| Jan-March 2011 | Vol. 1 | Issue 1 | Available online ©2011 IPS

A Review of Phytochemistry and Pharmacology of Flavonoids
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

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


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

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:, 25

and C6-C8-C6 carbon-skeleton skelton

[12, 13].

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


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

Internationale Pharmaceutica Sciencia

Jan-Mar 2011

Vol 1 Issue 1

whereas.The Fig (III): Chemical structure of different types of flavonoids [15] In plants. 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.Bimlesh Kumar. methoxy and glycosidic side groups and in the conjunction between A and B rings [8]. The average intake of flavonols and flavones was found to be 23 mg/day. et al: A Review of Phytochemistry and Pharmacology of Flavonoids 3' 2' 8 7 6 5 4 A O 4' 5' groups bound to Carbon of aglycone usually 6-C or 8-C [14]. The dietary (5) Anthocyanidin (6) Catechin (7) Dihydroflavonol (8) Chalcone intake of flavonoids is estimated to be 1-2 g/day [7]. but probably does not exceed 1% of the theoretical number of possible variants. or sulphated. flavonoids are often present as O-glycosides or C-glycosides. and 5’ as shown in fig (IV) which are frequently methylated. 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]. tea. 4’. acetylated. The flavonoids are often hydroxylated in positions 3. Distribution of flavonoids: Flavonoids are widely distributed among the plant 4 B 2' 5 6 [13]. flowers. wine etc. The O-glycosides possess sugar substituent bound to –OH of aglycone. among which. C-glycosides possess sugar table below (Table 1) describes various flavonoids present in our daily Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 26 . 5. nuts.Flavonoids are found in vegetables. stem. According to their molecular structure. 1 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. 3’. fruits. C 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 O 1 5' HO O OH 5 4 O OH O FLAVAN NUCLEUS Fig (II): Biosynthesis of flavonoids Flavonoids differ in their arrangement of hydroxyl. This abundance of variants is further augmented by the chirality of the subunits and their connections. These are an integral part of our daily diet [15. usually at position 3 or 7. seeds. 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]. 7. flavonol quercetin contributed 16 mg/day dietary food sources: [8]. 17. 18].

