Journal of Food and Nutrition Research Vol. 47, 2008, No. 4, pp.

151–162

Bioavailability and metabolism of flavonoids

JANA VISKUPIČOVÁ – MIROSLAV ONDREJOVIČ – ERNEST ŠTURDÍK

Summary
Flavonoids are natural polyhydroxylated compounds with proved positive impact on human health. However, majority
of the evidence relates to in vitro properties. In literature, attention has been focused on the in vitro mechanism of
the flavonoid action, while their metabolic transformations in humans have been almost omitted. Currently, only little
information is available on flavonoid bioavailability, formation of conjugates and their bioactivity in humans. It has
been established that after flavonoids enter the gastrointestinal tract, the process of absorption in the small intestine
takes place. The degree of absorption depends on several factors and differs among the individual flavonoid sub-
classes. The highest bioavailability has been determined for isoflavones, followed by flavanols, flavanones and flavonol
glycosides. Flavonoid glycosides are first deglycosylated prior to the intestinal uptake, whereas aglycones can freely
penetrate through cell membranes. Absorbed flavonoids are transported to the liver where they undergo extensive
metabolism generating different conjugation forms such as glucuronides, sulphates and methylated derivatives. It
has been proposed that these conjugates are responsible for the health-promoting effects of flavonoids. This review
provides the latest information on flavonoid research as far as biochemistry, absorption, metabolism and biological
activity of flavonoid conjugates in living systems is concerned.

Keywords
flavonoids; absorption; metabolism; conjugates; bioactivity

Flavonoids are secondary metabolites abun- Depending on the connection of the aromatic
dantly widespread throughout the plant kingdom. ring to the heterocyclic ring, flavonoids can be di-
The major sources of flavonoids are fruit products vided into three classes: flavonoids (2-phenylben-
(e.g. citrus fruits, rosehip, apricot, cherry, grapes, zopyrans), isoflavonoids (3-phenylbenzopyrans)
black currant, bilberry, apple), vegetables (e.g. and neoflavonoids (4-phenylbenzopyrans) [2].
onion, green pepper, broccoli, tomato, spinach), Based on the degree of oxidation and saturation in
beverages (red wine, coffee, tea), cocoa bean, soy the heterocyclic C-ring, flavonoids may be divided
products and herbs [1]. They are found in all plant into several groups which are depicted in Fig. 2
tissues, where they are present inside the cells or and Fig. 3.
on the surfaces of different plant organs. Flavonoids are often hydroxylated in positions
The chemical structures of this class of com- 3, 5, 7, 3‘, 4‘ and/or 5‘. One or more of these hy-
pounds are based on a diphenylpropane (C6-C3- droxyl groups are often methylated, acylated,
C6) skeleton containing two aromatic rings, which prenylated or sulphated. In plants, flavonoids are
are connected through a three-carbon “bridge” often present as O- or C-glycosides. The O-glyco-
and become a part of a six-member heterocyclic sides have saccharide substituents bound to a hy-
ring (Fig. 1). Their structures may range from that droxyl group of the aglycone, usually located at
of a simple phenolic molecule to that of a complex position 3 or 7, whereas the C-glycosides have sac-
high-molecular-weight polymer. charide groups bound to a carbon of the aglycone,

Jana Viskupičová, Institute of Biochemistry, Nutrition and Health Protection, Faculty of Chemical and Food Technology,
Slovak University of Technology, Radlinského 9, SK – 812 37 Bratislava, Slovakia.
Miroslav Ondrejovič, Department of Biotechnology, Faculty of Natural Sciences, University Ss. Cyril and Metodius,
Nám. J. Herdu 2, SK – 917 01 Trnava, Slovakia.
VÚP - Food Research Institute, Biocentre, Kostolná 7, SK – 900 01 Modra, Slovakia.
Ernest Šturdík, Institute of Biochemistry, Nutrition and Health Protection, Faculty of Chemical and Food Technology,
Slovak University of Technology, Radlinského 9, SK – 812 37 Bratislava, Slovakia.
Department of Biotechnology, Faculty of Natural Sciences, University Ss. Cyril and Metodius, Nám. J. Herdu 2,
SK – 917 01 Trnava, Slovakia.
Correspondence author:
Miroslav Ondrejovič, VÚP - Food Research Institute, Biocentre, Kostolná 7, SK – 900 01 Modra, Slovakia, [email protected]

© 2008 VÚP Food Research Institute, Bratislava 151

Viskupičová, J. – Ondrejovič, M. – Šturdík, E. J. Food Nutr. Res., 47, 2008, pp. 151–162

Fig. 1. Basic flavonoid skeleton.

