1394 Int J Pharm Sci Nanotech Vol 4; Issue 2 JulySeptember 2011

Review Article

Pharmacological Activities of Flavonoids: A Review
A. D. Agrawal
Shree Sureshdada Jain Pharmaceutical Education and Research Center, Jalgaon, India.
Received April 4, 2011; accepted July 17, 2011

ABSTRACT
Flavonoids belong to a group of polyphenolic compounds,
which are classified as flavones, flavanones, catechins and
anthocyanins. Flavonoids of different classes have several
pharmacological activities. Flavonoids possess
pharmacological and biochemical effects, which inhibit a
number of enzymes such as aldose reductase, cycloxygenase,
Ca
+2
-ATPase, xanthine oxidase, phosphodiesterase, and
lipoxygenase. They also have a regulatory role on different
hormones like androgens, estrogens and thyroids. In the view
of their wide pharmacological and biological actions, they
seem to have great therapeutic potential.
KEYWORDS: Flavonoids; biochemistry; pharmacology; therapeutic potential.
Introduction
Flavonoids are a group of polyphenolic compounds,
which are widely distributed throughout the plant
kingdom and about 3000 varieties of flavonoids are
known (Kuhnau, 1976). Many have low toxicity in
mammals and some of them are widely used in medicine
for maintenance of capillary integrity (Cesarone et al.,
1992). Flavonoids exhibit several biological effects such
as anti-hepatotoxic, anti-inflammatory and anti-ulcer
activity (Bors et al., 1990; Colerige et al., 1980). They
also inhibit enzymes such as aldose reductase,
cycloxygenase, Ca
+2
-ATPase, xanthine oxidase,
phosphodiesterase and lipoxygenase. They are potent
antioxidants and have free radical scavenging abilities.
Many have antiallergic, antiviral actions and some of
them provide protection against cardiovascular mortality
(Clack et al., 1950; Hertog et al., 1993). They have been
shown to inhibit the growth of various cancer cell lines in
vitro, and reduce tumor development in experimental
animals (Mori et al., 1988). Flavonoids can be divided
into various classes on the basis of their molecular
structure (Rice-Evans et al., 1996). The four main groups
of flavonoids are listed in Table 1, together with the
examples and the food source in which they are present.
Chemical structures of selected flavonoids are shown in
Figure 1. The flavones are characterized by a planar
structure because of a double bond in the central
aromatic ring.
Pharmacological effects of flavonoids
Antiatherosclerotic effects. Because of their
antioxidative properties, flavonoids are likely to have a
major influence on the vascular system. Oxygen radicals
can oxidize LDLs, which injures the endothelial wall and
thereby promotes atherosclerotic changes. A few clinical
studies have pointed out that flavonoid intake protects
against coronary heart disease (Hertog et al., 1995;
Hertog et al., 1993)
.
Hertog et al., 1995 stated that the
flavonoids in regularly consumed foods might reduce the
risk of death from coronary heart disease in elderly men.
Furthermore, a Japanese study reported an inverse
correlation between flavonoid intake and total plasma
cholesterol concentrations (Arai et al., 2000). Oxidative
stress and vascular damage are postulated to play a key
role in dementia, and the intake of red wine is reported
to prevent the development of dementia

(Orgogozo et al.,
1997). The intake of flavonoids appears inversely related
to the risk of dementia (Commenges et al., 2000).
Anti-inflammatory effects. Cyclooxygenase and
lipoxygenase play an important role as inflammatory
mediators. They are involved in the release of
arachidonic acid, which is a starting point for a general
inflammatory response. Selected phenolic compounds
were shown to inhibit the cyclooxygenase and 5-
lipoxygenase pathways (Ferrandiz et al., 1991; Ferrandiz
et al., 1990; Laughton et al., 1991).
This inhibition reduces the release of arachidonic acid
(Yoshimoto et al., 1983). Quercetin inhibits both
cyclooxygenase and lipoxygenase activities, thus
diminishing the formation of these inflammatory
metabolites (Robak and Gryglewski, 1996; Kim et al.,
1998). Another anti-inflammatory feature is that
flavonoids also inhibit eicosanoid biosynthesis (Formica
and Regelson, 1995; Damas et al., 1985). Eicosanoids,
such as prostaglandins, are involved in various
immunologic responses (Moroney et al., 1988).
Flavonoids also inhibit both cytosolic and membrane
tyrosine kinase (Formica et al., 1995). Integral
membrane proteins, such as tyrosine 3-monooxygenase

