INTERNATIONALE PHARMACEUTICA SCIENCIA

| Jan-March 2011 | Vol. 1 | Issue 1 | Available online http://www.ipharmsciencia.com 2011 IPS

REVIEW ARTICLE

A Review of Phytochemistry and Pharmacology of Flavonoids

ABSTRACT
Flavonoids are natural products widely distributed in plant kingdom and currently consumed in large amounts in the daily diet. These are categorised according to their molecular structures into flavonols, flavones, flavanones, isoflavone, Catechin, anthocyanidin and chalcones. Flavonoids are capable of modulating the activity of enzymes and affect the behaviour of many cell systems and exerting beneficial effects on body. This property of flavonoids has aroused considerable interest. This review has presented the recent research advancements of chemistry and pharmacological properties of flavonoids. Key words: Flavonoids, Quercetin, Rutin, Apigenin, Flavone, Chalcone, Kaempferol, Antioxidant, radical-scavengers Harleen Kaur Sandhar, Bimlesh Kumar*, Sunil Prasher, Prashant Tiwari, Manoj Salhan, Pardeep Sharma Lovely School of Pharmaceutical Sciences, Lovely Professional University, Jalandhar-Delhi G.T. Road (NH-1), Phagwara. Punjab (INDIA) 144402 Date of Submission: 22-01-2011 Date of Acceptance: 14-03-2011 Conflict of interest: Nil Source of support: None

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].

On the basis of C-skelton, polyphenols are classified as: 1. Flavonoids 2. Phenolic acids [2] FLAVONOIDS Flavonoids are low molecular weight polyphenols[9] which play a
[7, 8]

bioactive role in

Phenolics are defined as a class of polyphenols which are important secondary metabolites present in plants
[2]

vital

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 cofactors from the peels of lemons, which he first called "citrin," and, later, "vitamin P" [11]. Flavonoids are secondary metabolites characterised by flavan nucleus with feature a
[8]

and are also responsible for their antioxidant action are characterised as :

and various beneficial effects in a multitude of diseases

[3, 4].Polyphenols

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].
Address for correspondence *Bimlesh Kumar (Lecturer) Dept. of Pharmaceutical Sciences, Lovely Professional University, Ludhiana-Jalandhar G.T. Road, Phagwara (Punjab), 144402, India *Mob: +919872260354, +919216260354 E.mail: bimlesh.12474@lpu.co.in, bimlesh1@gmail.com 25

and C6-C8-C6 carbon-skeleton skelton

[14].

[12, 13].

These are group of structurally related compounds chromane-type of flavonoid is having phenyl substituent in C2-C3 position The basic structural

2-phenyl-benzo--pyrane

nucleus consisting of two benzene rings (A and B) linked through a heterocyclic pyran ring (C) as shown in fig (I) [10].

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3' 2' 8 7 6 5 4 A
O

4' 5'

groups bound to Carbon of aglycone usually 6-C or 8-C

[14].

1' 2 3

B 6'

Optical activity of flavonoids: The flavonoids are a class of natural product that gains interest due its great variety and the number of its members. The flavonoids are often hydroxylated in positions 3, 5, 7, 3, 4, and 5 as shown in fig (IV) which are frequently methylated, acetylated, or sulphated.

Fig (I): Basic structure of flavonoids [10]

Biosynthesis of Flavonoids:
O S-CoA

3CH3COOH

H2C CH3 CH2

O O O

2' 8 1' 2 3 6'

3' 4'

7 6

5'

HO O

OH

4
O

OH

FLAVAN NUCLEUS Fig (II): Biosynthesis of flavonoids Flavonoids differ in their arrangement of hydroxyl, methoxy and glycosidic side groups and in the conjunction between A and B rings [8]. A variation in C ring provides division of subclasses (fig III) classes [13]:
O O O O H H O O H O OH O

Fig (IV): Numbering of atoms in flavonoid aglycone ] at which substitution may occur [15 The actual number of flavonoids that have been found so far and for which the structure has been completely elucidated is large, but probably does not exceed 1% of the theoretical number of possible variants. This abundance of variants is further augmented by the chirality of the subunits and their connections. Since many stereoisomers do not differ significantly in their electronic or fluorescence spectra so the optical activity of the species is often a useful analytical parameter [16]. Distribution of flavonoids: Flavonoids are widely distributed among the plant
4 B 2' 5 6

[13].

According to

their molecular structure, they are divided into eight

(1) Flavone

(2) Flavonones

(3)Flavonol

(4) Isoflavone
3 2

O+ O H OH H H H OH H OH O O H H

3' 4' A 5' 6'

O

kingdom [10].Flavonoids are found in vegetables, fruits, nuts, seeds, stem, flowers, tea, wine etc. These are an integral part of our daily diet
[15, 17, 18].

The dietary

(5) Anthocyanidin (6) Catechin (7) Dihydroflavonol (8) Chalcone

intake of flavonoids is estimated to be 1-2 g/day [7]. The average intake of flavonols and flavones was found to be 23 mg/day, among which, flavonol quercetin contributed 16 mg/day dietary food sources:
[8].The

Fig (III): Chemical structure of different types of flavonoids [15] In plants, flavonoids are often present as O-glycosides or C-glycosides. The O-glycosides possess sugar substituent bound to OH of aglycone, usually at position 3 or 7, whereas, C-glycosides possess sugar

table below (Table 1)

describes various flavonoids present in our daily

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Table 1: Occurence of flavonoids in food [9, 19]:

S. No. 1. 2. 3. 4. 5. 6. Flavonoid subclass Flavonol Flavones Flavonones Catechins Anthocyanidins Isoflavones Food source Onion, kale, broccoli apples, cherries, berries, tea, red wine Parsley, Thyme Citrus Apple, tea Cherries, Grapes Soya beans, Legumes Representative flavonoids Kaempherol, myricetin, quercetin, rutin Apigenin, chrysin, luteolin Hesperitin, erodictyol, naringen Catechin, galocatechin ---------------Daidzen, genistein, glyciten, formanantine

Functions of Flavonoids in plants: 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,
[10].

