidins, prodelphinidins
Anthocyanins Cyanidin, delphinidin
Phenolic acids
Cinnamic acids Caffeic acid, ferulic acid, chlorogenic acid
Benzoic acids Gallic acid
Ellagitannins Casuarictin, sanguin H6
.
Fig. 1. Routes for dietary polyphenols and their metabolites in humans.
A. Scalbert et al. / Biomed Pharmacother 56 (2002) 276282 277
Polyphenol structure has a major impact on intestinal
absorption. The most widely discussed structural parameters
are molecular weight, glycosylation and esterication. The
high molecular weight of tea theaavins (M = 568) should
explain their low recovery in urine. Another important class
of high molecular weight polyphenols is that of proantho-
cyanidins (syn. condensed tannins). Proanthocyanidins are
avonoid polymers with varying degrees of polymerisation
and molecular weights of 578 or above. It is clear today that
they are virtually not absorbed in the gut [17,20,33].
Most avonoids, with the exception of catechins and
proanthocyanidins, are glycosylated in food, and this gly-
cosylation inuences absorption through the gut barrier. The
absorption of quercetin glycosides has been measured in
ileostomised volunteers. The absorption of the quercetin
glucosides contained in onions was higher (52%) than that
of quercetin aglycone (24%) [30]. The 3-O--glucoside of
quercetin is also better absorbed than quercetin, as shown by
the threefold higher plasma concentration 4 h after their
administration in the meal of rats [47]. In contrast, rham-
nosides of quercetin were poorly absorbed in the same
conditions. The gut absorption of these rhamnosides likely
requires deglycosylation by the colonic microora, as sug-
gested by their delayed absorption as compared to the
glycosides [31,45]. The facilitated absorption of quercetin
glucosides might be ascribed to their hydrolysis by the
lactase phlorizin hydrolase or the cytosolic -glycosidase in
the enterocyte [58]. However, the facilitation of absorption
by glycosylation observed for quercetin was not observed
for other avonoids such as naringenin [25] and phlorizin
[13].
Intestinal absorption is also inuenced by esterication
with gallic acid for catechins and with quinic acid for caffeic
acid. The recovery of galloylated catechins in human urine
after black tea consumption was about 10-fold lower than
that of non-galloylated catechins [67]. Similar results were
obtained in rats given decaffeinated green tea [12]. Caffeic
acid is also much better absorbed than chlorogenic acid, its
ester with quinic acid, common in many fruits and veg-
etables and particularly abundant in coffee. The intestinal
absorption reached 95% and only 33% for caffeic acid and
chlorogenic acid, respectively, in ileostomised human sub-
jects, and the recovery of intact chlorogenic acid in urine did
not exceed 3% of the dose ingested [49]. The amounts of
caffeic acid and its methylated metabolite, ferulic acid,
recovered in urine after administration of chlorogenic acid
by gastric intubation were 100-fold lower than those ob-
served after administration of caffeic acid [3].
Most dietary polyphenols are quickly eliminated in both
urine and bile after ingestion. In man, a post-prandial peak
is observed 12 h after ingestion of various avonols and
avanols but is longer for isoavones and other polyphenols
only absorbed after partial degradation by the colon micro-
ora [58]. With regard to rutin, the maximum concentration
of quercetin in the plasma is reached 9 h after ingestion
[32]. For most avonoids absorbed in the small intestine,
the plasma concentration then rapidly decreases (elimina-
tion half-life period of 12 h). 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 [66].
3. Polyphenol metabolism
Polyphenols are extensively metabolised either in tissues,
once they are absorbed through the gut barrier, or, for the
non-absorbed fraction and the fraction re-excreted in the
bile, by the colonic microora. All polyphenols are conju-
gated to form O-glucuronides, sulphate esters and O-methyl
ether. This conjugation rst occurs in the gut barrier, as has
been shown in experiments where quercetin was perfused in
the gut of living rats [14]. Quercetin glucuronides were
formed in the gut mucosa and secreted back either to the gut
lumen or to the serosal side. In the rat, the highest level of
glucuronyl transferase activity was observed in the intestine
[52]. These conjugates then reach the liver, where they are
further metabolised. For example, catechin is extensively
methylated in the liver. When it was perfused in the gut of
rats, only half of the catechin circulating in the mesenteric
plasma before reaching the liver was O-methylated, whereas
99% of the catechin excreted in the bile was O-methylated
[19].