Fig.2. The generic structures of major subclasses of flavonoids.

Fig.3. The generic structures of minor subclasses of flavonoids.

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usually C6 or C8. The most common saccharides bioavailability of flavonoids in humans are still
are rhamnose, glucose, galactose and arabinose. controversial.
Flavonoid diglycosides are also frequently found. Different dietary flavonoids show different
The saccharides are often further substituted by rates of absorption and bioavailability. Isoflavones
acyl residues such as malonate or acetate. Given are the best absorbed dietary flavonoids, flavanols,
the above structural variety, it is not surprising flavanones and flavonol glycosides are intermedi-
that there an extremely large number of flavonoids ate, whereas proanthocyanidins, flavanol gallates
is recognized [3]. and anthocyanins are the worst absorbed. How-
Flavonoids provide various important roles in ever, it is clear that the absorption of dietary fla-
the plant metabolism, defense, signalling, patho- vonoids may be influenced by the matrix in which
genesis and symbiosis [4–6]. These compounds are they are consumed, with enhanced excretion in
responsible for flower colouring and are involved urine of easily recognized mammalian conjugates
in response mechanisms against stress, as caused observed while presented in the food with a higher
by elevated UV-B radiation [7, 8], infection by mi- fat content [49]. It is not surprising that absorp-
croorganisms [9] or animal and insect herbivore tion kinetics vary considerably among different
attack [10–12]. They are also involved in the nitro- foods, owing to the heterogeneity of saccharides
gen fixation process and in the plant growth dur- and other functional groups on the flavan nucleus.
ing the reaction with plant growth hormones, prin- Absorption is also affected by dosage, vehicle of
cipally with auxins and cytokinins [13]. administration, antecedent diet, sex differences,
Flavonoids may play an important role in individual genetic properties and the microbial
the human and animal diet as long as they affect population of the colon [50, 51].
health. Many epidemiological studies proved the
correlation between flavonoid intake and a re- Absorption
duced risk of coronary heart disease, cancer and Glycosylated flavonoids
neurodegenerative diseases [14–24]. The protec- Flavonoids are present in the diet mainly as gly-
tive effect might be ascribed to their free-radical- cosides and the nature of the saccharide and posi-
scavenging and antioxidant activities [23, 25–28]. tion of substitution are important factors for intes-
In addition, they have been reported to possess an- tinal absorption, but the position of the saccharide
timicrobial [29, 30], antiviral [31–34], anticarcino- affects the mechanisms involved in the intestinal
genic [23, 34–38], anti-inflammatory [39–41], anti- uptake [38]. Glycosides need to undergo deglyco-
allergic [42, 43] and vasodilatory effects [44, 45]. sylation prior to be absorbed [38, 52–64]. Hydroly-
Flavonoids have also been shown to inhibit lipid sis of the saccharide moiety of flavonoids is carried
peroxidation, platelet aggregation, capillary per- out by intracellular cytoplasmic β-glucosidase [38,
meability and fragility, and to affect enzyme sys- 52, 55, 59, 63, 64]. Three different β-glucosidases
tems including phospholipase A2, cyclooxygenase have been found in humans: a broad-specificity cy-
and lipoxygenase [23, 46] as well as ATP-binding tosolic β-glucosidase, lactase phloridzin hydrolase
proteins, such as mitochondrial ATPase, myosin, (LPH) and glucocerebrosidase (CBG) [64, 65].
protein kinases, topoisomerase II and multidrug- Great differences in β-glucosidase activity may be
resistance proteins [47, 48]. a critical factor in the bioactivity of flavonoids [55].
Many activities of flavonoids were determined Next step after deglycosylation is passive diffusion
using in vitro or ex vivo tests. However, flavonoid of the resulting flavonoid aglycone through epithe-
transformation in living systems have not been lial cells, which is supported by increased hydro-
considered in these models. Therefore, the review phobicity [38, 64]. However, certain glycosylated
aims is to describe the bioavailability, absorption flavonoids (e.g. quercetin-4‘-glucoside) were found
and metabolism of flavonoids and their conjugates to be actively transported into epithelial cells via
in vivo. the active sodium-dependent glucose transporter
SGLT1 [66].
The absorption of quercetin-4‘-O-glucoside
BIOAVAILABILITY appears to follow both ‘LPH/diffusion’ and ‘trans-
port/CBG’ pathways, whereas quercetin-3-O-gluco-
It seems that there is a great difference be- side follows only the ‘LPH/diffusion’ pathway [54].
tween biological properties of flavonoids observed Rutin (quercetin-3-O-rutinoside) is deglycosylated
in vitro and their bioactivity in vivo. It is crucial by microfloral rhamnosidases and β-glucosidases
to understand the flavonoid absorption, bioavail- present in the colon. Absorption of rhamnoglu-
ability as well as metabolism prior to resolving the cosides is delayed and appears to be less efficient
question of bioactivity in vivo. The absorption and [67]. Anthocyanins were considered until recently