sex-

determination, energy transfer

Indian Plants containing Flavonoids: Table 2: Medicinal plants found in India and rich in flavonoids content
S. No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 18. 19. 20. 21. 22. Plant Aloe vera Family Asphodelaceae Luteolin Kaempferol glycosides: mauritianin, clitorin, nicrotiflorin, biorobin in its leaves and flowers Quercetin, kaempferol; Quercetin-3-O- -D-glucoside, myricetin-3-O-rutinoside, quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, kaempferol-3-O--D-glucoside and quercetin-3-O--L-rhamnoside in leaf; isorhamnetin, myricetin, nimbochalcone 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. Luteolin, luteolin-7-O- -glucopyranoside Quercetrin, myricetin galactoside, kaempferol, myricetin Genistein, prunetine in stem bark Quercetin-3-O-rutinoside, Quercetin quercetin-3-O- -d-galactopyranoside, quercetin-3-O--l-arabinopyranoside, the biflavonoid amentoflavone, (+)-catechin and ()-epicatechin, amentoflavone, in leaves Quercetin, isorhamnetin Orientin, luteolin, luteolin-7-O- -glucopyranoside Seed consists of eriocitrin, hesperidin. Peel consists of neoeriocitrin, naringin, neohesperidin Pectolinarigenin, 7-hydroxyflavone, 7-hydroxyflavonone, 7-O-glucoside Kaempferol-3-O- -glucoside, Quercetin-3-O- -glucoside, myricetin-3-O- -glucoside, isorhamnetin-3-O- glucoside, 3,5,7,4-tetrahydroxy-flavone-3-rhamoglycoside, kaempferol-3-neohesperidoside Liquiritin, isoliquiritin,liquritigenin,isoliquiritigenin, rhamnoliquiritin, liqcoumarin, 2-methylisoflavones Isoquercetin, avicularin, apigenin-7-O- -D-glucoside, cassiaocidentalin B, orientin, isoorientin in aerial parts (2S)-5,7,3,4-tetramethoxyflavone, 5,7,2,5-tetramethoxyflavone, 7-O-methylwogonin, skullcapflavone, 5hydroxy-7,20-dimethoxyflavone present in whole plant. 3,4-methlenedioxyflavone in roots and aerial parts Luteolin-7-O-glycoside,luteolin-7,3-O-diglycoside, apigenin, quercetin-3-O-glycoside, kaempferol-3-Oglycoside; 5,7,4-trihydroxy-6,2,3-trimethoxyflavone Luteolin, kaempferol, quercetin (Agarwal), Chrysin, baicalein, baicalein-7-O-glucoside, Oroxylin B Vitexin, isovitexin, orientin, iso-orientin, 2- -D-glucoside Pongaflavonol , tunicatacatachalcone; Pongamone A-E, 5-hydroxy-40-methoxy-7-[(3-methyl-2-buthenyl) oxy]-isoflavone, ovalichromene-B, pongachin, ponganone III, 5hydroxyfurano[7,6:4,5]flavone , pongaglabol, karanjin, pongapin, lancheolatin B, 50-methoxypongapin, karanjachromene, pongachromene; luteolin; (2S)-3,4-dimethoxy-6,6-dimethylpyrano[2,3:7,8]-flavanone , (2S)-6,3,4-trimethoxy-6,6dimethylpyrano[2,3:7,8]-flavanone, (2S)-7-methoxy-6-O-,-dimethylallyl-3,4-methylenedioxyflavanone, 2-hydroxy-3,4,5-trimethoxy-6,6-dimethylpyrano[2,3:4,3]chalcone, 2,4-dimethoxy-3,4methylenedioxydioxydihydrochalcone, 2,5,-trimethoxy-3,4-methylenedioxy-6,6dimethylpyrano[2,3:4,3]dihydrochalcone, 2,-dimethoxy-3,4-methylenedioxy-furano[2,3:4,3]dihydrochalcone, -hydroxy-2,4,6-trimethoxy-3,4-methylenedioxychalcone and 3-methoxy-furano[2,3:7,6]flavones present in roots Purpurin, pongamol, isolonchocarpin,karanjin, lanceolatin-B, kanjone present in seeds Quercetrin, rutin, hyperoside, tiliroside, astragalin Flavonoid present Reference 20 21 22,23 24, 25 21 26 27 28 29 26 21 1 30 25, 31 26 30 30 32, 33 34 30 26

Acalypha indica Euphorbiaceae Azadirachta indica Andrographis paniculata Bacopa moneirra Betula pendula Butea monospermea Bauhinia monandra Brysonima crassa Calendula officinalis Cannabis sativa Citrus medica Clerodendrum phlomidis Clitoria ternatea Glyccheriza glabra Mimosa pudica Limnophila indica Mentha longifolia Momordica charantia Oroxylum indicum Passiflora incarnate Meliaceae, Zingiberaceae Acanthaceae Scrophulariaceae Betulaceae Fabaceae Fabaceae Malphigaceae Compositae Cannabaceae Rutaceae Verbenaceae Fabaceae Leguminosae Mimosoideae Scrophulariaceae Lamiaceae Curcurbitaceae Bignoniaceaea Passifloraceae

23.

Pongamia pinnata

Fabaceae

35, 36, 37

24. 25.

Tephrosia purpurea Tilia cordata

Fabaceae Tiliaceae

30 26

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PHARMACOLOGY OF FLAVONOIDS: Reported flavonoids: Flavonoids have been reported to exert wide range of biological
11, 15],

Pharmacological

activities

of

O2

e-

.O 2

H+

HO2. HO2. O2

H2O2.

activities. cytotoxic

These antitumour,

includes: treatment

anti[10,

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). 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. 1. 2. Reactive species O2 (Superoxide anion) HO2 H2O2 (Hydrogen peroxide) - Mechanism One-electron reduction product of O2. Produced by phagocytes, formed in autoxidation reaction and generated by oxidases (heme proteins) Protonated form of O2 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 Three electrons reduction products of O2 generated by Fentons reaction, transition metal (iron, copper)catalysed Haber-Weiss reaction; also formed by decomposition of peroxynitrite produced by reaction of O2 with nitric oxide radical. Lipid peroxy radical (LOO ) produced from organic hydroperoxide, ROOH by hydrogen abstraction. Singlet Oxygen
.

inflammatory, antibacterial, antiviral, antiallergic neurodegenerative

[4,11,13,39].

of

diseases, platelet fragility,

vasodilatory aggregation,

action capillary and

In addition flavonoids are known to inhibit and cyclo-oxygenase

lipid-peroxidation, permeability

lipoxygenase enzyme activities. They exert these effects as antioxidants, free radical scavengers, chelators of divalent cation
[15, 39, 40].

These are also

.O 2

+ .O2-

2H+

reported to inhibit variety of enzymes like hydrolases, hyalouronidase, alkaline phosphatise, arylsulphatase, cAMP phosphodiesterase, lipase, -glucosidase, kinase [41]. 1. Flavonoids as antioxidants:

Mechanism of flavonoids as antioxidants: Flavonoids are powerful antioxidants against free 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.)

3.

4.

OH (Hydroxy radical)

5. 6.

(Alkoxy RO . radical), ROO (Peroxyl radical) 1 O2

According to kinetic studies of aroxyl radical 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]. 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 Bring, which confers greater stability 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.
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to aroxyl

radicals, possibly through hydrogen bonding, and

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)).