International Journal of Pharmaceutical Sciences and Nanotechnology
Volume 4 Issue 2 July September 2011
MS ID: IJPSN-17-07-11-AGRAWAL
1394
Agrawal: Pharmacological Activities of Flavonoids: A Review 1395
kinase, are involved in a variety of functions, such as
enzyme catalysis, transport across membranes, and
transduction of signals that function as receptors of
hormones and growth factors, and energy transfer in
ATP synthesis. Inhibition of these proteins results in
inhibition of uncontrolled cell growth and proliferation.
Tyrosine kinase substrates seem to play key roles in the
signal transduction pathway that regulates cell
proliferation. Another anti-inflammatory property of
flavonoids is their suggested ability to inhibit neutrophil
degranulation. This is a direct way to diminish the
release of arachidonic acid by neutrophils and other
immune cells (Hoult et al., 1994; Tordera et al., 1994).
TABLE 1
Main groups of flavonoids, the individual compounds, and food
sources.
Group Compound Food sources
Flavones Apigenin Apple skins
Chrysin Berries
Kaempferol Broccoli
Luteolin Celery
Myricetin Fruit peels
Quercetin Lettuce
Rutin Cranberries
Sibelin Grapes
Olives
Onions
Parsley
Flavanones Fisetin Citrus fruit
Hesperetin Citrus peel
Narigin
Naringenin
Taxifolin
Strawberries
Tea
Fruit peels with
Catechins Catechin Red wine
Anthocyanins Cyanidin Berries
Delphinidin Cherries
Epicatechin Tea

