Review Article

Flavonoids: a review of probable mechanisms of action and

potential applications1–3
Robert J Nijveldt, Els van Nood, Danny EC van Hoorn, Petra G Boelens, Klaske van Norren, and Paul AM van Leeuwen

ABSTRACT The aim of this review, a summary of the puta- became clear that this substance was a flavonoid (rutin), a flurry
tive biological actions of flavonoids, was to obtain a further of research began in an attempt to isolate the various individual
understanding of the reported beneficial health effects of these flavonoids and to study the mechanism by which flavonoids act.
substances. Flavonoids occur naturally in fruit, vegetables, and Flavonoids can be divided into various classes on the basis of
beverages such as tea and wine. Research in the field of their molecular structure (7). The 4 main groups of flavonoids are
flavonoids has increased since the discovery of the French para- listed in Table 1, together with the best-known members of each
dox, ie, the low cardiovascular mortality rate observed in group and the food source in which they are present. The molec-
Mediterranean populations in association with red wine con- ular structure of each group of flavonoids is given in Figure 1.

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sumption and a high saturated fat intake. Several other potential The flavones are characterized by a planar structure because
beneficial properties of flavonoids have since been ascertained. of a double bond in the central aromatic ring. One of the best-
We review the different groups of known flavonoids, the proba- described flavonoids, quercetin, is a member of this group.
ble mechanisms by which they act, and the potential clinical Quercetin is found in abundance in onions, apples, broccoli, and
applications of these fascinating natural substances. Am J berries. The second group is the flavanones, which are mainly
Clin Nutr 2001;74:418–25. found in citrus fruit. An example of a flavonoid of this group is
narigin. Flavonoids belonging to the catechins are mainly found
KEY WORDS Flavonoids, bioflavonoids, antioxidants, in green and black tea and in red wine (2), whereas anthocyanins
French paradox, review, polyphenols are found in strawberries and other berries, grapes, wine, and tea.
An important effect of flavonoids is the scavenging of oxy-
gen-derived free radicals. In vitro experimental systems also
INTRODUCTION showed that flavonoids possess antiinflammatory, antiallergic,
Flavonoids belong to a group of natural substances with vari- antiviral, and anticarcinogenic properties (1). The aim of this
able phenolic structures and are found in fruit, vegetables, grains, review was to give an overview of the research in the field of
bark, roots, stems, flowers, tea, and wine (1). These natural prod- flavonoids. The potential valuable working mechanisms of
ucts were known for their beneficial effects on health long before flavonoids are discussed, followed by present knowledge on the
flavonoids were isolated as the effective compounds. More than absorption, conjugation, and toxicity of these substances. In the
4000 varieties of flavonoids have been identified, many of which last part of this review, the potential clinical applications of
are responsible for the attractive colors of flowers, fruit, and flavonoids are discussed.
leaves (2). Research on flavonoids received an added impulse
with the discovery of the French paradox, ie, the low cardiovas-
cular mortality rate observed in Mediterranean populations in WORKING MECHANISMS
association with red wine consumption and a high saturated fat
intake. The flavonoids in red wine are responsible, at least in part, Antioxidative effects
for this effect (3). Furthermore, epidemiologic studies suggest a The best-described property of almost every group of flavonoids
protective role of dietary flavonoids against coronary heart dis- is their capacity to act as antioxidants. The flavones and catechins
ease (2). The association between flavonoid intake and the long-
term effects on mortality was studied subsequently (4) and it was
1
suggested that flavonoid intake is inversely correlated with mor- From the Department of Surgery, Vrije Universiteit Medical Center,
Amsterdam, and Numico Research, Wageningen, Netherlands.
tality due to coronary heart disease (5). 2
Supported by the Council for Medical Research of the Netherlands
Until 50 y ago, information on the working mechanisms of
Organization for Scientific Research (fellowship to RJN).
flavonoids was scarce. However, it has been widely known for 3
Reprints not available. Address correspondence to PAM van Leeuwen,
centuries that derivatives of plant origin possess a broad spec- Department of Surgery, Vrije Universiteit Medical Center, PO Box 7057,
trum of biological activity (6). In 1930 a new substance was iso- 1007 MB Amsterdam, Netherlands. E-mail: [email protected].
lated from oranges, which is believed to be a member of a new Received November 17, 2000.
class of vitamins, and was designated as vitamin P. When it Accepted for publication May 14, 2001.