(a)
OH OH OH OH OH OH

Ulcer is a commonly occurring disease in developed countries and its occurrence is emerging with increase in modernisation of living standards. Etiology of gastric ulcer: The stress hormones like epinephrine, norepinephrine, and ACTH, causes a vasoconstriction in the integument and the periphery, whereas, they dilate the vessels of muscles, heart, and brain. But, if the duration of this state gets prolonged, then blood supply to major organs, e.g., stomach, intestine, liver, kidneys, and skin get reduced and thus failing to satisfy demand for oxygen, antibodies and other agents that are required to maintain a healthy condition. As a result, the stress hormones increases the glandular secretion which denatures proteins in plasma membranes and catalyses the hydrolysis of polysaccharide moieties of proteoglycans in the protective mucous coat covering the luminal surface of the stomach and the upper intestine to a perilous extent during prolonged stress. When the walls of the blood vessels supplying oxygen, nutrients, and protective substances to this area gets sufficiently weakened, then slight mechanical insults easily cause ruptures, resulting in leakage of blood into the tissue. Such events start inflammation and repair processes in which eicosanoids, e.g., PGs, participate [16]. Flavonoids in treatment of gastric ulcer: Flavonoids inhibit regulation of protein phosphorylation. Inhibition of P-kinase signalling influence protein phosphatase which reverses the action of protein P-kinase as shown in fig (VIII):
(-) cAMP (-) protein kinase C (-) protein phosphorylation (-) COX

(b)

(c)

HO

HO

HO

OH

OH

b
OH O OH O

OH

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 3rhamnoside (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 3O--rhamnoside possesses lowest antioxidant activity
[47].

Salucci et al., reported that dietary flavonoids like epicatechin, epigallocatechin, galate, gallic acid, quercetin-3-glucoside activity [48]. Gulati et al., reported that quercetin at a dose of 15 mg/ 100g p.o. produced significant hepatoprotection
[49].

FLAVONOID

Inhibit gastric ulcer

possess

strong

antioxidant

Fig (VIII): Effect of flavonoids on gastric ulcer

Flavonoids are favourable, effective, and usually innocuous substitutes for the classical therapeutic agents. It has also been reported that flavonoids protect against gastric cancer. Similar to aspirin, acylated flavonoids may transfer their acyl group to
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2. Effect of flavonoids on gastric ulcer:

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the side chain hydroxyl group of serine in the active site of COX
[16].

battle against invasion by microorganisms or their toxins which are recognised by specific antibodies mounted on the surface of the macrophages in a receptor enzymes from the (FcR). i.e. Fc receptor is non-covalently lipase which inositol associated with a second messenger producing phosphatidylinositol membrane. liberates inositol phosphates and diacylglycerol (DAG) plasma Several phosphates activate specific protein phosphokinases

Flavonoids glycosides of Ocimum basilicum decreased ulcer index and thus inhibit gastric acids in aspirininduced ulcers. Quercetin, Kaempferol, rutin when administered intraperitoneally (25-100 mg/kg) inhibited dose-dependent gastric damage produced by ethanol in rats [43]. 3. Effect of flavonoids on inflammation: Etiology: Inflammation is the integrated response of many defence systems of the body to the invasion of a foreign body. Inflammation involves action of the complement system, blood coagulation, humoral and cellular immunity, cytokines, tissue hormones, angiogenesis, and repair processes. It is both a free radical generating and free-radical producing process
[50].

and DAG stimulates PKC.

The toxin-antibody

complexes are endocytised, and raise the alarm in the cell, with the result that the latter emits IL-1. This substance induces the expression of the COX gene, which encodes the PG COX that produces the eicosanoids, i.e., signal substances for the pain pathway (fig IX), chemotaxis, and smooth muscle contraction [16].

An important mechanism in inflammation is the recruitment of macrophages to participate in the MEMBRANE PHOSPHOLIPIDS ARACHIDONIC ACID PATHWAY FLAVONOIDS CYCLOOXYGENASE COX-1 COX-2 LIPOOXYGENASE 5-LOX 5-HPETE 12-LOX 12-HETE

PGG2 PGH2

LTA4

PGI2

PGD2

PGE2

PGF2

TXA2

LTE4

LTB4

Fig IX: Arachidonic acid pathway [51] Flavonoids in treatment of inflammation: Flavonoids have been found to be prominent inhibitors of COX or LOX
[42, 45].

catechins) have also been shown to have antiinflammatory activity by inhibiting cycloxygenase-2 (COX2) and inducible nitric oxide synthase [52], which is related to antioxidant activity inhibit neutrophil degranulation inflammation.
[50].

Flavonoids prevent

synthesis of PGs that suppress T-cells. The immune cells communicate with chemical signals called cytokines site. which are also controlled promote by IFN flavonoids. synthesis Flavonoids inhibit the activity of PKC at ATP-binding Flavonoids
[16].Various

Flavonoids also
[40, 53]

inhibit cytosolic and tyrosine kinase

[40].

and also

The figure (X)

represents the effect of flavonoids in the treatment of

flavonoids (e.g., quercetin, apigenin, tea

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(-) COX (-) iNOS (-) cytosolic kinase (-) tyrosine kinase (-) neutrophil degranulation (-) protein kinase C (+) Promote IFN synthesis

head of the bone. These spikes cause tissue lesions, bleeding, inflammation, and pain [16].
INHIBIT INFLAMMATION

FLAVONOID

Flavonoids

in

treatment

of

Rheumatic

diseases: The beneficial effect of orally consumed flavonoids includes the elimination of the PGs which mediate the pain. An additional effect of the flavonoids may be to activate cytotoxic Tlymphocytes, which kill cells presenting the harmful foreign antigen. Flavonoids do activate cytotoxic Tlymphocytes, but the antigen, against which the lymphocytes are directed, remains unidentified shown in fig (XI).
FLAVONOIDS Activate Cytotoxic T-lymphocytes
[16]

Fig X: Effect of flavonoids on Inflammation Citrus flavonoids, hesperidin is known to possess antiinflammatory and analgesic effects. Apigenin, luteolin, quercetin are known to possess antiinflammatory activity [43]. Guardia et al., reported quercetin and hesperedin given at a daily dose of 80 mg/kg inhibit both acute and chronic phase of inflammation while rutin was found to be effective only in chronic case [54]. Kaempferol, quercetin, myricetin, fisetin are reported to possess COX and LOX inhibitory activities [43]. 4. Effect of flavonoids on rheumatic disease: Etiology of Rheumatic disease: Autoimmunity and inflammation is an important component of rheumatoid arithritis. Since rheumatic disease is associated with painful joints, it is believed that the antigen specificity of the T-cells is directed against an epitope characteristic of the cartilage in a joint, e.g., a part of chondroitin sulphate. IL-1 is produced by macrophages. It acts as a growth hormone on T-lymphocytes, which are induced to proliferate and secrete IL-2, which, in turn, is a mitogen to T and B-lymphocytes, macrophages, granulocytes, and blood vessel endothelial cells. Osteoclasts resembles macrophages because both produce and secrete IL-1 and are phagocytic. If osteoclasts respond to IL-2 secreted from immune cells, then, the enhanced osteoclastic activity leads to the destruction of the heads of the long bones in the joints. In rheumatic arithritis, such a destruction is followed by repair processes, which are uncoordinated with the mechanical requirements defined by the stress gradients. The topological activation pattern of the osteocytes leads to the formation of bony spikes in the