Virtually all circulating polyphenols are glucuronidated
and/or sulphated, and no free aglycones are found in plasma
[6,44], except for particular avonoids such as phloretin,
which was present in both conjugated (90%) and non-
conjugated (10%) forms in rat plasma [13]. Free avonoid
aglycones were also detected in studies in which pharma-
Fig. 2. Recovery of various dietary polyphenols in urines after dietary
intake in humans. From Refs. [10,24,29,32,33,41,48,49].
278 A. Scalbert et al. / Biomed Pharmacother 56 (2002) 276282
cological doses were administered, indicating a possible
saturation of the conjugation pathways [15]. The formation
of anionic derivatives by conjugation with glucuronides and
sulphate groups facilitates their urinary and biliary excretion
and explains their rapid elimination. Although the conjuga-
tion of polyphenols has been recognised for many years,
most of the biological studies have only been carried with
polyphenol aglycones, and very little is known on the
biological properties of conjugated derivatives due to the
lack of commercial standards. Sulphate esters and glucu-
ronides were shown to retain part of their antioxidant
properties and still delay the in vitro oxidation of low
density lipoproteins [44]. However, two other studies
showed that glucuronidation of avonoids reduces their
biological potency. Daidzein and genistein glucuronides
had, respectively, a 10- and 40-fold lower affinity for
estrogenic receptors as compared to their aglycones, but still
showed weakly estrogenic activity at physiological concen-
trations [70]. An epicatechin glucuronide differed from
epicatechin and 3-O-methylepicatechin as it failed to pro-
tect primary cultures of neurones and broblasts from
damage induced by hydrogen peroxide [63]. More such
studies are needed to properly evaluate the in vivo proper-
ties of polyphenol conjugates.
The extent of polyphenol methylation should also affect
the biological properties of polyphenols. Most dietary
polyphenols have catechol groups in their structures, which
can be oxidised in vivo and form toxic quinones. Similar
quinones derived from drugs or endogenous estrogens and
catecholamines are known to be toxic for cells through the
elicitation of redox-cycling and the formation of superoxide
radical or through the reaction with nucleophilic constitu-
ents of the cell [4,5,11]. A variable proportion of the
catechol group of polyphenols such as catechin [21,52],
quercetin [47] or caffeic acid [3,8] are O-methylated in vivo.
This reaction was proposed to explain the absence of
carcinogenicity of quercetin in vivo, despite its well-
established in vitro mutagenicity [72].
Polyphenol conjugates could also exert biological activi-
ties after deconjugation at the cellular level. Phenolic
estrogen conjugates were deglucuronidated and demethy-
lated in the presence of lysosomes isolated from hamster
kidney and liver [71]. Similarly, estrone sulphates were
hydrolysed by mammary cancer cell lines [51]. They also
showed estrogenic potency with a 10-fold lower activity
than that of the non-conjugated estrone, which depended on
their deconjugation. Similarly, a glucuronide of a avone
(luteolin) was shown to be deconjugated in the plasma of
rats following induction of inammation with lipopolysac-
charide [61]. The absence of any effects of epicatechin
glucuronide on neurones and broblasts, as compared to
epicatechin aglycone [63], raises doubts on the capacity of
tissues to deconjugate polyphenols in non-inammatory
conditions.
Polyphenols, once they reach the colon, are extensively
metabolised by the microora. The avonoid glycosides
such as rutin not absorbed in the upper part of the intestinal
tract can be hydrolysed and the aglycone absorbed [7]. The
avonoid glucuronides excreted in the bile can also be
hydrolysed by the microora and the resulting aglycone
reabsorbed, thus entering into an enterohepatic cycle [2].