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Viskupičová, J. – Ondrejovič, M. – Šturdík, E. J. Food Nutr. Res., 47, 2008, pp. 151–162

that they do not undergo deglycosylation and me- been suggested that the depolymerization occurs
tabolism as they were found in plasma and urine in the stomach by acid [57]. However, TSANG et al.
intact rather than as glucuronate and sulphate con- [79] reported that oligomeric procyanidins were
jugates [68, 69]. However, recent evidence suggests not cleaved into bioavailable monomers at any
that anthocyanins are absorbed and transported in point during the digestive process of the rat.
human serum and urine primarily as metabolites,
namely, glucuronide and sulphate conjugates [70]. Intestinal efflux
Experiments on flavanones (hesperidin, naringin, Intestinal excretion is an important step
narirutin) proved that they also need to undergo that limits the absorption of certain flavonoids
hydrolysis of the glycoside moiety prior to the ab- [80]. The extent of absorption and bioavailabil-
sorption [71]. The intestinal enzymes involved in ity of drugs has long been known to be affected
this reaction are most likely α-rhamnosidases and by various membrane transporters. Members of
β-glucosidases [72, 73]. The isoflavones must also the adenosine triphosphate (ATP)-binding cas-
first undergo hydrolysis prior to intestinal absorp- sette (ABC) superfamily of transporters including
tion. KIM et al. [50] studied puerarin and daidzin multidrug-resistance protein (MRP), P-glycopro-
absorption. These compounds are metabolized tein (P-gp) and breast cancer resistance protein
by the intestinal microflora to daidzein, which is (BCRP) are involved in regulating the intestinal
partially absorbed into the blood [50]. However, efflux of some flavonoids and ultimately influence
MEEZAN et al. [74] reported that puerarin is rapid- the net amount that is absorbed into systemic cir-
ly absorbed from the intestine without metabo- culation [16, 81, 82]. The activities of these trans-
lism, while daidzin is hydrolysed to the aglycone. porters are expected to be important determinants
It seems that all main flavonoid glycosides are first for the pharmacokinetics and pharmacodynamics
hydrolysed to the aglycones prior to intestinal ab- of flavonoids [82].
sorption. The efflux of quercetin and epicatechin metabo-
lites is thought to occur by MRP2, located on the
Non-glycosylated flavonoids luminal side of epithelial cells [80]. The monocar-
The only subclass of flavonoids that are present boxylate transporter P-gp, MRP1 and MPR2 play
in the non-glycosylated form in the diet are fla- important roles in the cellular accumulation and
van-3-ols. They are the most abundant flavonoids potential effects of (−)-epicatechin gallate [83].
in the human diet, but only little is known about The amount of active intestinal efflux of flavo-
their absorption and metabolism. Although they noids representing the major subclasses of flavo-
are found as monomers in the diet, it has been ob- noids was studied after in situ intestinal perfusion,
served that epimerization at C2 may occur during where quercetin was excreted the most efficiently,
their metabolism [75]. The results on monomers, followed by luteolin, eriodicytol and kaempferol,
such as (+)-catechin, (−)-epicatechin and (−)-epi- whereas no reaction with efflux transporters was
gallocatechin (EGC), suggest that these com- observed in (+)-catechin and (−)-epicatechin [84].
pounds are absorbed mainly in the small intestine, Since ABC transporters are located in cell
in particular in the jejunum and ileum [76]. In the membranes all over the organism, the interaction
case of (−)-epigallocatechin gallate (EGCG), the between flavonoids and ABC transporters will not
hydrolysis of the gallate moiety prior to absorption only affect the extent of intestinal efflux and bio-
has been proposed. The results suggest that EGCG availability but also the distribution of flavonoid
is converted to EGC in the oral cavity, and both conjugates to the target sites of action and their
catechins are absorbed through the oral mucosa. elimination. Moreover, bioavailability of different
A catechin esterase activity that converts EGCG compounds may be increased or decreased at co-
to EGC was found in the saliva [77]. Catechins are administration of flavonoids by a selective interac-
freely available by passive diffusion, and the mecha- tion with ABC transporters [85].
nism is generally dose-dependent [78]. Due to
molecular size, absorption of oligomeric and poly- Metabolism
meric flavonoids across the intestinal epithelium Flavonoids are well recognized to undergo ex-
requires preliminary degradation to smaller, low- tensive metabolism prior to the entry into systemic
molecular-weight compounds. Procyanidin dimers circulation. Absorbed flavonoids are bound to al-
and trimers are capable of translocating across the bumin and transported to the liver via the portal
small intestinal epithelium. Since these molecules vein [86]. Liver is the crucial organ responsible
generally consist of (+)-catechin and (−)-epicate- for various biotransformations leading to differ-
chin subunits, it is conceivable that catechins are ent conjugated forms of flavonoids. However, the
predominant degradation products [51]. It has intestinal mucosa, kidney and other tissues are