as

Inhibit PGs

Kill T-cells prone to antigen

Fig (XI): Effect of flavonoids in Rheumatoid arithritis

Kang

et

al.,

reported

that

apigenin

inhibits

autoantigen-presenting and stimulatory functions of APCs necessary for activation and expansion of autoreactive Th1 and Th17 cells and B cells and reported that it could suppress inflammation in rheumatoid arithritis [53].Guardia et al., reported rutin to be most effective plant flavonoids for the treatment of inflammation in chronic phase [54]. 5. Flavonoids in treatment of thrombosis: Etiology of Thrombosis: Arachidonic acid released by in inflammatory conditions is metabolized by platelets to form prostaglandin, endoperperoxides and thromboxane A2 thus contributing to platelet activation and aggregation. Platelet aggregation further contributes to atherosclerosis and acute platelet thrombus formation. Activated platelets adhering to vascular endothelium generate lipid peroxides and oxygen free radicals which inhibit endothelial function of prostacyclin and nitric oxide
[40].

Flavonoids

in

treatment

of

thrombosis:

Flavonoids are used as antithrombotic due to their ability to scavenge free radicals. They inhibit

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cyclooxygenase and lipooxygenase pathway. The main antiaggregatory effect is by the inhibition of thromboxane A2 formation. Flavonoids like quercetin, kaempferol and myricetin are known to possess antiaggregatory properties
[40, 43].

Cancer

cells

manifest

to

varying

degree

of

uncontrolled proliferation, dedifferentiation and loss of function, invasiveness and metastasis that differ it from normal cells [51]. Flavonoids in treatment of Cancer: Flavonoids for a long time have been part of the herbal treatment by lay practitioners, but they were recognised only recently as effector substances. Examples of herbal preparations owing their growing recognition as

The fig XII

represents mechanism of flavonoid in thrombosis.

FLAVONOIDS

(+) cAMP in platelets (-) intracellular Ca++ (-) IP3 formation (-)TxB2 formation (-)TxA2 formation (-) Phospholipase C (-)PIP2 levels (-) Intracellular production of H2O2

effective anticancer drugs to flavonoids are propolis

(-) THROMBOSIS and PLATELET AGGREGATION

and Essiac [16]. Flavonoids are potent bioactive molecules that possess anticarcinogenic effects since they can interfere with the initiation, development and progression of cancer by the modulation of cellular

Fig (XII): Effect of flavonoids on thrombosis 6. Effect of flavonoids on cancer-related pathways: Etiology of Cancer: Cancer is a growth of diseases caused by disturbance in growth metabolism
[52].

proliferation, differentiation, apoptosis, angiogenesis and metastasis [55] as shown in fig (XIII). Flavonoids have emerged as potential chemopreventive candidates for cancer treatment due to their ability to induce apoptosis[55].

Normal cell

Initiated cell
Prevent further DNA damage Induces apoptosis

Preneoplasts
Prevent further DNA damage, Induces apoptosis cell cycle arrest Inhibit angiogenesis

ROS scavenging , Alter carcinogen metabolism

Metastasis

Tumour
Prevent further DNA damage, Inhibit angiogenesis, Inhibit invasion

Fig XIII: Multistage of carcinogenesis and potential effects of polyphenols on cancer progression [55] Flavonoids have been shown to be highly effective scavengers of most types of oxidizing molecules, including singlet oxygen and various free radicals, which are possibly involved in DNA damage and tumor promotion. Flavonoids may also have a beneficial effect through their impact on the
OH

OH OH OH HO HO O HO O OH OH OH OH O OH O OH O O

OH

Fig(XIV): Kaempferol Fig(XV): Quercetin Fig(XVI): Apigenin

OH O

bioactivation of carcinogens.
O

The flavonols quercetin (fig XV), kaempferol (fig XIV) and galangin, and the flavones apigenin (fig XVI) have been reported to inhibit cytochrome P450 enzymes of the CYP1A family.

Fig (XVII): Naringin

Quercetin (fig XIV) and naringin (fig XVII) have also been shown to inhibit CYP3A4, which is the most abundant P450 enzyme in the liver and beneficial in metabolizing a significant number of carcinogens and medications
[16].

Quercetin is abundantly found in

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Bimlesh Kumar, et al: A Review of Phytochemistry and Pharmacology of Flavonoids

human diet and it gets extensively metabolized during absorption in the small intestine and in the liver, and thus exerts a dose-dependent inhibitory effect on cell proliferation activity of
[55].

has been speculated that this classical hydrogendonating antioxidant activity cannot account for the bioactivity of flavonoids in the brain as they are present in very low concentrations. Instead, it has been postulated that their effects in the brain is mediated by an ability to protect vulnerable neurons, enhance existing neuronal function, stimulate neuronal regeneration and induce neurogenesis. Indeed, it has become evident that flavonoids are able to exert neuroprotective actions even at low concentration via their interactions with critical neuronal intracellular signalling pathways pivotal in controlling neuronal survival and differentiation, long-term potentiation and memory. Early indications regarding the ability of flavonoids to impact upon brain function were reported in the 1950s, with flavones reported
[14].

In addition, animal and in vitro detoxifying and antioxidant

studies have shown that tea catechins increase the several enzymes, such as glutathione reductase, glutathione peroxidase, glutathione S-reductase, catalase, and quinone reductase
[16, 55].

In estrogen-dependent

tumor cells or animal models, this anti-proliferative effect has been related to the antiestrogenic properties of certain flavonoids (e.g., isoflavonoids, quercetin). In other in vitro models, flavonoids have also been to affect cell-signaling and cell cycle progression. For example, tea flavonoids inhibit signal transduction pathways mediated by epidermal growth factor and platelet-derived growth factor, favorably affecting downstream events such as angiogenesis. Genistein (fig XVIII) and quercetin inhibit protein tyrosine kinase which is also involved in cell proliferation [16, 55,
56].

to

act

as

novel

brain-stem

stimulants

Studies suggest that flavonoids, in

particular isoflavones such as genistein might be detrimental to memory processes in the brain due to their ability to act as tyrosine kinase inhibitors. Researches revealed that isoflavones results in positive effects on neuro-cognitive functions which is apparent in post-menoupausal women. Activation of

Finally, apigenin, luteolin (fig XIX) and quercetin

have been shown to cause cell cycle arrest and apoptosis by a p53-dependent mechanism [52].
OH OH O OH HO O HO

both synaptic plasticity and new neural growth may act together to enhance memory and cognition as shown in fig (XX) [57]. It has been found that flavonoids subclasses flavonols, flavanols, flavanones, flavones and anthocyanins do not exert exert oestrogen like effects and thus cannot influence memory and cognition via similar