418 Am J Clin Nutr 2001;74:418–25. Printed in USA. © 2001 American Society for Clinical Nutrition
 REVIEW OF FLAVONOIDS 419

TABLE 1 Flavonoids are oxidized by radicals, resulting in a more stable,

Main groups of flavonoids, the individual compounds, and food sources less-reactive radical. In other words, flavonoids stabilize the
Group Compound Food sources reactive oxygen species by reacting with the reactive compound
of the radical. Because of the high reactivity of the hydroxyl
Flavones Apigenin Apple skins
Chrysin Berries group of the flavonoids, radicals are made inactive, according to
Kaempferol Broccoli the following equation (11):
Luteolin Celery
Myricetin Fruit peels Flavonoid(OH) + R• > flavonoid(O•) + RH (1)
Rutin Cranberries • •
where R is a free radical and O is an oxygen free radical.
Sibelin Grapes
Quercetin Lettuce Selected flavonoids can directly scavenge superoxides, whereas
Olives other flavonoids can scavenge the highly reactive oxygen-
Onions derived radical called peroxynitrite. Epicatechin and rutin are
Parsley also powerful radical scavengers (12). The scavenging ability of
rutin may be due to its inhibitory activity on the enzyme xan-
Flavanones Fisetin Citrus fruit
Hesperetin Citrus peel thine oxidase. By scavenging radicals, flavonoids can inhibit
Narigin LDL oxidation in vitro (13). This action protects the LDL parti-
Naringenin cles and, theoretically, flavonoids may have preventive action
Taxifolin against atherosclerosis.

Catechins Catechin Red wine Nitric oxide

Epicatechin Tea Several flavonoids, including quercetin, result in a reduction
Epigallocatechin gallate
in ischemia-reperfusion injury by interfering with inducible
nitric-oxide synthase activity (14). Nitric oxide is produced by