Aglycones are also further metabolised to a wide array of
low molecular weight aromatic acids, well absorbed through
the colonic barrier [59]. These aromatic acids are phenylva-
leric, phenylpropionic, phenylacetic and benzoic acids. It is
realised today that their yields can be high. The cumulative
urinary excretion of phenylvalerolactones, the main metabo-
lites of catechins, was higher than that of their precursors
after green tea consumption by volunteers [42]. The various
aromatic acid metabolites were estimated in the 24-h urine
of rats fed a diet supplemented with either catechin or wine
polyphenols (Gonthier et al., in preparation). The highest
yields were observed with the wine extract, rich in poorly
absorbed proanthocyanidins, which reach the colon, where
they are metabolised into phenolic acids [16]. Therefore, the
lowest is the absorption of polyphenols in the small intes-
tine; the highest should be the amount of substrates reaching
the colon and the tissue exposure to their microbial metabo-
lites.
4. Polyphenol bioavailability and health effects
Most studies on the biological properties of polyphenols
have been carried out on avonoids in their native form.
They were shown to interact with receptors, to inhibit
enzymes and to induce various responses in cultured cells.
However, many of their biological effects observed in
animal experiments or clinical studies may equally be
explained by their microbial metabolites. The biological
properties of the polyphenol microbial metabolites have
rarely been explored. Because of their phenolic nature, they
should contribute to the protection against oxidative stress.
Other reported activities include the inhibition of platelet
aggregation: the 3,4-dihydroxyphenylacetic and
4-hydroxyphenylacetic acid metabolites were more active
than their precursors rutin or quercetin [37]. Equol, a
metabolite of daidzein isoavone, showed a higher affinity
for estrogen receptors than daidzein itself [62]. The activi-
ties of the various microbial metabolites should be explored
in more detail. Just as short chain fatty acids may explain
part of the health benets of bre intake, they could be
responsible for some of the health effects of polyphenols,
particularly of those poorly absorbed through the small
intestine.
A. Scalbert et al. / Biomed Pharmacother 56 (2002) 276282 279
Alternatively, some health effects of polyphenols may
not require their absorption through the gut barrier. The
highest local concentration of polyphenols is found in the
gut lumen [55]. They may have a direct impact on the gut
mucosa and protect it against oxidative stress or the action
of carcinogens. The poorly absorbed wine and tea polyphe-
nols given orally to rats were shown to limit DNAoxidative
damage in caecal mucosal cells [28,43] and reduced the
number of tumours in rats treated with azoxymethane [9].
Polyphenols also interact with nutrients in the gut lumen.
They form stable complexes with non-heme dietary iron and
limit its absorption in the gut [34]. It is advisable for
population groups most susceptible to developing iron
deciency (infants, children and pregnant women) to avoid
an excessive intake of polyphenol-rich beverages such as
tea or coffee or to avoid their consumption together with the
meals, the source of iron. On the other hand, the consump-
tion of polyphenol-rich beverages or supplements has been
suggested as a strategy for reducing iron absorption in
patients with iron overload disorders and may provide
health benets for persons with high body iron stores. A
high level of serum ferritin, a marker of iron status, has been
associated with a lower risk of myocardial infarction in men
and in women over 55 years old [38,64]. The consumption
of black tea was shown to reverse endothelial dysfunction in
patients with coronary artery disease, a mechanism that may
reduce the risk of cardiovascular diseases [23]. Such an
effect could be explained by a reduction of iron bioavail-
ability, as similar effects on endothelial dysfunction were
observed by arterial infusion of deferoxamine, an iron
chelator that decreased the level of serum iron [22].
5. Conclusions
Much progress has been recently made in the eld of
polyphenol bioavailability. It is now essential that all
biologists integrate this knowledge in the conception of
their experiments and in the interpretation of the results.
Numerous experiments have been carried out on the effects
on cultured cells derived from inner tissues with dietary
polyphenols such as proanthocyanidins, which are not
absorbed through the gut barrier. The value of such data
must seriously be questioned. Great attention should also be
paid to the dose and mode of administration of polyphenols
when interpreting the results of animal experiments.
Not all polyphenols are equal. It is still difficult today to
determine which particular polyphenols are the most pro-
tective against the different degenerative diseases such as
cancers or cardiovascular diseases. If some generic proper-
ties of polyphenols are responsible for these effects, they
will be largely inuenced by the highly variable bioavail-
ability and, more particularly, by their absorption in the gut.