OH

O OH O

Fig (XVIII): Genistein

Fig (XIX): Luteolin

In a nutshell, multiple mechanisms have been identified for the anti-neoplastic effects of flavonoids, including antioxidant, anti-inflammatory and antiproliferative activities, inhibition of bioactivating enzymes, and induction of detoxifying enzymes [52]. Ghasemzadeh et al., studies have shown that some flavonoids components such as quercetin had

mechanism.
SENSORY INFORMATION (EXPERIENCE) AFFERENT NERVE INPUT

Increased Blood flow FLAVONOIDS Angiogenesis Neurogenesis Old neurons Neuronal Maturation Functional integration New Synapses Memory Immature neurons

anticancer activities and were able to inhibit cancer cell growth [46]. 7. Effect of flavonoids on memory: Flavonoids in treatment of memory cognition: Historically, the biological actions of flavonoids to their ability to exert antioxidant actions. However, it
33

Synaptic Activit Synaptic plasticity

Fig XX: Overview of functions of flavonoids on memory system[57] Jan-Mar 2011 Vol 1 Issue 1

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Bimlesh Kumar, et al: A Review of Phytochemistry and Pharmacology of Flavonoids

Jung et al., showed that quercetin at a dose of 10, 20, 40 mg/kg p.o. impairs cognitive function by suppressing pAkt and pCaMKII thus decreasing pCREB expression in hippocampus [49]. Maher et al., reported fisetin to facilitate memory by activating ERK and inducing cAMP response elementbinding protein phosphorylation [58]. 8. Effect of flavonoids on allergy: Flavonoids in treatment of allergy: Flavonoids inhibit cyclic AMP phosphodiesterase and calciumdependent ATPase which are responsible for histamine release from mast cells and basophils [11].

FLAVONOID

(-) cAMP (-)PDEase (-) Ca++ dependent ATPase

PREVENT ALLERGY

Fig (XXI): Effect of flavonoids on allergy The fig (XXI) depicts the mechanism of flavonoids in allergy. Quercetin prevents immune cells
[59]

and

inhibits both the production and release of histamine and is useful in allergic conditions like asthma, hayfever etc [60]. 9. Effect of flavonoids on depression: Etiology of Depression: Depression is caused by functional deficiency of monoamine transmitters at certain sites in brain [51] as shown in fig (XXII).

STRESS

GLUTAMATE

NA

5- HT

BDNF

CRF release

Hypothalamus

NMDA receptor

2 receptor

5HT1A

TrkB receptors

ACTH hormone

Signal Transduction Pathways _ _ + + +

Pituitary Detrimental gene

Cortisol release

Beneficial gene transcription response _ + Neurogenesis

transcription response + _

Neural apoptosis

DEPRESSIVE SYMPTOMS Fig XXII: Pathophysiology of depression [51]

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Bimlesh Kumar, et al: A Review of Phytochemistry and Pharmacology of Flavonoids

Flavonoids in treatment of depression: Flavonoids have found to be ligands for GABAA receptors in the central nervous system and it led to hypothesis that they act as benzodiazepine-like molecules. Many flavone derivatives were found to be ligands for the GABAA receptors in the CNS; and thus they bind to the benzodiazepine binding site with resulting depressant actions in mice anticonvulsant. Considering the
[7].

propolis. It has been reported to possess inhibitory actions against Aspergillus tamarii, Aspergillus flavus, Cladosporium sphaerospermum, Pencillium digitatum, Penicillium italicum [10]. 5,7,4-trihydroxy-8-methyl-6-(3-methyl-[2-butenyl])2S-flavonone texana isolated from shrub Eysenhardtia and flavonoids 7-hydroxy-3,4-

These were the

also found to possess sedative action, tranquilizers, sedative, spontaneous locomotor activity and thiopental-induce sleeping time effects obtained with the flavonoid glycosides, the following decreasing order of action results: 2S-hesperidin>linarin>rutin>diosmin\cong2Sneohesperidin> gossypin2S-naringin.

(methylenedioxy) flavan isolated from Termanalia bellerica possess antifungal activity against Candida albicans. 6,7,4-trihydroxy-3,5-dimethoxyflavone and 5,5-dihydroxy-8,2,4-trimethoxyflavone are effective against Aspergillus flavus [10]. Nobiletin and langeritin isolated from peelings of tangerine orange showed fungistatic action towards Deuterophoma tracheiphila while
[43].

hesperidin

Position of the sugar on the flavonoids nucleus seems relevant as well and position-7 is the most effective but the presence of a double bond between carbons 2 and 3, resulting in flavone derivatives with planar configuration (i.e. linarin) does not appear to be critical for activity. Flavonoid glycosides form the newest group within the growing family of flavonoids with activity on the CNS [7]. Yi et al., reviewed that dietary flavonoids possess multiple neuroprotective actions in Central nervous pathophysiological conditions including depression and it was reported that naringenin possess potent antidepressant-like property via central seotonergic and noradrenergic system. It was further suggested that dietary flavonoids possess a therapeutic potential in disorders especially where monoaminergic system is involve [61]. 10. Effect of flavonoids on antimicrobial activity: Flavonoids have been used extensively since centuries for the treatment of various diseases. Propolis has been used referred even in old testament for its healing properties. The antimicrobial activity of propolis has been attributed to its high flavonoids content. Galangin is a flavonol commonly found in
35

stimulate fungal growth slightly

Quercetin, naringenin are reported to be inhibitors of Bacillus subtilis, Candida albicans, Escherichia coli, Staphylococcus nervous, Staphylococcus epidermis, Saccharomyces cerevisiae [62]. Rattanachaikunsopon et al., isolated morin-3-Olyxoside, leaves and morin-3-O-arabinoside, from reported bacteria coli, that these quercetin, guajava possess Bacillus four quercetin-3-O-arabinoside Psidium

bacteriostatic action action against all foodborne pathogenic Escherichia Pseudomonas including Listeria stearothermophilus, Brochothrix thermosphacta, monocytogenes, enteric,
[63].

fluorescens,

Salmonella

Staphyloccus aureus, Vibrio cholera

Flavonones having sugar moiety showed antimicrobial activity while none of the flavonols and flavonolignans showed inhibitory activity on microorganisms. Quercetin has been reported to completely inhibit growth of Staphylococcus aureus [43].

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Table 4: Antibacterial, antimicrobial and antiviral activities of flavonoids [41]

S. No. Activity Organism Staphylococcus aureus Staphylococcus albus Streptococcus pyogenes Streptococcus viridians Streptococcus jaccalis Streptococcus baris Streptococcus pneumonia Pseudomonas aeruginosa Escherichia coli Baccilus subtilis Bacillus anthracis Proteus vulgaris Clostrium perfingens Rabies virus Herpes virus Para influenza virus Herpes simplex virus Respiratory synctial virus Immuno-deficiency virus infection Auzesky virus Polio virus Mengo virus Pseudorabies virus Candida albicans Candida tropicalis Fusarium solani Botrytis cinerea Verticillum dahlia Azotabacter vinelandii Alternacia tennisima Cladosporium herbarum Flavonoid Quercetin, Baicalin, Hesperitin, Fisetin, Naringin+rutin, Naringin+hespertin, iso-liquiritigenin Fisetin Apigenin Apigenin Chrysin Chrysin Chrysin Rutin,naringin,baicalin, hydroxyethylrutosine Quercetin Quercetin Rutin Datisetin Hydroxyethylrutoside Quercetin,quercetrin, rutin Quercetin Quercetin, rutin Galangin, quercetin, kaempferol,apigenin Quercetin,naringin Apigenin Quercetin, Quercetrin, morin, apigenin Quercetin Quercetin Quercetin Chloroflavonin Quercetin Chrysoeriol Chrysoeriol Chrysoeriol Quercetin,rutin, epicatechin Apigenin, Echinacin Phaseolinisoflavan

1.