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also involved in the metabolism of flavonoids. The are mostly glucuronides and possibly methylated
most abundant metabolic transformation reactions glucuronides. It has been established that these
of flavonoids are oxidation, reduction, hydrolysis polar conjugates gain access to hepatocytes and
and conjugation with sulphate, glucuronate, or are further modified therein. Although querce-
O-methylation [60]. DAY et al. [62] suggested that tin and flavan-3-ol metabolites are clearly able to
these reactions significantly affect the antioxidant enter hepatocytes, the mechanism of uptake into
activity of flavonoids and their interactions with hepatocytes is unknown. In the liver, they are fur-
proteins. Conjugation reactions with glucuronic ther methylated on the catechol ring [91]. Cate-
acid and/or sulphate seem to be the most com- chin glucuronides formed in the small intestine are
mon type of metabolic pathways for flavonoids. subsequently sulphated, as well as methylated [78].
It seems that the small intestine is the major or- Certain flavonoid glucuronides can be hydrolysed
gan responsible for glucuronidation of many fla- and then re-glucuronidated at a different position,
vonoids. This reaction occurs on the luminal side or conjugated with sulphate [91]. Unabsorbed fla-
of the endoplasmic reticulum by uridine-5‘-di- vonoids can be further degraded by colon microor-
phosphate glucuronosyltransferases (UGTs). The ganisms. A scheme of the metabolism of flavonoid
process is very fast and even more efficient than glycosides is presented in Fig. 4 [60].
cytochrome P450-mediated oxidation [87]. The The fraction of flavonoids that reaches colon
UGT superfamily of enzymes demonstrates re- can be extensively metabolized by microflora en-
markable diversity in substrate recognition and ca- zymes. This may be an important step in the fla-
talyses glucuronidation of a large number of func- vonoid bioavailability, in particular for flavonoids
tional groups (e.g., -OH, -COOH, -NH2, -SH). The that are not essentially absorbed from the small
UGT1A family is thought to be responsible for intestine [47]. Scission of the flavonoid structure
glucuronidation of flavonoids [88]. Sulphation and can occur as shown in Fig. 5, and this depends on
methylation both occur in the cytosol by sulpho- their hydroxylation patterns. The most widespread
transferases (SULTs) and catechol-O-methyltrans- dietary flavonoids catechin and quercetin, having
ferases [89]. SULT1A1 and SULT1A2 are involved a 5,7,3‘,4‘-hydroxylation pattern, would enhance
in the sulphation of phenol-type substrates, while ring opening after hydrolysis. Enzymes responsible
SULT1A1 and SULT1A3 were determined to be for the initial ring fission of flavonoids and for
responsible for (−)-epicatechin sulphation [90]. demethylation and dehydroxylation of the result-
After absorption and intestinal metabolism, ing phenolic acids are, to a great extent, those of
hepatic metabolism of flavonoids takes place. The intestinal microorganisms. It was found that the
major products found in the hepatic portal vein ring scission depends on the type and extent of

Fig. 4. Metabolism of flavonoids [60].