Their metabolism will also alter their specic properties and
the biological responses at the cellular levels. Much re-
search effort is still needed to evaluate the biological effects
of the conjugated derivatives and microbial metabolites of
polyphenols. This will allow the determination of the active
fraction of phenolic compounds among all those circulating
in the organism, and to determine their best dietary precur-
sors and dietary sources. This knowledge will contribute to
the development of diets with optimal health benets.
References
[1] Adlercreutz H, Mazur W. Phyto-oestrogens and Western diseases.
Ann Med 1997;29:95.
[2] Aura AM, OLeary KA, Williamson G, Ojala M, Bailey M,
Puupponen-Pimia R, et al. Quercetin derivatives are deconjugated
and converted to hydroxyphenylacetic acids but not methylated by
human fecal ora in vitro. J Agric Food Chem 2002;50:1725.
[3] Azuma K, Ippoushi K, Nakayama M, Ito H, Higashio H,
Terao J. Absorption of chlorogenic acid and caffeic acid in rats after
oral administration. J Agric Food Chem 2000;48:5496.
[4] Bachur NR, Gordon SL, Gee MV. A general mechanism for
microsomal activation of quinone anticancer agents to free radicals.
Cancer Res 1978;38:1745.
[5] Baez S, Segura-Aguilar J, Widersten M, Johansson AS, Manner-
vik B. Glutathione transferases catalyse the detoxication of oxidized
metabolites (o-quinones) of catecholamines and may serve as an
antioxidant system preventing degenerative cellular processes. Bio-
chem J 1997;324:25.
[6] Bell JR, Donovan JL, Wong R, Waterhouse AL, German JB,
Walzem RL, et al. (+)-Catechin in human plasma after ingestion of
a single serving of reconstituted red wine. Am J Clin Nutr
2000;71:103.
[7] Bokkenheuser VD, Shackleton CHL, Winter J. Hydrolysis of dietary
avonoid glycosides by strains of intestinal Bacteroides from
humans. Biochem J 1987;248:953.
[8] Booth AN, Emerson OH, Jones FT, DeEds F. Urinary metabolites of
caffeic and chlorogenic acids. J Biol Chem 1957;229:51.
[9] Caderni G, De Filippo C, Luceri C, Salvadori M, Giannini A,
Biggeri A, et al. Effects of black tea, green tea and wine extracts on
intestinal carcinogenesis induced by azoxymethane in F344 rats.
Carcinogenesis 2000;21:1965.
[10] Cassidy A, Bingham S, Setchell KD. Biological effects of a diet of
soy protein rich in isoavones on the menstrual cycle of premeno-
pausal women. Am J Clin Nutr 1994;60:333.
[11] Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I,
Higginbotham S, et al. Molecular origin of cancer: catechol
estrogen-3,4-quinones as endogenous tumor initiators. Proc Natl
Acad Sci USA 1997;94:10937.
[12] Chen LS, Lee MJ, Li H, Yang CS. Absorption, distribution, and
elimination of tea polyphenols in rats. Drug Metabol Dispos
1997;25:1045.
[13] Crespy V, Aprikian O, Morand C, Besson C, Manach C, Dem-
igne C, et al. Bioavailability of phloretin and phloridzin in rats. J
Nutr 2001;131:3227.
[14] Crespy V, Morand C, Manach C, Besson C, Demigne C, Remesy C.
Part of quercetin absorbed in the small intestine is conjugated and
further secreted in the intestinal lumen. Am J Physiol
1999;277:G120.
280 A. Scalbert et al. / Biomed Pharmacother 56 (2002) 276282
[15] Das NP. Studies on avonoid metabolism. Absorption and metabo-
lism of (+)-catechin in man. Biochem Pharmacol 1971;20:3435.
[16] Dprez S, Brzillon C, Rabot S, Philippe C, Mila I, Lapierre C, et al.
Polymeric proanthocyanidins are catabolized by a human colonic
microora into low molecular weight phenolic acids. J Nutr
2000;130:2733.
[17] Dprez S, Mila I, Huneau JF, Tom D, Scalbert A. Transport of
proanthocyanidin dimer, trimer and polymer across monolayers of
human intestinal epithelial Caco-2 cells. Antioxid Redox Signal
2001;3:957.