Epigallocatechin
gallate
Malvidin Grapes
Pelargonidin Raspberries
Peonidin Red grapes
Petunidin Red wine
Dark pigments
Antitumor effects. Antioxidant systems are frequently
inadequate, and damage from reactive oxygen species is
proposed to be involved in carcinogenesis (Hoult et al.,
1994; Tordera et al., 1994). Reactive oxygen species can
damage DNA, and the division of cells with unrepaired or
misrepaired damage leads to mutations. Reactive oxygen
species can interfere directly with cell signaling and
growth. The cellular damage caused by reactive oxygen
species can induce mitosis, increasing the risk that
damaged DNA will lead to mutations, and can increase
the exposure of DNA to mutagens. It has been stated
that flavonoids, such as antioxidants, can inhibit
carcinogenesis (Stefani et al., 1999). Some flavonoids
such as apigenin, fisetin and luteolin are stated to be
potent inhibitors of cell proliferation (Fotsis et al., 1997).
Quercetin and apigenin inhibited melanoma growth and
influenced the invasive and metastatic potential in mice
(Caltagirone et al., 2000). Flavonoids inhibit
angiogenesis, which is regulated by a variety of
endogenous angiogenic and angiostatic factors (Fotsis et
al., 1997). Pathologic, unregulated angiogenesis occurs in
cancer (Fan et al., 1995). Angiogenesis inhibitors can
interfere with various steps in angiogenesis, such as the
proliferation and migration of endothelial cells and
lumen formation. Flavonoids seem to play an important
role among the known angiogenesis inhibitors, (Fotsis et
al., 1997 ; Paper, 1998). However, the mechanism behind
the antiangiogenic effect of flavonoids is unclear. A
possible mechanism could be the inhibition of protein
kinases (Oikawa et al., 1992). These enzymes are
implicated to play an important role in signal
transduction and are known for their effects on
angiogenesis.
Antithrombogenic effects. Platelet aggregation
contributes to both the development of atherosclerosis
and acute platelet thrombus formation, followed by
embolization of stenosed arteries. Activated platelets
adhering to vascular endothelium generate lipid
peroxides and oxygen free radicals, which inhibit the
endothelial formation of prostacyclin and nitrous oxide.
It was shown in the 1960s that tea pigments can reduce
blood coagulability, increase fibrinolysis, and prevent
platelet adhesion and aggregation (Lou et al., 1989).
Selected flavonoids, such as quercetin, kaempferol, and
myricetin were shown to be effective inhibitors of platelet
aggregation in dogs and monkeys (Osman et al., 1998).
Flavonols are particularly antithrombotic because they
directly scavenge free radicals, thereby maintaining
proper concentrations of endothelial prostacyclin and
nitric oxide (Gryglewski et al., 1987). Flavonoids are
powerful antithrombotic agents in vitro and in vivo
because of their inhibition of the activity of
cyclooxygenase and lipoxygenase pathways (Alcaraz and
Ferrandiz, 1987). It is well known that arachidonic acid,
which is released in inflammatory conditions, is
metabolized by platelets to form prostaglandin,
endoperoxides, and thromboxane A2, leading to platelet
activation and aggregation (Tzeng et al., 1991). The main
antiaggregatory effect of flavonoids is thought to be by
inhibition of thromboxane A2 formation. Flavonoids
affect arachidonic acid metabolism in different ways.
Some flavonoids specifically block cyclooxygenase or
lipoxygenase, whereas others block both enzymes
(Landolfi et al., 1984). In vitro studies showed that
flavonoids bind to platelet membranes and may therefore
have an accumulative effect over time (Van Wauwe and
Goosens, 1983).
Antiosteoporotic effects. In an English study, bone
mineral density was compared between older women who
consumed tea and those who did not. Women in the
study who drank tea had higher bone mineral density
measurements than did those who did not drink tea. The
flavonoids in tea might be responsible for the prevention
of osteoporosis (Hegarty et al., 2000).
1396 Int J Pharm Sci Nanotech Vol 4; Issue 2 JulySeptember 2011
Antiviral effects. Wang et al (1998) has shown an
antiviral activity of flavonoids. Herpes simplex,
parainfluenza, respiratory syncytial and adenovirus were
affected by flavonoids. Quercetin was reported to exhibit
both antiinfective and antireplicative abilities. The
interaction of flavonoids with the different stages in the
replication cycle of viruses was previously described
(Kaul et al., 1985). Flavonoids in their glycone form seem
to be more inhibitory on rotavirus infectivity than are
flavonoids in their aglycone form (Bae et al., 2000).
Because of the worldwide spread of HIV since the 1980s,
investigations of the antiviral activity of flavonoids have
mainly focused on HIV. Most of these studies focused on
the inhibitory activity of reverse transcriptase, or RNA-