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Anthocyanins Cyanidin Berries several different types of cells, including endothelial cells and
Delphinidin Cherries
macrophages. Although the early release of nitric oxide through
Malvidin Grapes
Pelargonidin Raspberries the activity of constitutive nitric-oxide synthase is important in
Peonidin Red grapes maintaining the dilation of blood vessels (15), the much higher
Petunidin Red wine concentrations of nitric oxide produced by inducible nitric-oxide
Strawberries synthase in macrophages can result in oxidative damage. In these
Tea
circumstances, activated macrophages greatly increase their
Fruit peels with
dark pigments
simultaneous production of both nitric oxide and superoxide
anions. Nitric oxide reacts with free radicals, thereby producing
the highly damaging peroxynitrite. Nitric oxide injury takes
seem to be the most powerful flavonoids for protecting the body place for the most part through the peroxynitrite route because
against reactive oxygen species. Body cells and tissues are contin- peroxynitrite can directly oxidize LDLs, resulting in irreversible
uously threatened by the damage caused by free radicals and reac- damage to the cell membrane. When flavonoids are used as
tive oxygen species, which are produced during normal oxygen antioxidants, free radicals are scavenged and therefore can no
metabolism or are induced by exogenous damage (8, 9). The mech- longer react with nitric oxide, resulting in less damage (16).
anisms and the sequence of events by which free radicals interfere Interestingly, nitric oxide can be viewed as a radical itself, and it
with cellular functions are not fully understood, but one of the most is was reported that nitric oxide molecules are directly scavenged
important events seems to be lipid peroxidation, which results in by flavonoids (17). Therefore, it has been speculated that nitric
cellular membrane damage. This cellular damage causes a shift in oxide scavenging plays a role in the therapeutic effects of
the net charge of the cell, changing the osmotic pressure, leading to flavonoids (17). Silibin is a flavonoid that has been reported to
swelling and eventually cell death. Free radicals can attract various inhibit nitric oxide dose dependently (18).
inflammatory mediators, contributing to a general inflammatory
response and tissue damage. To protect themselves from reactive Xanthine oxidase
oxygen species, living organisms have developed several effective The xanthine oxidase pathway has been implicated as an
mechanisms (10). The antioxidant-defense mechanisms of the important route in the oxidative injury to tissues, especially after
body include enzymes such as superoxide dismutase, catalase, and ischemia-reperfusion (19). Both xanthine dehydrogenase and
glutatione peroxidase, but also nonenzymatic counterparts such as xanthine oxidase are involved in the metabolism of xanthine to
glutathione, ascorbic acid, and -tocopherol. The increased pro- uric acid. Xanthine dehydrogenase is the form of the enzyme
duction of reactive oxygen species during injury results in con- present under physiologic conditions, but its configuration is
sumption and depletion of the endogenous scavenging compounds. changed to xanthine oxidase during ischemic conditions. Xan-
Flavonoids may have an additive effect to the endogenous scav- thine oxidase is a source of oxygen free radicals. In the reperfu-
enging compounds. Flavonoids can interfere with ≥ 3 different free sion phase (ie, reoxygenation), xanthine oxidase reacts with
radical–producing systems, which are described below, but they molecular oxygen, thereby releasing superoxide free radicals. At
can also increase the function of the endogenous antioxidants. least 2 flavonoids, quercetin and silibin, inhibit xanthine oxidase
activity, thereby resulting in decreased oxidative injury (14, 20, 21).
Direct radical scavenging Cos et al (22) carried out a study on structure-function relations
Flavonoids can prevent injury caused by free radicals in vari- in which luteolin (3,45,7- tetrahydroxyflavone) was reported to
ous ways. One way is the direct scavenging of free radicals. be the most potent inhibitor of xanthine oxidase.
420 NIJVELDT ET AL

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FIGURE 1. The molecular structure of each group of flavonoids.

Leukocyte immobilization effects may be a result of a combination of radical scavenging

The immobilization and firm adhesion of leukocytes to the and an interaction with enzyme functions.
endothelial wall is another major mechanism responsible for the When reactive oxygen species are in the presence of iron,
formation of oxygen-derived free radicals, but also for the release lipid peroxidation results (27). Specific flavonoids are known to
of cytotoxic oxidants and inflammatory mediators and further chelate iron (28), thereby removing a causal factor for the devel-
activation of the complement system. Under normal conditions, opment of free radicals. Quercetin in particular is known for its
leukocytes move freely along the endothelial wall. However, dur- iron-chelating and iron-stabilizing properties. Direct inhibition
ing ischemia and inflammation, various mainly endothelium- of lipid peroxidation is another protective measure (29).
derived mediators and complement factors may cause adhesion of Selected flavonoids can reduce complement activation, thereby
the leukocytes to the endothelial wall, thereby immobilizing them decreasing the adhesion of inflammatory cells to the endothe-
and stimulating degranulation of the neutrophil. As a result, oxi- lium (24) and in general resulting in a diminished inflammatory
dants and inflammatory mediators are released, resulting in injury response. Another feature of flavonoids is a reduction in the release
to tissues. Oral administration of a purified micronized flavonoid of peroxidase. This reduction inhibits the production of reactive
fraction was reported to decrease the number of immobilized oxygen species by neutrophils by interfering with 1-antitrypsin
leukocytes during reperfusion (23). The decrease in the number activation. A progressive inactivation of proteolytic enzymes was
of immobilized leukocytes by flavonoids may be related to the described in neutrophils (30).
decrease in total serum complement and is a protective mecha- Another interesting effect of flavonoids on enzyme systems is
nism against inflammation-like conditions associated with, for the inhibition of the metabolism of arachidonic acid (31). This
example, reperfusion injury (23, 24). Some flavonoids can inhibit feature gives flavonoids antiinflammatory and antithrombogenic
degranulation of neutrophils without affecting superoxide pro- properties. The release of arachidonic acid is a starting point for
duction (25). The inhibitory effect of some flavonoids on mast a general inflammatory response. Neutrophils containing lipoxy-
cell degranulation was shown to be due to modulation of the genase create chemotactic compounds from arachidonic acid.
receptor-directed Ca2+ channels in the plasma membrane (26). They also provoke the release of cytokines.