[18] Donovan J, Crespy V, Manach C, Morand C, Besson C, Scal-
bert A, et al. Absorption and metabolism of catechin in-situ
perfusion in the small intestine of rats. 20th International Conference
on Polyphenols. Germany: Freising; 2000. p. 317.
[19] Donovan JL, Crespy V, Manach C, Morand C, Besson C, Scal-
bert A, et al. Catechin is metabolized by both the small intestine and
the liver in rats. J Nutr 2001;131:1753.
[20] Donovan JL, Manach C, Rios L, Morand C, Scalbert A, Rmsy C.
Procyanidins are not bioavailable in rats fed a single meal containing
a grape seed extract or the procyanidin dimer B3. Br J Nutr
2002;87:299.
[21] Donovan UM, Gibson RS. Iron and zinc status of young women
aged 14 to 19 years consuming vegetarian and omnivorous diets. J
Am College Nutr 1995;14:463.
[22] Duffy SJ, Biegelsen ES, Holbrook M, Russell JD, Gokce N, Keaney
Jr JF, et al. Iron chelation improves endothelial function in patients
with coronary artery disease. Circulation 2001;103:2799.
[23] Duffy SJ, Keaney Jr JF, Holbrook M, Gokce N, Swerdloff PL,
Frei B, et al. Short- and long-term black tea consumption reverses
endothelial dysfunction in patients with coronary artery disease.
Circulation 2001;104:151.
[24] Erlund I, Meririnne E, Alfthan G, Aro A. Plasma kinetics and urinary
excretion of the avanones naringenin and hesperetin in humans
after ingestion of orange juice and grapefruit juice. J Nutr
2001;131:235.
[25] Felgines C, Texier O, Morand C, Manach C, Scalbert A,
Regerat F, et al. Bioavailability of the avanone naringenin and its
glycosides in rats. Am J Physiol Gastrointest Liver Physiol
2000;279:G1148.
[26] Fuhrman B, Lavy A, Aviram M. Consumption of red wine with
meals reduces the susceptibility of human plasma and low-density
lipoprotein to lipid peroxidation. Am J Clin Nutr 1995;61:549.
[27] Gee JM, Du Pont MS, Rhodes MJC, Johnson IT. Quercetin
glucosides interact with the intestinal glucose transport pathway.
Free Rad Biol Med 1998;25:19.
[28] Giovannelli L, Testa G, De Filippo C, Cheynier V, Clifford MN,
Dolara P. Effect of complex polyphenols and tannins from red wine
on DNA oxidative damage of rat colon mucosa in vivo. Eur J Nutr
2000;39:207.
[29] Hodgson JM, Morton LW, Puddey IB, Beilin LJ, Croft KD. Gallic
acid metabolites are markers of black tea intake in humans. J Agric
Food Chem 2000;48:2276.
[30] Hollman PCH, Devries JHM, Vanleeuwen SD, Mengelers MJB,
Katan MB. Absorption of dietary quercetin glycosides and quercetin
in healthy ileostomy volunteers. Am J Clin Nutr 1995;62:1276.
[31] Hollman PCH, Katan MB. Absorption, metabolism and health
effects of dietary avonoids in man. Biomed Pharmacother
1997;51:305.
[32] Hollman PCH, van Trijp JMP, Buysman MNCP, Gaag MSvd,
Mengelers MJB, de Vries JHM, et al. Relative bioavailability of the
antioxidant avonoid quercetin from various foods in man. FEBS
Lett 1997;418:152.
[33] Holt RR, Lazarus SA, Sullards MC, Zhu QY, Schramm DD,
Hammerstone GF, et al. Procyanidin dimer B2 (epicatechin(4b-
8)epicatechin) in human plasma after the consumption of a
avanol-rich cocoa. Am J Clin Nutr 2002 [in press].
[34] Hurrell RF, Reddy M, Cook JD. Inhibition of non-haem iron
absorption in man by polyphenolic-containing beverages. Br J Nutr
1999;81:289.
[35] Jacobson EA, Newmark H, Baptista J, Bruce WR. A preliminary
investigation of the metabolism of dietary phenolics in humans. Nutr
Rep Int 1983;28:1409.
