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*Bimlesh Kumar (Lecturer) Dept. of Pharmaceutical Sciences, Lovely Professional University, Ludhiana-Jalandhar G.T. Road, Phagwara (Punjab), 144402, India *Mob: +919872260354, +919216260354 E.mail: [email protected], [email protected]
Address for correspondence
A Review of Phytochemistry and Pharmacology of Flavonoids
INTRODUCTION
Phytochemicals are defined as the substances found in
edible fruits and vegetables that exhibit a potential for
modulating human metabolism in a manner beneficial
for the prevention of chronic and degenerative diseases
[1].
Phenolics are defined as a class of polyphenols which
are important secondary metabolites present in plants
[2] and are also responsible for their antioxidant action
and various beneficial effects in a multitude of diseases
[3, 4].Polyphenols are characterised as :
1. Phenolic compounds: Are aromatic organic
compounds with at least one hydroxyl group
attached directly to a benzene ring. These are
hydroxylated derivatives of benzoic acid, present
in form of esters and glycosides.
2. Phenolic acids: cinnamic acid derivatives. Often
present in esterified form.
3. Glycosidic phenylpropanoid esters [5,6].
On the basis of C-skelton, polyphenols are classified as:
1. Flavonoids
2. Phenolic acids [2]
FLAVONOIDS
Flavonoids are low molecular weight [7, 8] bioactive
polyphenols[9] which play a vital role in
photosynthesising cells[10]. The original "flavonoid"
research apparently began in 1936, when Hungarian
scientist Albert Szent-Gyorgi was uncovering a synergy
between pure vitamin C and as yet unidentified co-
factors from the peels of lemons, which he first called
"citrin," and, later, "vitamin P" [11].
Flavonoids are secondary metabolites characterised by
flavan nucleus [8] and C6-C8-C6 carbon-skeleton [12, 13].
These are group of structurally related compounds
with a chromane-type skelton having phenyl
substituent in C2-C3 position [14]. The basic structural
feature of flavonoid is 2-phenyl-benzo-γ-pyrane
nucleus consisting of two benzene rings (A and B)
linked through a heterocyclic pyran ring (C) as shown
Anthocyanin pigment present in flowers provide colour
to it contributing to pollination [8, 10, 20]. Flavonoids
present in leaves promote physiological survival of
plant by protecting it from fungal infections and UV
radiations. In addition, flavonoids are involved in
photosensitisation, energy transfer, respiration and
photosynthesis control, morphogenesis, sex-
determination, energy transfer [10].
Indian Plants containing Flavonoids:
Table 2: Medicinal plants found in India and rich in flavonoids content
S. No. Plant Family Flavonoid present Reference
1. Aloe vera Asphodelaceae Luteolin 20
2. Acalypha indica Euphorbiaceae Kaempferol glycosides: mauritianin, clitorin, nicrotiflorin, biorobin in its leaves and flowers 21
3. Azadirachta indica
Meliaceae, Zingiberaceae
Quercetin, kaempferol; Quercetin-3-O-�-D-glucoside, myricetin-3-O-rutinoside, quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, kaempferol-3-O-β-D-glucoside and quercetin-3-O-α-L-rhamnoside in leaf; isorhamnetin, myricetin, nimbochalcone
22,23
4. Andrographis paniculata Acanthaceae
5-methoxy-7,8,2’,3’-tetramethoxyflavone, monohydroxytrimethylflavones, dihydroxy-di-methoxyflavone, skullcaflavone; 5-hydroxy-7,8-dimethoxyflavanone and 5-hydroxy-3,7,8,2′-tetramethoxyflavone, as well as the known flavonoid 5-hydroxy-7,8- dimethoxyflavone.