Interaction with other enzyme systems

Compared with research on the antioxidant capacities of INTAKE, ABSORPTION, CONJUGATION, AND TOXICITY
flavonoids, there has been relatively little research on other ben- OF FLAVONOIDS
eficial effects of flavonoids. The major effects of flavonoids (eg,
antiallergic effects) may be the result of radical scavenging. Intake
Another possible mechanism by which flavonoids act is through The average daily flavonoid intake in the Netherlands is esti-
interaction with various enzyme systems. Furthermore, some mated to be 23 mg/d (32). Intakes of flavonoids exceed those of
 REVIEW OF FLAVONOIDS 421

FIGURE 2. Hypothesis of the links between the working mechanisms of flavonoids and their effects on disease. NO, nitrous oxide.

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vitamin E and -carotene, whereas the average intake of vita- data suggest that the regular intake of flavonoids results in a
min C is 3 times higher than the intake of flavonoids. Flavonoid more predominant formation of several conjugates, which prob-
intakes seem to vary greatly between countries; the lowest ably results in greater activity. A detailed example is given in the
intakes (2.6 mg/d) are in Finland and the highest intakes study by Manach et al (43), in which a high dose of quercetin
(68.2 mg/d) are in Japan (4, 24, 33). Quercetin is the most was administered to a group of rats adjusted to flavonoid intake
important contributor to the estimated intake of flavonoids, and to a nonadjusted group. Results of this study indicated that
mainly from the consumption of apples and onions (34). A major the conjugated compound isorhamnetin was formed in higher
problem in cohort studies of flavonoid intakes is that only a lim- quantities in the adjusted group, which is important because it is
ited number of flavonoids can be measured in biological sam- known to be even more active than is the aglycone form of
ples, and more importantly, only a relatively small number of quercetin on xanthine oxidase inhibition (45).
fruit and vegetables are used to make an accurate estimation. Concentrations of individual flavonoids and their biologically
active conjugates may not be high enough after occasional intake
Absorption to explain the low mortality rates from cardiovascular disease in
Data on the absorption, metabolism, and excretion of flavonoids Mediterranean countries. However, because the half-lives of con-
in humans are contradictory and scarce (35–40). Some studies jugated flavonoids are rather long (23–28 h) (41), accumulation
showed that the most intensely studied dietary flavonoid, quercetin, may occur with regular intakes, which may in turn result in suf-
is absorbed in significant amounts (35, 41). Naturally occurring ficiently active flavonoid concentrations.
flavones exist predominantly in a glycosylated form rather than in
their aglycone form. The form of the flavonoid seems to influence Toxicity
the rate of absorption. Hollman and Katan (39) suggested that the There is much controversy regarding the purported toxic or even
glycosylated forms of quercetin are absorbed more readily than mutagenic properties of quercetin. Formica and Regelson (3) gave
are the aglycone forms; however, this has been questioned by an interesting overview of the in vitro and vivo studies on
other researchers (40). The role of flavonoid glycosylation in facil- quercetin. The early data on toxic side effects are mainly derived
itating absorption is questioned by the fact that catechin, which is from in vitro studies. At a conference of the Federation of Ameri-
not glycosylated in nature, is absorbed relatively efficiently (42). can Societies for Experimental Biology in 1984 on mutagenic food
flavonoids, carcinogenicity was reported in just 1 of 17 feeding
Conjugation studies conducted in laboratory animals (46, 47). Dunnick and Hai-
It is generally accepted that the conjugation pathway for ley (48) reported that high doses of quercetin over several years
flavonoids (catechins) begins with the conjugation of a glu- might result in the formation of tumors in mice. However, in other
curonide moiety in intestinal cells. The flavonoid is then bound to long-term studies, no carcinogenicity was found (49). In contrast
albumin and transported to the liver (43, 44). The liver can extend with the potential mutagenic effects of flavonoids in earlier studies,
the conjugation of the flavonoid by adding a sulfate group, a several more recent reports indicate that flavonoids, including
methyl group, or both. The addition of these groups increases the quercetin, seem to be antimutagenic in vivo (3, 50, 51). A large
circulatory elimination time and probably also decreases toxicity. clinical study by Knekt et al (34), in which 9959 men and women
There are several possible locations for the conjugates on the were followed for 24 y, showed an inverse relation between the
flavonoid skeleton. The type of conjugate and its location on the intake of flavonoids (eg, quercetin) and lung cancer. One possible
flavonoid skeleton probably determine the enzyme-inhibiting explanation for these conflicting data is that flavonoids are toxic to
capacity, the antioxidant activity, or both of the flavonoid. Recent cancer cells or to immortalized cells, but are not toxic or are less
422 NIJVELDT ET AL