Plant Aloe vera Family Asphodelaceae Luteolin Kaempferol glycosides: mauritianin. 10. broccoli apples.-glucopyranoside Quercetrin. Chrysin. kaempferol-3-neohesperidoside Liquiritin. myricetin. 19. Grapes Soya beans. In addition. 7. myricetin-3-O-rutinoside. rutin Apigenin. dihydroxy-di-methoxyflavone. pongaglabol. 3. 50-methoxypongapin.4′-dimethoxy-6″.-glucoside. kaempferol-3-O-rutinoside. 2′. 3. Thyme Citrus Apple.8]-flavanone. isorhamnetin Orientin.3″:4′. pongachromene. red wine Parsley.7. 6. No.3″:7. 25 21 26 27 28 29 26 21 1 30 25. 19]: S. lanceolatin-B.-d-galactopyranoside.3′]dihydrochalcone. tea. 5.5′.liquritigenin. 7-hydroxyflavonone. nimbochalcone 5-methoxy-7. 11. sex- determination.4′-methylenedioxyflavanone. pongachin. kaempferol-3-Oglycoside. (2S)-7-methoxy-6-O-γ.6′-trimethoxy-3. luteolin. Flavonoid subclass Flavonol Flavones Flavonones Catechins Anthocyanidins Isoflavones Food source Onion. 16.3’-O-diglycoside. isovitexin. myricetin galactoside. energy transfer. 2-methylisoflavones Isoquercetin.-glucoside. astragalin Flavonoid present Reference 20 21 22. isorhamnetin-3-O. myricetin-3-O.7.8]-flavanone .4. 18. 10. Zingiberaceae Acanthaceae Scrophulariaceae Betulaceae Fabaceae Fabaceae Malphigaceae Compositae Cannabaceae Rutaceae Verbenaceae Fabaceae Leguminosae Mimosoideae Scrophulariaceae Lamiaceae Curcurbitaceae Bignoniaceaea Passifloraceae 23. 2′-hydroxy-3.4methylenedioxydioxydihydrochalcone.8. 7-O-methylwogonin. Quercetin-3-O.8. Flavonoids present in leaves promote physiological survival of plant by protecting it from fungal infections and UV radiations. energy transfer Indian Plants containing Flavonoids: Table 2: Medicinal plants found in India and rich in flavonoids content S.4-methlenedioxyflavone in roots and aerial parts Luteolin-7-O-glycoside. 21.3′.4-tetramethoxyflavone. 37 24. orientin. tea Cherries. tunicatacatachalcone. kaempferol.6:4’.4-methylenedioxychalcone and 3-methoxy-furano[2″.8-dimethoxyflavanone and 5-hydroxy-3. prunetine in stem bark Quercetin-3-O-rutinoside.dimethoxyflavone. (2S)-3′. monohydroxytrimethylflavones.3″:4′. quercetin-3-O-α-l-arabinopyranoside.4-methylenedioxy-furano[2″. (2S)-6.-D-glucoside Pongaflavonol . 20. [10]. luteolin. luteolin-7-O. Luteolin.4′-trimethoxy-6″.Bimlesh Kumar. genistein. kale. quercetin (Agarwal).4′.3′]chalcone. 9. lancheolatin B. 3. 5. apigenin-7-O. 25. respiration and photosynthesis control. 7-hydroxyflavone. baicalein. kaempferol.20-dimethoxyflavone present in whole plant. 3. apigenin. 1.6″dimethylpyrano[2″.2′. pongamol.7.luteolin-7.8. 20]. iso-orientin. luteolin-7-O. Legumes Representative flavonoids Kaempherol.3″:7. 22.2.-D-glucoside. morphogenesis. galocatechin ---------------Daidzen. myricetin Genistein. chrysin. biorobin in its leaves and flowers Quercetin. β-hydroxy-2′. kaempferol-3-O-β-D-glucoside and quercetin-3-O-α-L-rhamnoside in leaf. liqcoumarin.4-tetrahydroxy-flavone-3-rhamoglycoside.5’’]flavone . hesperidin. 2′. naringen Catechin.5-tetramethoxyflavone. flavonoids are involved in photosensitisation.3.2′-tetramethoxyflavone. 2. isoliquiritin. cherries. orientin. berries. formanantine Functions of Flavonoids in plants: Anthocyanin pigment present in flowers provide colour to it contributing to pollination [8. et al: A Review of Phytochemistry and Pharmacology of Flavonoids Table 1: Occurence of flavonoids in food [9. kaempferol. baicalein-7-O-glucoside. luteolin Hesperitin. glyciten.4′-trihydroxy-6. 7-O-glucoside Kaempferol-3-O.isoliquiritigenin. quercetin. rutin. the biflavonoid amentoflavone.-glucopyranoside Seed consists of eriocitrin.6″dimethylpyrano[2″. 5. 13. quercetin-3-O-glycoside.-D-glucoside. Quercetin quercetin-3-O.7. Quercetin-3-O. Peel consists of neoeriocitrin.6″-dimethylpyrano[2″.-glucoside. karanjachromene. ovalichromene-B. cassiaocidentalin B. hyperoside. tiliroside. isolonchocarpin.3′-trimethoxyflavone Luteolin. nicrotiflorin. kanjone present in seeds Quercetrin. skullcaflavone. in leaves Quercetin.2’. 31 26 30 30 32. 14. 2. skullcapflavone. (+)-catechin and (−)-epicatechin.3″:4′. isorhamnetin. karanjin. 4. 2’’. ponganone III. Tephrosia purpurea Tilia cordata Fabaceae Tiliaceae 30 26 27 Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 . 5.3″:7. quercetin-3-O-rutinoside.karanjin. erodictyol. 4. 5-hydroxy-7. 15. Pongamone A-E. 8.7. 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. neohesperidin Pectolinarigenin.3′]dihydrochalcone.5′-trimethoxy-6″. naringin. 12.4-methylenedioxy-6″. 6.23 24. 36.β-trimethoxy-3. rhamnoliquiritin.6″-dimethylpyrano[2″. Pongamia pinnata Fabaceae 35.3’-tetramethoxyflavone. 5hydroxyfurano[7.glucoside. 5-hydroxy-40-methoxy-7-[(3-methyl-2-buthenyl) oxy]-isoflavone. myricetin. isoorientin in aerial parts (2S)-5. avicularin.γ-dimethylallyl-3′. clitorin.5.4′-dimethoxy-3. Oroxylin B Vitexin. No. 1. pongapin. 5hydroxy-7.6]flavones present in roots Purpurin. 2. amentoflavone.β-dimethoxy-3. as well as the known flavonoid 5-hydroxy-7.