quercetin-3-O-�-d-galactopyranoside, quercetin-3-O-α-l-arabinopyranoside, the biflavonoid amentoflavone,(+)-catechin and (−)-epicatechin, amentoflavone, in leaves
16. Mimosa pudica Mimosoideae Isoquercetin, avicularin, apigenin-7-O-�-D-glucoside, cassiaocidentalin B, orientin, isoorientin in aerial parts 30
18. Limnophila indica Scrophulariaceae
(2S)-5,7,3,4-tetramethoxyflavone, 5,7,2,5-tetramethoxyflavone, 7-O-methylwogonin, skullcapflavone, 5-hydroxy-7,20-dimethoxyflavone present in whole plant. 3,4-methlenedioxyflavone in roots and aerial parts
radicals and are described as free-radical scavengers
[42]. This activity is attributed to their hydrogen-
donating ability. Indeed, the phenolic groups of
flavonoids serve as a source of a readily available ‘‘H”
atoms such that the subsequent radicals produced can
be delocalized over the flavonoid structure [1].
Free radical scavenging capacity is primarily
attributed to high reactivities of hydroxyl substituents
that participate in the reaction [8] as shown in fig (IV):
F-OH + R. F-O. + RH
Fig (IV): Scavenging capacity of free radical (R.)
Flavonoids inhibit lipid peroxidation in vitro at an
early stage by acting as scavengers of superoxide
anion and hydroxyl radicals. They terminate chain
radical reaction by donating hydrogen atom to a
peroxy radical as in fig (V), thus, forming flavonoids
radical, which, further reacts with free radicals thus
terminating propagating chain [15, 6].
e- H+ O2 .O2 HO2. H2O2.
HO2. O2
Fig (V): Formation of peroxy radical
Naturally, the organism has developed a defence
against toxic substances such as peroxynitrite and
nitrous acid. An important mechanism is catalyzed by
the enzyme superoxide dismutase (SOD), which
converts two superoxide anions to H2O2 and O2 [16] as
shown in fig (VI).
2H+
.O2- + .O2- H2O2 + O2
SOD Fig (VI): Mechanism catalysed by SOD
Table 3: Reactive oxygen species that can be scavenged or their formation can be inhibited by
flavonoids[43]
S. No.
Reactive species Mechanism
1. O2 (Superoxide anion)
One-electron reduction product of O2. Produced by phagocytes, formed in autoxidation reaction and generated by oxidases (heme proteins)
2. HO2 Protonated form of O2
3. H2O2 “-“ (Hydrogen peroxide)
Two electron reduction product of O2 formed from O2 by “-“ dismutation or directly from O2. Reactivity of O2 and H2O2 is amplified in presence of heme proteins
4. OH (Hydroxy radical)
Three electrons reduction products of O2 generated by Fenton’s reaction, transition metal (iron, copper)-catalysed Haber-Weiss reaction; also formed by decomposition of peroxynitrite produced by reaction of O2 with nitric oxide radical.
5.
RO. (Alkoxy radical), ROO. (Peroxyl radical)
Lipid peroxy radical (LOO.) produced from organic hydroperoxide, ROOH by hydrogen abstraction.
6. 1O2 Singlet Oxygen
According to kinetic studies of aroxyl radical
formation and decomposition reactions, the
antioxidant capacity of a flavonoid is linked to its
three structural groups as shown in fig (VII).
1. The ortho-dihydroxy (catechol) structure in the B-
ring, which confers greater stability to aroxyl
radicals, possibly through hydrogen bonding, and
which participates in electron dislocation.
2. The 2,3-double bond, in conjugation with a 4-oxo
function, responsible for electron dislocation from the
B-ring.
28 Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1
Bimlesh Kumar, et al: A Review of Phytochemistry and Pharmacology of Flavonoids
3. The presence of both 3-(a)-and 5-(b)-hydroxyl
groups (Fig.VII(c)).
OHO
OH
OH
OH
(a)
O
HO
OH
OH
OH
OH
O
(b)
HO
OH
OH
OH
OH
O
(c)
ab
Fig VII: Structural groups responsible for antioxidant activity [1]
3’,4’-catechol structure in B-ring strongly enhances
lipid peroxide inhibition and this arrangement is an
important characteristic of most potent scavengers of
peroxyl, superoxide and peroxynitrite radicals [8] and
its absence decreases antioxidant activity. The
absence of the hydroxyl group at position 3 in
flavanones and flavones decreases their antioxidant
ability[1].