Antibacterial activity

2.

Antiviral activity

3.

Antifungal activity

11. Flavonoids in treatment of cardiovascular diseases: 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:

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.

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

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Table 5: Proposed positive effects of flavonoids on CVS:

S. No. 1. 2. 3. 4. 5. Cardiovascular diseases Atherosclerosis Acute myocardial infarction Heart Failure Arrhythmia Hypertension Influence of flavonoids 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 Decrease in ROS burst, inhibition of platelet aggregation Decrease in oxidative stress (direct ROS scavenging) inhibition of metalloproteinase Decrease in oxidative stress 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].

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 alloxaninduced 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 DNAdependent RNA polymerase I, thus activating the enzyme. As a result, protein synthesis gets increased leading to regeneration and production of hepatocytes
[11].

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
[66]. [16].

Silymarin,

apigenin,

quercetin,

naringenin

are

Flavonoids have been

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

identified to be good inhibitors of aldose reductase The fig (XXIII) depicts the mechanism of flavonoids in diabetes mellitus.
(-) Aldose reductase, Regenerate pancreatic islets, (+) insulin release, (+) Ca++ uptake PREVENT DIABETES MELLITUS

FLAVONOID

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]. 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
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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 streptozotocininduced diabetes. Also, it has been reported to
37

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Bimlesh Kumar, et al: A Review of Phytochemistry and Pharmacology of Flavonoids

cells, whereas isovitexin and trifolin possess no protective effect

[70].

phytochemicals on an individual basis but are less toxic to normal cells

[40].

[10].

Flavonoids

are found to be toxic to cancer or immortalized cells 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 majority of disases. Antioxidant activity is the foundation of many actions which lead to its beneficial effects in majority of the diseases. used in

Oh et al., 2004 reported that among various flavonoids i.e. apigenin, luteolin, kaempherol-3-Oglucoside 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 toxic and have been previously traditional medicines, so they are believed to be non[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 toxicity appears is to vary to from be compound on to compound, a study regarding assessment of its required done these

Table 6: Diseases treated with Flavonoids

S. No. 1. 2. 3. Ulcer Rheumatoid arithritis Inflammation Disease Flavonoid Kaempferol, (+)-Cyandidanol-3, meciadanol, catechins Sofalcone, Quercetin Apigenin, rutin Quercetin, apigenin, catechin Hesperidin,rutin, luteolin Kaempferol, quercetin, myricetin, fisetin Quercetin, Kaempferol, Galangin, Apigenin Quercetin, naringin Genistein, Quercetin Apigenin, luteolin, quercetin Catechins Genistein Quercetin Fisetin Naringenin, 2S-hesperidin, Linarin Quercetin 7-monohydroxyethylrutoside, 7,3,4-trihydroxyrutoside Fisetin Quercetin Quercetin Rutin, citrin Disodium cromoglycate Quercetin Avicularin, hirustrin Onitin, luteolin Tangeratin, hesperidin, quercetin, rutin Trihydroxyethylrutoside, O-( hydroxyethyl)rutoside, (+)-catechol Nobelitin, sinesetin Target PAF Gastric H+/K+ ATPase PG synthesis Suppress inflammation by acting on COX COX and iNOS PG synthesis Na /K ATPase, Cyt P450 Cyt P3A4 Tyrosine kinase P53 dependent Glutathione reductase, glutathione peroxidise, catalase, quinine reductase Tyrosine kinase pAKt and pCREB ERK and cAMP response element ------------------------LDL Aldose reductase Mast cell Capillary wall + H ATPase ------------------------Horse erythrocytes Blood vessels Erythrocyte aggregation Vascular permeability
+ +

Reference 41, 43 41 41, 43 54, 53 50, 52 43, 54 43 16 16 16,55, 51 46, 52 16, 55 49 49 58 61 7 43 68, 41 58, 59 41 41 69, 71 71 71 41

4.

Cancer

5. 6. 7. 8. 9. 10. 11.

Memory dysfunction Depression Cardiovascular diseases Diabetes mellitus Antiallergic Hepatoprotective

Thrombosis

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REFERENCES
1. Tripoli, E, Guardia, ML, Giammanco, S, Majo, DD, Giammanco, structure, 466-479. 2. Slade, D, Ferreira, D, Marais, JPJ. Circular M. Citrus flavonoids: and Molecular nutritional biological activity

12.

Peterson, J, Dwyer, MSJ, RD, DSc. Flavonoids: Dietary occurrence H. and biochemical activity. Nutrition Research 1998; 18: 1995-2018.

13.

Tsuchiya,

Structure-dependent

membrane

properties: A review. Food Chemistry 2007; 104: 14.

interaction of flavonoids associated with their bioactivity. Food Chemistry 2010; 120: 1089-1096. Rijke, ED, Out, P, Niessen, WMA, Ariese, F, Goojer, C, Brinkman, UAT. 2006. Analytical separation and detection 15. methods for flavonoids. Journal of Chromatography A 2006; 1112: 31-63. Cook, NC, Samman, S. Flavonoids: Chemistry, metabolism, cardioprotective effects and dietary sources. Nutritional Biochemistry 1996; 7: 66-76. 16. Havsteen, BH. The biochemistry and medical significance of the flavonoids. Pharmacology and Therapeutics 2002; 96: 67-202. 17. Sahu, SC, Gray, GC. Pro-oxidant activity of flavonoids: effect on glutathione and glutathione-Stransferase in isolated rat liver nuclei. Cancer letters 1996; 104: 193-196. 18. Prey, JO, Brown, J, Fleming, J, Harrison, PR. Effect of dietary flavonoids on major signal transduction pathways in human epithelial cells. Biochemical Pharmacology 2003; 66: 2075-2088. 19. Ren, W, Qiao, Z, Wang, H, Zhu, L, Zhang, L. Flavonoids: Promising Anticancer agents. Medicinal Research Reviews 2003; 23: 519-534. 20. Aderogba, MA, Ogundaini, AO, Eloff, JN. Isolation of two flavonoids from Bauhinia monandra leaves and their antioxidative effects. African Journal of Traditional 21. Complementary and Alternative Medicines 2006; 3: 59-65. Lopez-Lazaro, Miguel. Distribution and Biological activities of flavonoids luteolin. Mini-Reviews in medicinal Chemistry 2009; 9: 31-59. 22. Nahrstedt, A, Hungeling, M, Petereit, F. Flavonoids from Acalypha indica. Fitoterapia 2006; 77: 484488. 23. Chakroborty, T, Verotty, L, Poddar, G. Evaluation of Azadirachta indica leaf extract for hypoglycaemic activity in rats. Phytotherapy Research 1989; 3: 3032. 24. Babu, VS, Narasimhan, : S, Nair, GM. Short of communication Enhanced accumulation