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Fig. 5. Potential sites of biotransformation and ring cleavage of flavonoids [60].

oxidation of the carbon atoms of the heterocyclic Conjugation will effectively reduce the number of
ring. Another important structural component un- free hydroxyl groups, which is supposed to alter
dergoing biotransformation is the B-ring [60]. the antioxidant properties and possibly the ability
Several flavonoids with 3‘,4‘-dihydroxylation to interact with important functional cellular pro-
in the B ring are excreted in mammalian species teins including enzymes, receptors and transport-
as conjugates of their 3‘-O-methyl esters. Glu- ers [49]. It is therefore important to determine
curonide and sulphate conjugates of these methyl the impact of these conjugates or metabolites on
esters are major urinary metabolites in man [60]. relevant tissues, cells and proteins in order to pro-
However, elimination in bile is quantitatively the vide mechanistic insight regarding the role of fla-
most important route of elimination for flavo- vonoids in protecting against age-related diseases
noids. Crespy et al. [84] found that the flavanone and maintaining optimal health.
eriodicytol has the highest elimination in bile fol- Quercetin is one of the most extensively studied
lowed by luteolin, kaempferol, quercetin and polyphenols. It serves as a good example because
then (+)-catechin which has minor elimination by its metabolism in humans is well understood, and
this route. The flavonoids eliminated in bile are many conjugates of it have been identified [57,
present as conjugated metabolites. 91-96]. More than 95% of the absorbed querce-
tin was in the form of more than 20 different me-
thylated glucuronated and/or sulphated quercetin
FLAVONOID METABOLITES conjugates. The main detected metabolites were
AND THEIR BIOLOGICAL EFFECTS IN VIVO quercetin diglucuronides in the gut, liver and kid-
ney, and glucuronyl sulphates of methylated quer-
Flavonoids form an integral part of the human cetin in plasma [92, 97]. The major forms found in
diet. Currently there is a broad interest in the ef- plasma were quercetin-3‘-O-sulphate (comprising
fects of dietary polyphenols on human health. approximately 50% of total quercetin), quercetin-
An inverse correlation between the intake of cer- 3-O-glucuronide, isorhamnetin-3-O-glucuronide
tain polyphenols and the risk of cardiovascular and quercetin-3‘-O-glucuronide [97]. The con-
disease, cancer and other age-related diseases has jugates and approximate concentrations of com-
been determined in epidemiological studies. The mon dietary flavonoids present in vivo after oral
potential beneficial effects of these compounds consumption of a physiologically relevant amount
make them an attractive target for genetic engi- of a common dietary source are summarized in
neering strategies aimed at producing plants with Tab. 1.
increased nutritional values. Biological proper- The metabolisms of other most abundant die-
ties of flavonoids depend on their bioavailability. tary flavonoids of humans is comparable in several
Conjugation in the flavonoid metabolism affects ways:
properties such as size or mass, charge and hy- 1. glycosides are generally not found in plasma or
drophobicity, which may influence their solubility urine in the form ingested,
and ability to cross biological membranes. It is also 2. the major forms in plasma and urine are sul-
likely to affect their rate of excretion (via kidney phate and glucuronate conjugates of the parent
or liver) and therefore their half-life in plasma. aglycones,