toxic to normal cells. If this is true, flavonoids might play a role in from reactive oxygen species is proposed to be involved in car-
the prevention of cancer that is worthy of further investigation. cinogenesis (64, 65). Reactive oxygen species can damage DNA,
and division of cells with unrepaired or misrepaired damage
leads to mutations. If these changes appear in critical genes, such
CLINICAL EFFECTS as oncogenes or tumor suppressor genes, initiation or progres-
An overview of the hypothetical links between the working sion may result. Reactive oxygen species can interfere directly
mechanisms and clinical effects of flavonoids is given in Figure 2. with cell signaling and growth. The cellular damage caused by
The different clinical effects of flavonoids are discussed in greater reactive oxygen species can induce mitosis, increasing the risk
detail below. that damaged DNA will lead to mutations, and can increase the
exposure of DNA to mutagens.
Antiatherosclerotic effects It has been stated that flavonoids, as antioxidants, can inhibit
Because of their antioxidative properties, flavonoids are likely carcinogenesis (66). Some flavonoids—such as fisetin, apigenin,
to have a major influence on the vascular system. Oxygen radicals and luteolin—are stated to be potent inhibitors of cell prolifera-
can oxidize LDL, which injures the endothelial wall and thereby tion (67). A large clinical study suggested the presence of an
promotes atherosclerotic changes. A few clinical studies have inverse association between flavonoid intake and the subsequent
pointed out that flavonoid intakes protect against coronary heart incidence of lung cancer (34). This effect was mainly ascribed to
disease (4, 52). Hertog et al (4) stated that the flavonoids in reg- quercetin, which provided > 95% of the total flavonoid intake in
ularly consumed foods might reduce the risk of death from coro- that particular study. Quercetin and apigenin inhibited melanoma
nary heart disease in elderly men. Furthermore, a Japanese study growth and influenced the invasive and metastatic potential in
reported an inverse correlation between flavonoid intake and total mice (68). This finding may offer new insights about possible
plasma cholesterol concentrations (53). Oxidative stress and vas- therapies for metastatic disease. Furthermore, it has been specu-
cular damage are postulated to play a key role in dementia, and lated that flavonoids can inhibit angiogenesis (67). Angiogenesis
the intake of red wine is reported to prevent the development of is normally a strictly controlled process in the human body. The