dichroism, a powerful tool for the assessment of absolute configuration of flavonoids. Phytochemistry 2005. 66; 2177-2215. 3. Hotta, H, Nagano, S, Ueda, M, Tsujino, Y, Koyama, J, Osakai, T. Higher radical scavenging activity of polyphenolic antioxidants ascribed to chemical reactions 4. following oxidation. Biochimica et Biophysica Acta 2002; 1572: 123-132. Williams, RJ, Spencer, JPE, Rice-Evans, C. Serial review: Flavonoids and isoflavonones Metabolism and (Phytoestrogens): 36: 838-849. 5. Skerget, M, Kotnik, P, hadolin, M, Hras, AR, Simonic, M, Knez, Z. Phenols, proanthocyanidins, flavones and flavonols in some plant materials and their 6. antioxidant activities. Food Chemistry 2005;89: 191-198. Ferreira, J,F,S, Luthria, D,L, Sasaki, T, Heyerick, A. Flavonoids from Artemisia annua as antioxidants and their potential synergism with Artemisinin against malaria and cancer. Molecules 2010; 15: 3135-3170. 7. Fernandez, SP, Wasowski, C, Loscalzo, LM, Granger, RE, Johnston, GAR, Paladini, AC, Marder, M. Central flavonoid 8. nervous system depressant action of of glycosides. European Journal Absorption,

Bioactivity. Free Radical Biology and Medicine 2004;

Pharmacology 2006; 539: 168-176. Heim, KE, Tagliaferro, AR, Bobliya, DJ. Flavonoids antioxidants: Chemistry, metabolism and structureactivity relationships. The Journal of Nutritional Biochemistry 2002; 13: 572-584. 9. Hollman, PCH, Katan, MB. Dietary Flavonoids: Intake, Health Effects and Bioavailability. Food and Chemical Toxicology 1999; 37: 937-942. 10. Cushnie, TPT, Lamb, AJ. Antimicrobial activity of flavonoids. International Journal Agents 2005; 26: 343-356. 11. Murray, MT. Quercetin: Natures antihistamine. Better Nutrition 1998. Of Antimicrobial

triterpenoids and flavonoids in cell suspension cultures of Azadiracta indica with an extended stationary phase. Indian Journal of Biotechnology 2008; 7: 270-272.

39

Internationale Pharmaceutica Sciencia

Jan-Mar 2011

Vol 1 Issue 1

Bimlesh Kumar, et al: A Review of Phytochemistry and Pharmacology of Flavonoids 25. Niranjan, A, Tewari, SK, Lehri, A. Biological activities of Kalmegh (Andrographis paniculata) and its active principles: A Review. Indian Journal of Natural Products and Resources 2010; 1: 125-135. 26. Gupta, KK, Taneja, SC, Ahar, KL, Atal, CK. Flavonoids 27. of Andrographis paniculata. Phytochemistry 22: 314-315. Evans, WC. Trease and Evans Pharmacognosy. 16th edition. Elseveir. 28. Murlidhar, A, Babu, KS, Sankar, TR, Redenna, P, Reddy GV, Latha J. Antiinflammatory activity of flavonoids from stem bark of Butea monosperma : A mechanism based study. International Journal of Phytopharmacology ; 1: 124-132. 29. Aderogba, MA, Ogundaini, AO, Eloff, JN. Isolation of two flavonoids from Bauhinia monandra leaves and their antioxidative effects. 30. Sannomiya, M., Fonseca, VB, Silva, MAD, Rocha, LRM, Santos LCD, Hiruma-Lima, CA, Brito, ARMS, Vilegas, W. Flavonoid and antiulcerogenic activity from Brysonima crassa leaves extract. Journal of Ethnopharmacology 2005; 97: 1-6. 31. Sankaranarayanan, S, Bama, P, Ramachandran,J, Kalaichelvan, PT, Deccaraman, M, Vijayalakshmi, M, Dhamotharan, R, Dananjeyan, B, Bama, SS. 43. Ethnobotanical study of medicinal plants used by traditional users in Villupuram district of Tamil Nadu, India. Journal of Medicinal Plants Research 2010; 4: 1089-1101. 32. Kogawa, K, Kazuma, K, Kato, N, Noda, N, Suzuki, M. Biosynthesis of malonylated flavonoids glycosides on basis of malonyl transferase activity in petals of Clitoria ternatea. Journal of Plant Physiology 2007; 164: 886-894. 33. Akorum, S, bendjeddou, D, Satta, D, Lalaoui, K. Antibacterial activity and acute toxicity effect of flavonoids extracted from Mentha longifolia. American-Eurasian Journal of Scientific research 2009; 4: 93-99. 34. Ghoulami, S, Idrissi, study of AI, Fkih-Tetouani, longifolia S. of 47. Phytochemical 35. Mentha 45. 42. 41. 39. 37. Pongamia pinnata with a Modified Ring A. Molecules 2006; 11: 786-791. Li, L, Li, X, Shi, C, Deng, Z, Fu, H, Proksch, P, Lin, W. Pongamone A-E, five flavonoids from the stems of mangrove plant, Pongamia pinnata. Phytochemistry 2006; 67: 1347-1352. 38. Tanaka, T, Linuma, M, Yuki, K, Fujii, Y, Mizuno, M. Flavonoids in root bark of Pongamia pinnata. Phytochemistry 1992, 31: 993-998. Chebil, L, Humeau, C, Falcimaigne, A, Engasser, J, Ghoul, M. Enzymatic acylation of flavonoids. Process Biochemistry 2006; 41: 2237-2251. 40. Middleton, EJR Kandaswami, C, Theoharides, TC. The Effects of Plant Flavonoids on Mammalian cells: Implications for inflammation, heart disease, and cancer. Pharmacological Reviews 2000; 52: 673-751. Narayana, KR, Reddy, SR, Chaluvadi, MR, Krishna, DR. Bioflavonoids classification, pharmacological, biochemical effects and therapeutic potential. Indian Journal of Pharmacology 2001; 33: 2-16. Pal, RS, Ariharasivakumar, G, Girhepunjhe, K, Upadhay, A. In-vitro antioxidative activity of phenolic and flavonoids compounds extracted from seeds of Abrus precatorius. International Journal of Pharmacy and Pharmaceutical Sciences 2009; 1: 136-140. Tapas, AR, Sakarkar, DM, Kakde, RB. Flavonoids as nutraceuticals: A Review. Tropical Journal of Pharmaceutical Research 2008; 7: 1089-1099. 44. Ghasemzadeh, A, Jaafar, HZE, Rahmat, A. Antioxidant activities, total Phenolics and flavonoids content in two varieties of Malaysia Young Ginger ( Zingiber officinale Roscoe). Molecules 2010; 15: 4324-4333. Bitis, L, Kultar, S, Melikoglu, G, Ozsoy, N, Can, A. Flavonoids and antioxidant activity of Rosa agrestis leaves. Natural Product Radiance 2003; 24: 580589. 46. Sharififar, F, Dehghn-Nudeh, G, Mirtajaldini, M. Major flavonoids with antioxidant activity from Teucrium polium. Food Chemistry 2009; 112: 885888. Braca, A, Sortino, C, Politi, M, Morelli, I, Mendez, J. Antioxidant activity of flavonoids from Licania licaniaeflora. Journal of Ethnopharmacology 2002; 79: 379-381. 48. Salucci, M, Stivala, LA, Maiani, G, Vannini, V. Flavonoids uptake and their effect on cell cycle of