directed DNA polymerase (Huang et al., 1997), but
antiintegrase and antiprotease activities were also
described (Middleton, 1998). Again, flavonoids have
mainly been studied in in vitro experiments; therefore,
no clear contribution of flavonoids to the treatment of
HIV-infected patients has yet been shown (Vlietinck
et al., 1998).
Antibacterial Activity. Antibacterial activity has been
displayed by a number of flavonoids. Most of the
flavonones having no sugar moiety showed antimicrobial
activities, whereas none of the flavonols and
flavonolignans tested showed inhibitory activity on the
microorganisms (Wild and Fosel, 1969).
Antifungal Activity. Flavonoids isolated from the
peels of tangerine oranges and tested for fungistatic
activity towards Deuterophoma tracheiphila showed
promising activity. Chlorflavonin was the first chlorine-
containing flavonoid type antifungal antibiotic produced
by strains of Aspergillus candidus (Tencate et al., 1973).
Biochemical effects of flavonoids
(i) On enzymes. Flavonoids are known to inhibit a
number of enzymes such as aldose reductase
(Jager et al., 1998), xanthine oxidase (Koch et al.,
1992), phosphodiesterase (Alcaraz et al., 1987),
Ca
2+
A TPase (Scerola et al., 1984), lipo-oxygenase
(Baumann et al., 1980) and cyclooxygenase
(Varma and Kinosita, 1976). Flavonols like
myricetin, quercetin and kaempferol inhibit the
activity of the adenosine deaminase of endothelial
cells, while flavones are inactive (Hayashi et al.,
1993). Quercetin, myricetin and kaempferol are
effective in antagonizing bradykinin responses
(Nagai et al., 1992). Effects of luteolin and
quercetin on inhibition of tyrosine kinase, on cell
growth and metastasis (Bamard et al., 1993).
They have inhibitory properties on the 5'-
nucleotidase (5'- ribonucleotide phosphohydrolase)
activity (Hur et al., 1994). Flavonoids inhibit
intracellular Ca
2+
elevation by reducing
phospholipase-C activity (Beladi et al., 1987) and
they possess potent inhibitory effects on several
enzyme systems such as protein kinase-C, protein
tyrosine kinase, phospholipase A2 and others
(Musci et al., 1985). Flavonoids have high
potencies and selectivities for inhibition of CYPlA
isoenzymes (Melzig, 1996). Silymarin acts as a
strong antioxidant by virtue of its ability to act as
an acceptor of O2 or CCl3 radicals. By trapping O2
related free radicals, silymarin hinders their
interaction with polyunsaturated fatty acid and
abolishes the enhancement of lipid peroxidation.
Some flavonoids are predominant inhibitors of
either cyclooxygenase or lipoxygenase, others are
equally effective against both enzymes (Calixto
and Yunes, 1991; Huang et al., 1999).
(ii) On hormones. Flavonoids have also been shown to
have regulatory activities on hormones by binding
to 17 beta-hydroxy steroid dehydrogenases which
regulates estrogen and androgen levels in
humans, and to 3 beta-hydroxy steroid
dehydrogenase, which regulates progestin and
androgen levels in humans (Noro et al., 1983).
Quercetin, myricetin, rutin, kaempferol affect the
transport, metabolism, and action of thyroid
hormones. Quercetin myricetin, rutin, kaempferol,
galangin, spirenoside and robinin are potent non-
toxic ITH deiodinase inhibitors in microsomal
membranes, and intact rat hepatocytes. Myricetin,
rutin, kaempferol are specific high affinity
competitors for L- T4-binding to human TBPA,
weaker antagonists in the T3-5-deiodinase
reaction, and very poor inhibitors of T3 binding to
the nuclear T3 receptor.



O O H
O
OH
OH
OH
OH
OH

O O H
O
OH
OH
OH
OH

OH
O O H
O OH

Myricetin Quercetin Apigenin
Agrawal: Pharmacological Activities of Flavonoids: A Review 1397
O O H
O
OH
OH
OH

O O H
O
OH
OH

OH
OH
O
O O H
O
O
OH
O H
OH
C H
3
O H
O H
OH

Kaempferol Galangin Rutin
Fig. 1. Chemical structures of selected flavonoids.
Conclusion
Flavonoids have received much attention in the
literature over the past 10 years and a variety of
potential beneficial effects have been elucidated. The
flavonoids as natural compounds have several great
advantages over other therapeutic agents because many
diets are rich in polyphenolics compounds and are
consumed daily having a relatively long half-life with
minimum side effects and is easily absorbed in the
intestine after ingestion. However, most of the research
is involved in vitro studies; therefore, it is difficult to
draw definite conclusions about the usefulness of
flavonoids in the diet. Currently, the intake of fruit,
vegetables, and beverages (eg, tea and moderate
amounts of red wine) containing flavonoids is
recommended, although it is too early to make
recommendations on daily flavonoid intakes.
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ceutical Education and Research Center, Jalgaon, India.

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