[36] Jovanovic SV, Steenken S, Simic MG, Hara Y. Antioxidant proper-
ties of avonoids: reduction potentials and electron transfer reac-
tions of avonoid radicals. In: Rice-Evans C, Packer L, editors.
Flavonoids in health and disease. New York: Marcel Dekker; 1998.
p. 137.
[37] Kim DH, Jung EA, Sohng IS, Han JA, Kim TH, Han MJ. Intestinal
bacterial metabolism of avonoids and its relation to some biologi-
cal activities. Arch Pharmacol Res 1998;21:17.
[38] Klipstein-Grobusch K, Koster JF, Grobbee DE, Lindemans J,
Boeing H, Hofman A, et al. Serum ferritin and risk of myocardial
infarction in the elderly: the Rotterdam Study. Am J Clin Nutr
1999;69:1231.
[39] Khnau J. The avonoids: a class of semi-essential food compo-
nents: their role in human nutrition. World Rev Nutr Diet
1976;24:117.
[40] Kuiper GG, Lemmen JG, Carlsson B, Corton JC, Safe SH,
van der Saag PT, et al. Interaction of estrogenic chemicals and
phytoestrogens with estrogen receptor beta. Endocrinology
1998;139:4252.
[41] Lee MJ, Wang ZY, Li H, Chen L, Sun Y, Gobbo S, et al. Analysis of
plasma and urinary tea polyphenols in human subjects. Cancer
Epidemiol Biomarkers Prev 1995;4:393.
[42] Li C, Lee MJ, Sheng S, Meng X, Prabhu S, Winnik B, et al.
Structural identication of two metabolites of catechins and their
kinetics in human urine and blood after tea ingestion. Chem Res
Toxicol 2000;13:177.
[43] Lodovici M, Casalini C, De Filippo C, Copeland E, Xu X,
Clifford M, et al. Inhibition of 1,2-dimethylhydrazine-induced
oxidative DNA damage in rat colon mucosa by black tea complex
polyphenols. Food Chem Toxicol 2000;38:1085.
[44] Manach C, Morand C, Crespy V, Demign C, Texier O,
Rgrat F, et al. Quercetin is recovered in human plasma as
conjugated derivatives which retain antioxidant properties. FEBS
Lett 1998;426:331.
[45] Manach C, Morand C, Texier O, Favier ML, Agullo G, Dem-
igne C, et al. Quercetin metabolites in plasma of rats fed diets
containing rutin or quercetin. J Nutr 1995;125:1911.
[46] Maxwell S, Cruickshank A, Thorpe G. Red wine and antioxidant
activity in serum. Lancet 1994;344:193.
[47] Morand C, Manach C, Crespy V, Rmsy C. Quercetin 3-O-beta-
glucoside is better absorbed than other quercetin forms and is not
present in rat plasma. Free Rad Res 2000;33:667.
[48] Mulder TP, van Platerink CJ, Wijnand Schuyl PJ, van Amels-
voort JM. Analysis of theaavins in biological uids using liquid
chromatographyelectrospray mass spectrometry. J Chromatogr B
Biomed Sci Appl 2001;760:271.
[49] Olthof MR, Hollman PCH, Katan MB. Chlorogenic acid and caffeic
acid are absorbed in humans. J Nutr 2001;131:66.
[50] Parr AJ, Bolwell GP. Phenols in the plant and in man. The potential
for possible nutritional enhancement of the diet by modifying the
phenols content or prole. J Agric Food Chem 2000;80:985.
[51] Pasqualini JR, Gelly C, Nguyen BL, Vella C. Importance of estrogen
sulfates in breast cancer. J Steroid Biochem 1989;34:155.
A. Scalbert et al. / Biomed Pharmacother 56 (2002) 276282 281
[52] Piskula MK, Terao J. Accumulation of ()-epicatechin metabolites in
rat plasma after oral administration and distribution of conjugation
enzymes in rat tissues. J Nutr 1998;128:1172.
[53] Rice-Evans CA, Miller NJ, Paganga G. Structureantioxidant activ-
ity relationships of avonoids and phenolic acids. Free Rad Biol
Med 1996;20:933.
[54] Rios LY, Bennett RN, Lazarus SA, Rmsy C, Scalbert A, William-
son G. Cocoa procyanidins are stable during gastric transit in
humans. Am J Clin Nutr 2002 [in press].