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dementia (54). The intake of flavonoids was reported to be process of angiogenesis is regulated by a variety of endogenous
inversely related to the risk of incident dementia (55). angiogenic and angiostatic factors. It is switched on, for exam-
ple, during wound healing. Pathologic, unregulated angiogenesis
Antiinflammatory effects occurs in cancer (69). Angiogenesis inhibitors can interfere with
Cyclooxygenase and lipoxygenase play an important role as various steps in angiogenesis, such as the proliferation and
inflammatory mediators. They are involved in the release of migration of endothelial cells and lumen formation. Among the
arachidonic acid, which is a starting point for a general inflamma- known angiogenesis inhibitors, flavonoids seem to play an
tory response. Neutrophils containing lipoxygenase create chemo- important role (67, 70). However, the mechanism behind the
tactic compounds from arachidonic acid. They also provoke the antiangiogenetic effect of flavonoids is unclear. A possible
release of cytokines. Selected phenolic compounds were shown to mechanism could be inhibition of protein kinases (71). These
inhibit both the cyclooxygenase and 5-lipoxygenase pathways enzymes are implicated to play an important role in signal trans-
(31, 56, 57). This inhibition reduces the release of arachidonic duction and are known for their effects on angiogenesis.
acid (58). The exact mechanism by which flavonoids inhibit
these enzymes is not clear. Quercetin, in particular, inhibits both Antithrombogenic effects
cyclooxygenase and lipoxygenase activities, thus diminishing the Platelet aggregation contributes to both the development of
formation of these inflammatory metabolites (6, 59). atherosclerosis and acute platelet thrombus formation, followed
Another antiinflammatory feature is the ability of flavonoids by embolization of stenosed arteries. Activated platelets adhering
to inhibit eicosanoid biosynthesis (3, 60). Eicosanoids, such as to vascular endothelium generate lipid peroxides and oxygen free
prostaglandins, are involved in various immunologic responses radicals, which inhibit the endothelial formation of prostacyclin
(61) and are the end products of the cyclooxygenase and lipoxy- and nitrous oxide. It was shown in the 1960s that tea pigment can
genase pathways. Flavonoids also inhibit both cytosolic and reduce blood coagulability, increase fibrinolysis, and prevent
membranal tyrosine kinase (3). Integral membrane proteins, platelet adhesion and aggregation (72). Selected flavonoids, such
such as tyrosine 3-monooxygenase kinase, are involved in a vari- as quercetin, kaempferol, and myricetin were shown to be effec-
ety of functions, such as enzyme catalysis, transport across tive inhibitors of platelet aggregation in dogs and monkeys (73).
membranes, transduction of signals that function as receptors of Flavonols are particularly antithrombotic because they directly
hormones and growth factors, and energy transfer in ATP syn- scavenge free radicals, thereby maintaining proper concentrations
thesis. Inhibition of these proteins results in inhibition of uncon- of endothelial prostacyclin and nitric oxide (74). One study
trolled cell growth and proliferation. Tyrosine kinase substrates showed that flavonoids are powerful antithrombotic agents in
seem to play key roles in the signal transduction pathway that vitro and in vivo because of their inhibition of the activity of
regulates cell proliferation. Another antiinflammatory property cyclooxygenase and lipoxygenase pathways (75). It is well
of flavonoids is their suggested ability to inhibit neutrophil known that arachidonic acid, which is released in inflammatory
degranulation. This is a direct way to diminish the release of conditions, is metabolized by platelets to form prostaglandin,
arachidonic acid by neutrophils and other immune cells (62, 63). endoperoxides, and thromboxane A2, leading to platelet activa-
tion and aggregation (76). The main antiaggregatory effect of
Antitumor effects flavonoids is thought to be by inhibition of thromboxane A2
formation. Flavonoids affect arachidonic acid metabolism in dif-
The antitumor activity of flavonoids is still a point of discus- ferent ways. Some flavonoids specifically block cyclooxygenase
sion. Antioxidant systems are frequently inadequate, and damage or lipoxygenase, whereas others block both enzymes (77). In
 REVIEW OF FLAVONOIDS 423

vitro studies showed that flavonoids bind to platelet membranes picture for the future. Currently, the intake of fruit, vegetables,
and may therefore have an accumulative effect over time (78). and beverages (eg, tea and moderate amounts of red wine) con-
taining flavonoids is recommended, although it is too early to
Antiosteoporotic effects make recommendations on daily flavonoid intakes.
In an English study, bone mineral density was compared
between older women who consumed tea and those who did not.
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