Morrocco. Fitoterapia 2001; 72: 596-598. Agarwal, M, Kamal R. Studies on flavonoids production using in-vitro cultures of Momordica charantia. Indian Journal of Biotechnology 2007; 6: 277-279. 36. Yin, H, Zhang, S, Wu, J, Nan, H, Long, L, Yang, J, Li, Q. Pongaflavanol: a prenylated Flavonoid from

Internationale Pharmaceutica Sciencia

Jan-Mar 2011

Vol 1 Issue 1

40

Bimlesh Kumar, et al: A Review of Phytochemistry and Pharmacology of Flavonoids human colon adenocarcinoma cells. British Journal of Cancer 2002; 86: 1645-1651. 49. Jung, WY, Park, SJ, Park, DH, Kim, JM, Kim, DH, Ryu, JH. Quercetin impairs learning and memory in normal mice via suppression of hippocampal phosphorylated binding 50. Miller, protein AL. cyclic AMP response elementletters 62. expression.Toxicological flavonoids: 61. Yi, L, Li, C, Zhan, X, Cui, C, Xiao, F, Zhou, L, Xie, Y. Involvement of monoaminergic system in antidepressant-like effect of flavonoids naringenin in mice. Progress in Neuro-Psychopharmacology and Biological Psychiatry 2010; 34: 1223-1228. Taleb-Contini, SH, Salvador, MJ, Watanabe, E, Ito, I., Oleveira, DCRD. Antimicrobial isolated activity from of two flavonoids Structure, 63. and steroids

2010; 197: 97-105. Antioxidant function and Clinical Usage. Alternative Medicine Review 1996; 1: 103-111. 51. Rang, HP, Dale, M.,M., Ritter, J.,M., Flower, R.,J., 2007. Rand and Dales Pharmacology. Seventh Edition, Churchill Livingstone. 52. Marchand, flavonoids53. LL. a Cancer preventive effects of & review. Biomedicine

Chromolaena species. Revista Brasileira de Ciencias Farmaceuticas 2003; 39: 403-408. Rattanachaikunsopon, P, Phumkhachorn, P. Contents and antibacterial activity of flavonoids extracted from leaves of Psidium guajava. Journal of Medicinal Plants Research 2010; 4: 393-396. 64. Mladenka, P, Zatloukalova, L, Filipsky, T, Hrdina, R. Cardiovascular effects of flavonoids are not caused only by antioxidant activity. Free radical Biology and Medicine 2010; 49: 963-975. 65. Zhou, T, Luo, D, Li, X, Luo, Y. Hypoglycaemic and hypolipidemic effects of flavonoids from lotus (Nelumbo nuficera) leaf in diabetic mice. Journal of medicinal Plants Research 2009; 3: 290-293. 66. Patra, JC, Chua, BH. Artificial neutral network-based drug design for diabetes mellitus using flavonoids. Journal of Computational Chemistry 2010; 32: 555567. 67. Li, F, Li, Q, Gao, D, Peng, Y. The optimal extraction parameters and anti-diabetic activity of flavonoids from Ipmoea batatas leaf. African Journal of Traditional, Complementary and Alternative Medicines 2009; 6: 195-202. 68. Sriram, PG, Subramanian, S. Fisetin, a bioflavonoid ameliorates hyperglycaemia in streptozotocininduced experimental diabetes in rats. International Journal of Pharmaceutical Sciences Review and Research 2011; 6: 68-74. 69. Gulati, RK, Agarwal, S, Agarwal, SS. Hepatoprotective studies on Phyllanthus emblica and quercetin. Indian Journal of Experimental Biology 1995; 33: 261-268. 70. Kim, SM, Kang, K, Jho, EH, Jung, Y, Nho, CW, Um, B, Pan, C. Hepatoprotective effect of flavonoids glycoside from Lespedeza cuneata against oxidative stress induced by tert-Butyl hyperoxide. Phytotherapy Research 2011.

Pharmacotherapy 2002; 56: 296-301. Kang, H, Ecklund, D, Liu, M, Datta, SK. Apigenin, a non-mutagenic dietary flavonoids, suppresses lupus by inhibiting autoantigen presentation for expansion of autoreactive Th1 and Th17 cells. Research and Therapy 2009; 11: 1-13. 54. Guardia, T, Rotelli, AE, Osvaldo, A. Antiinflammatory properties of plant flavonoids. Effect of rutin, quercetin and hesperidin on adjuvant arithritis in rats. Il farmaco 2001; 56. 55. Ramos, S. Effects of dietary flavonoids on apoptic pathways 442. 56. Lamson, DW, Brignall, MS. Antioxidants and Cancer III: Quercetin. Alternative Medicine Review 2000; 5: 196-208. 57. Spencer, JPE, Vanzour, D, Rendeiro, C. Flavonoids and cognition: The molecular mechanisms underlying their behavioural effects. Archives of Biochemistry and Biophysics 2009; 492: 1-9. 58. Maher, P, Akalshi, T, Abe, K. Flavonoid fisetin promotes ERK-dependent long-term potentiation and enhances memory. Proceedings of National academy of Sciences United States of America 2006; 103: 16568-16573. 59. Carlo, GD, Mascolo, N, Izzo, AA, Capasso, F. Flavonoids: Old and New aspects of a class of Natural Therapeutic Drugs. Life Sciences 1999; 65: 337-353. 60. http://www.umm.edu/altmed/articles/quercetin000322.htm related to cancer chemoprevention. Journal of Nutritional Biochemistry 2007; 18: 427Arithrits

71. Oh, H, Kim, D, Cho, J, Kim, Y. Hepatoprotective and

free radical activities of phenolic petrosins and flavonoids isolated from Equisetum arvense. Journal of Ethnopharmacology 2004; 95: 421-424.

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Internationale Pharmaceutica Sciencia

Jan-Mar 2011

Vol 1 Issue 1