Ghasemzadeh et al., reported that high level of total
phenolic and flavonoid in Halia Bara variety
possessses potent antioxidant activities [44].
Bitis et al., isolated diosmetin, kaempherol, quercetin,
kaempherol 3-glucoside (astragalin), quercetin 3-
rhamnoside (quercitrin), quercetin 3-xyloside and
quercetin 3-galactoside (hyperoside) from Rosa
agrestis leaves and reported it to possess antioxidant
activity [45].
Shariffer et al., reported antioxidant activity of
methanolic extract of Teucrium polium and rutin and
apigenin were found to be potent inhibitors of lipid
peroxidation and oxidation of beta-carotene [46].
Braca et al., isolated several flavonoids from the leaves
of Licania licaniaeflora and reported quercetin
derivatives to possess strongest antioxidant activity
and flavonone 8-hydroxy-naringen and kaempferol 3-
Cardiovascular diseases are today the principal cause
of death in both developing and developed countries.
CVS diseases include atherosclerosis, coronary heart
disease, arterial hypertension, and heart failure. The
major reason behind CVS diseases is oxidative stress.
Oxidative stress is a condition of imbalance between
endogenous oxidants and reactive oxygen/nitrogen
species (RONS) with predominance of reactive
species.
Etiology of Cardiovascular Diseases:
Atherosclerosis involves modification of LDL particles
by oxidative stress with subsequent induction of
inflammation which is caused by increased leucocyte
adherence [16].
Endothelial dysfunction with increased platelet
aggregation facilitates procoagulation, which may
induce a thrombosis resulting in an acute myocardial
infarction. In the ischemic phase of AMI platelet
aggregation, the activation of neutrophils, an increase
in cellular free redox active iron, and the
transformation of xanthine dehydrogenase into ROS
producing xanthine oxidase (XO) play important role
[16].
Common consequences of AMI are heart failure and
arrhythmias. Here again, ROS can mediate the cardiac
hypertrophy and patients with heart failure have an
increased production of ROS. Similarly, ROS, and in
particular the superoxide radical, may play an
important role in the genesis of some arrhythmias.
Patients with arterial hypertension have an increased
oxidative stress status [64].
Flavonoids in treatment of CVS: Studies ensure
that long-term administration of flavonoids can
decrease, or tend to decrease the incidence of
cardiovascular diseases and their consequences.
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Table 5: Proposed positive effects of flavonoids on CVS:
S. No. Cardiovascular diseases Influence of flavonoids
1. Atherosclerosis Decrease in LDL oxidation by LOX inhibition and attenuation of oxidative stress, inhibition of leucocyte leucocyte adhesion, myeloperoxidase, decreased expression of iNOS and COX-2
2. Acute myocardial infarction Decrease in ROS burst, inhibition of platelet aggregation
3. Heart Failure Decrease in oxidative stress (direct ROS scavenging) inhibition of metalloproteinase
4. Arrhythmia Decrease in oxidative stress
5. Hypertension Vasodilatory properties, inhibition of NADPH oxidase, recovery of NO due to inhibition of superoxide production
Flavonoid consumption prevent many cardiovascular
diseases including hypertension and atherosclerosis.
Quercetin protects LDL against oxidative
modifications effect. 7-monohydroxyethylrutoside and
7’, 3’, 4’-trihydroxyethylrutoside are reported to be
cardioprotective [43].
12. Effect of flavonoids on diabetes mellitus:
Etiology of diabetes mellitus: Diabetes mellitus is
a serious chronic disease. Effective control of the
blood glucose level is a key step in preventing or
reversing diabetic complications and improving the
quality of life in both types 1 and 2 diabetic patients
[65].
Flavonoids in treatment of diabetes mellitus:
All flavonoids cannot cure diabetes mellitus because
most types of this disease are basically genetic and no
single drug can correct an inborn error. However,
flavonoids can ameliorate some of the consequences
of diabetes mellitus [16]. Flavonoids have been
identified to be good inhibitors of aldose reductase
[66]. The fig (XXIII) depicts the mechanism of
flavonoids in diabetes mellitus.