[55] Santos-Buelga C, Scalbert A. Proanthocyanidins and tannin-like
compounds: nature, occurrence, dietary intake and effects on nutri-
tion and health. J Sci Food Agric 2000;80:1094.
[56] Scalbert A. Antimicrobial properties of tannins. Phytochemistry
1991;30:3875.
[57] Scalbert A, Manach C, Morand C, Rmsy C. Dietary intake and
bioavailability of polyphenols. International Conference on Dietary
Factors: Cancer Causes and Prevention, Vienna. 2001 [abstract].
[58] Scalbert A, Williamson G. Dietary intake and bioavailability of
polyphenols. J Nutr 2000;130:2073S.
[59] Scheline RR. CRC handbook of mammalian metabolism of plant
compounds. Boca Raton: CRC Press; 1991. p. 514.
[60] Serani M, Maiani G, Ferro-Luzzi A. Alcohol-free red wine en-
hances plasma antioxidant capacity in humans. J Nutr
1998;128:1003.
[61] Shimoi K, Saka N, Nozawa R, Sato M, Amano I, Nakayama T, et al.
Deglucuronidation of a avonoid, luteolin monoglucuronide, during
inammation. Drug Metab Dispos 2001;29:1521.
[62] Shutt DA, Cox RI. Steroid and phyto-oestrogen binding to sheep
uterine receptors in vitro. J Endocrinol 1972;52:299.
[63] Spencer JP, Schroeter H, Crossthwaithe AJ, Kuhnle G, Williams RJ,
Rice-Evans C. Contrasting inuences of glucuronidation and
O-methylation of epicatechin on hydrogen peroxide-induced cell
death in neurons and broblasts. Free Radic Biol Med
2001;31:1139.
[64] Tuomainen TP, Punnonen K, Nyyssonen K, Salonen JT. Association
between body iron stores and the risk of acute myocardial infarction
in men. Circulation 1998;97:1461.
[65] van het Hof KH, deBoer HSM, Wiseman SA, Lien N, Weststrate JA,
Tijburg LBM. Consumption of green or black tea does not increase
resistance of low-density lipoprotein to oxidation in humans. Am J
Clin Nutr 1997;66:1125.
[66] van het Hof KH, Wiseman SA, Yang CS, Tijburg LB. Plasma and
lipoprotein levels of tea catechins following repeated tea consump-
tion. Proc Soc Exp Biol Med 1999;220:203.
[67] Warden BA, Smith LS, Beecher GR, Balentine DA, Clevidence BA.
Catechins are bioavailable in men and women drinking black tea
throughout the day. J Nutr 2001;131:1731.
[68] Whitehead TP, Robinson D, Allaway S, Syms J, Hale A. Effect of
red wine ingestion on the antioxidant capacity of serum. Clin Chem
1995;41:32.
[69] Young JF, Nielsen SE, Haraldsdottir J, Daneshvar B, Lauridsen ST,
Knuthsen P, et al. Effect of fruit juice intake on urinary quercetin
excretion and biomarkers of antioxidative status. Am J Clin Nutr
1999;69:87.
[70] Zhang Y, Song TT, Cunnick JE, Murphy PA, Hendrich S. Daidzein
and genistein glucuronides in vitro are weakly estrogenic and
activate human natural killer cells at nutritionally relevant concen-
trations. J Nutr 1999;129:399.
[71] Zhu BT, Evaristus EN, Antoniak SK, Sarabia SF, Ricci MJ,
Liehr JG. Metabolic deglucuronidation and demethylation of estro-
gen conjugates as a source of parent estrogens and catecholestrogen
metabolites in Syrian hamster kidney, a target organ of estrogen-
induced tumorigenesis. Toxicol Appl Pharmacol 1996;136:186.
[72] Zhu BT, Ezell EL, Liehr JG. Catechol-O-methyltransferase-
catalyzed rapid O-methylation of mutagenic avonoids. Metabolic
inactivation as a possible reason for their lack of carcinogenicity in
vivo. J Biol Chem 1994;269:292.
282 A. Scalbert et al. / Biomed Pharmacother 56 (2002) 276282