activities. ROOH by hydrogen abstraction. responsible for electron dislocation from the B-ring. F-O. 4. of diseases. The ortho-dihydroxy (catechol) structure in the Bring. copper)catalysed Haber-Weiss reaction. vasodilatory aggregation. Singlet Oxygen .O 2 + . 6. hyalouronidase. Reactive species O2 (Superoxide anion) HO2 H2O2 (Hydrogen peroxide) “-“ Mechanism One-electron reduction product of O2. which confers greater stability which participates in electron dislocation. They terminate chain radical reaction by donating hydrogen atom to a peroxy radical as in fig (V).Bimlesh Kumar. 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. This activity is attributed to their hydrogen- donating ability. the organism has developed a defence against toxic substances such as peroxynitrite and nitrous acid. permeability lipoxygenase enzyme activities. ROO (Peroxyl radical) 1 O2 .11. kinase [41]. antiviral. formation and decomposition reactions. HO2. cAMP phosphodiesterase. 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. also formed by decomposition of peroxynitrite produced by reaction of O2 with nitric oxide radical. antiallergic neurodegenerative [4. which.13. Fig (V): Formation of peroxy radical Naturally. (Alkoxy RO . Pharmacological activities of O2 e- . 6].O 2 H+ HO2. antibacterial. 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]. lipase.O2- 2H+ reported to inhibit variety of enzymes like hydrolases. and . 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. 15]. Flavonoids as antioxidants: Mechanism of flavonoids as antioxidants: Flavonoids are powerful antioxidants against free radicals and are described as free-radical scavengers [42]. No. in conjugation with a 4-oxo function. 39. platelet fragility. Produced by phagocytes. Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 28 to aroxyl radicals. transition metal (iron. further reacts with free radicals thus terminating propagating chain [15. An important mechanism is catalyzed by the enzyme superoxide dismutase (SOD). Indeed. which converts two superoxide anions to H2O2 and O2 [16] as shown in fig (VI). Reactivity of O2 and H2O2 is amplified in presence of heme proteins Three electrons reduction products of O2 generated by Fenton’s reaction. + RH Fig (IV): Scavenging capacity of free radical (R. α-glucosidase. 2. These are also . cytotoxic These antitumour. 1.39]. 1. arylsulphatase. chelators of divalent cation [15. O2 H2O2. action capillary and In addition flavonoids are known to inhibit and cyclo-oxygenase lipid-peroxidation. forming flavonoids radical. Lipid peroxy radical (LOO ) produced from organic hydroperoxide. They exert these effects as antioxidants. includes: treatment anti[10. 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. thus.) 3. 1. 2. possibly through hydrogen bonding.3-double bond. The 2. radical). 40]. inflammatory. et al: A Review of Phytochemistry and Pharmacology of Flavonoids PHARMACOLOGY OF FLAVONOIDS: Reported flavonoids: Flavonoids have been reported to exert wide range of biological 11. OH (Hydroxy radical) 5. the antioxidant capacity of a flavonoid is linked to its three structural groups as shown in fig (VII). alkaline phosphatise. free radical scavengers.