Fig (XXIII): Effect of flavonoids on diabetes mellitus
It has been reported by several researchers that
quercetin possess antidiabetic activity and it has been
found that it brings about regeneration of pancreatic
islets and increases insulin release in streptozotocin-
induced diabetes. Also, it has been reported to
stimulate Ca2+ uptake from isolated islet cells thus
suggesting it to be effective even in non-insulin
dependent diabetes [43].
Li et al., indicated that flavonoids in Ipmoea batalas
leaf possesses antidiabetic activity against alloxan-
induced diabetes at a dose of 100 mg/kg [67].
Sriram et al., reported fisetin to be a therapeutic agent
for treatment of diabetes mellitus at a dose of 10
mg/kg [68].
13. Effect of flavonoids in treatment of
hepatotoxicity:
Role of flavonoids in treatment of
hepatotoxicity: Flavonoids bind to subunit of DNA-
dependent RNA polymerase I, thus activating the
enzyme. As a result, protein synthesis gets increased
leading to regeneration and production of hepatocytes
[11].
Silymarin, apigenin, quercetin, naringenin are
reported to be potent therapeutic agents against
microcrystin LR-induced hepatotoxicity. Rutin and
venoruton are reported to show regeneration and
hepatoprotective effects in experimental cirrhosis [43].
Gulati et al., studied hepatoprotective studies on
Phyllanthus emblica and quercetin and quercetin and
found that if the extract is producing hepatoprotection
at a dose of 100 mg/ 100 g p.o., then quercetin is
producing hepatoprotection at a dose of 15 mg/ 100 g
p.o.; thus concluding that quercetin is a potent
hepatoprotective agent [69].
(-) Aldose reductase, PREVENT DIABETES MELLITUS
Regenerate pancreatic islets, FLAVONOID
(+) insulin release, (+) Ca++ uptake
Kim et al., isolated isovitexin, hirustin, trifolin,
avicularin and quercetin. It was observed that
hirustrin, avicularin, quercetin possess
hepatoprotective action against t-BHP in HepG2
37 Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1
Bimlesh Kumar, et al: A Review of Phytochemistry and Pharmacology of Flavonoids
cells, whereas isovitexin and trifolin possess no
protective effect [70].
Oh et al., 2004 reported that among various
flavonoids i.e. apigenin, luteolin, kaempherol-3-O-
glucoside and quercetin-3-O-glucoside isolated from
Equisetum arvense, onitin and luteolin exhibited
hepatoprotective activity against tacrine-induced
cytotoxicity in human liver-derived Hep G2 cells [57].
Toxicological Profile of flavonoids:
Flavonoids are widely distributed in edible plants and
beverages and have been previously used in
traditional medicines, so they are believed to be non-
toxic [10, 15]. However, this family of compounds
possess a diverse range of activities in mammalian
cells. So, in-vivo confirmation of their side effects
would be necessary for full evaluation of their
practical usefulness in the field of modern medicine.
Given that the selectivity of flavonoids for eukaryotic
enzymes appears to vary from compound to
compound, a study regarding assessment of its
toxicity is required to be done on these
phytochemicals on an individual basis [10]. Flavonoids
are found to be toxic to cancer or immortalized cells
but are less toxic to normal cells [40]. Due to the low
solubility of flavonoid aglycones in water, to the short
residence time of flavonoids in the intestine, and to
the low coefficient of absorption, it is not possible for
humans to suffer acute toxic effects from the
consumption of flavonoids, with the exception of a
rare occurrence of allergy. The margin of safety for the
therapeutic use of flavonoids in humans, therefore, is
very large and probably not surpassed by any other
drug in current use [16].
CONCLUSION
Flavonoids constitute a wide array of biological active
compounds that are found abundantly in plant
kingdom and dietary intake. They are gaining interest
due to their wide variants and number of members.
These are reported to be effective in pathogenesis of