156
 Bioavailability and metabolism of flavonoids

3. methylation may occur on polyphenols that myeloid HL-60 leukemia cells [104]. LOKE et al.
contain orthohydroxy functional groups, [92] found that at least two of the major in vivo
4. aglycones are absent, or constitute only metabolites of quercetin have significant activity
a very small proportion of the total amount for the inhibition of pro-inflammatory eicosanoids
of polyphenols present, except for green tea such as LTB4 and PGE2. Quercetin-3-glucuronide
catechins, of which aglycones can constitute was shown to prevent angiotensin-II–induced vas-
a significant proportion of the total amount in cular smooth muscle cell hypertrophy in cultured
plasma [99]. rat aortic smooth muscle cells through its inhibi-
tory effects on the JNK and AP-1 signalling path-
It has been shown that some conjugates of ways [105]. There are some reports suggesting
quercetin possess significant antioxidant prop- that genistein glucuronides may be active in vivo
erties [92, 100], delay lipid peroxidation of cell because they have been shown to have estrogenic
membranes [101], and reduce Cu2+-induced LDL activity and can activate human natural killer cells
oxidation [102]. They also exhibit the ability to in vitro [106]. Also daidzein sulphoconjugates were
inhibit lipoxygenase (quercetin-3‘-O-sulphate) found to competitively inhibit sterol sulphatase in
[92], xanthine oxidase (particularly quercetin-4‘- hamster liver microsomes [107]. Some glucuro-
glucuronide) [62] and cyclo-oxygenase (isorham- nides and sulphates of (+)-catechin and methylat-
netin and tamarixetin) in vitro [94]. SAITO et al. ed (+)catechin obtained after oral administration
[103] reported that quercetin-3-sulphate reduced of pure (+)-catechin to rats were found to inhibit
H2O2-induced chromosomal damage in cultured both generation of reactive oxygen species and
human lymphocytes. Furthermore, quercetin glu- binding of U937 monocyte cells to interleukin 1β–
curonides were shown to inhibit N-acetylation of stimulated human aortic endothelial cells, whereas
2-aminofluroene (a carcinogen) in human acute (+)-catechin did not do so [108].

Tab. 1. A list of flavonoids and their conjugates found in human plasma and urine (adapted from [98]).
Flavonoid Conjugates in plasma/rurine Concentration
Quercetin Quercetin-3’-sulphate, quercetin-3-glucuronide, isorhamnetin-3-glucuro- 0,1–1 mol.l-1
nide and quercetin-3’-glucuronide
Kaempferol Kaempferol-3-glucuronide and free kaempferol –
Chrysin Chrysin-7-sulphate (major) and chrysin-7-glucuronide (minor) –
Daidzein Daidzein-7-glucuronide (54%), daidzein-4’-glucuronide (25%), –
daidzein 7- and 4‘-sulphates (13%), daidzein-4‘,7-diglucuronide (0.4%),
daidzein sulphoglucuronides (0.9%), and non-conjugated daidzein (7%)
Genistein Genistein-7-glucuronide, genistein-4’-glucuronide, genistein 7- and –
4’-sulphates, genistein-4’,7-diglucuronide, genistein sulphoglucuronides,
and unconjugated genistein
Epicatechin Non-conjugated epicatechin in plasma 0,15–0,22 μmol.l-1
(–)-Epicatechin-3‘-glucuronide, 4‘-methyl-(–)-epicatechin-3‘-glucuronide
and 4‘-methyl-(–)-epicatechin-5 or 7-glucuronide in urine
Epigallocatechin Non-conjugated (–)-epigallocatechin in plasma, 0,08 μmol.l-1
4’-O-methyl-epigallocatechin
Epigallocatechin Gallate Non-conjugated epigallocatechin gallate in plasma, 0,14–0,34 μmol.l-1
4’,4’’-dimethylepigallocatechin gallate
Delphinidin Unchanged delphinidin glycosides, methylated delphinidin pmol.l-1–nmol.l-1
Cyanidin Unchanged cyanidin glycosides, cyanidin monoglucuronides, pmol.l-1–nmol.l-1
methylated cyanidin
Malvidin Unchanged malvidin glycosides, methylated malvidin pmol.l-1–nmol.l-1
Petunidin Unchanged petunidin glucoside, methylated petunidin pmol.l-1–nmol.l-1
Peonidin Unchanged peonidin arabinoside, peonidin monoglucuronides, pmol.l-1–nmol.l-1
methylated peonidin
Pelargonidin Unchanged pelargonidin-3-glucoside, pelargonidin monoglucuronides, –
sulphoconjugate of pelargonidin

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7. Rosenberg Zand, R. S. – Jenkins, D. J. A. –

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