Shariffer et al. effective. It has also been reported that flavonoids protect against gastric cancer. Braca et al... stomach.4’-catechol structure in B-ring strongly enhances lipid peroxide inhibition and this arrangement is an important characteristic of most potent scavengers of peroxyl. and brain. e. But.. quercetin 3rhamnoside (quercitrin). causes a vasoconstriction in the integument and the periphery.g.. superoxide and peroxynitrite radicals [8] and its absence decreases antioxidant activity. resulting in leakage of blood into the tissue. antibodies and other agents that are required to maintain a healthy condition. intestine.Bimlesh Kumar. and usually innocuous substitutes for the classical therapeutic agents.. nutrients. FLAVONOID Inhibit gastric ulcer possess strong antioxidant Fig (VIII): Effect of flavonoids on gastric ulcer Flavonoids are favourable. Gulati et al. Similar to aspirin. 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 O HO HO OH OH b OH O OH O a OH O Fig VII: Structural groups responsible for antioxidant activity [1] 3’. kaempherol 3-glucoside (astragalin). isolated diosmetin. and protective substances to this area gets sufficiently weakened. kaempherol. 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-α-rhamnoside possesses lowest antioxidant activity [47]. Flavonoids in treatment of gastric ulcer: Flavonoids inhibit regulation of protein phosphorylation. Bitis et al.. quercetin 3-xyloside and quercetin 3-galactoside (hyperoside) from Rosa agrestis leaves and reported it to possess antioxidant activity [45]. When the walls of the blood vessels supplying oxygen. produced significant hepatoprotection [49]. 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]. (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. they dilate the vessels of muscles. participate [16]. if the duration of this state gets prolonged. reported that dietary flavonoids like epicatechin. e. As a result. Effect of flavonoids on gastric ulcer: 29 Internationale Pharmaceutica Sciencia .VII(c)). quercetin. Such events start inflammation and repair processes in which eicosanoids. kidneys. galate. Salucci et al. 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. and ACTH. acylated flavonoids may transfer their acyl group to Jan-Mar 2011 Vol 1 Issue 1 2. Etiology of gastric ulcer: The stress hormones like epinephrine. reported that high level of total phenolic and flavonoid in Halia Bara variety possessses potent antioxidant activities [44]. whereas.g.. The absence of the hydroxyl group at position 3 in flavanones and flavones decreases their antioxidant ability[1]. et al: A Review of Phytochemistry and Pharmacology of Flavonoids 3. PGs. The presence of both 3-(a)-and 5-(b)-hydroxyl groups (Fig. reported that quercetin at a dose of 15 mg/ 100g p. liver. then blood supply to major organs. quercetin-3-glucoside activity [48]. then slight mechanical insults easily cause ruptures. norepinephrine. heart. Ghasemzadeh et al. gallic acid.o. epigallocatechin. and skin get reduced and thus failing to satisfy demand for oxygen..

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. 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. quercetin. Inflammation involves action of the complement system. which is related to antioxidant activity inhibit neutrophil degranulation inflammation.. Fc receptor is non-covalently lipase which inositol associated with a second messenger producing phosphatidylinositol membrane. catechins) have also been shown to have antiinflammatory activity by inhibiting cycloxygenase-2 (COX2) and inducible nitric oxide synthase [52]. with the result that the latter emits IL-1.Various Flavonoids also [40. angiogenesis. cytokines. humoral and cellular immunity.g. i. 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 PGF2α 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. 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). tissue hormones. apigenin. The toxin-antibody complexes are endocytised.Bimlesh Kumar. signal substances for the pain pathway (fig IX). Quercetin. which are also controlled promote by IFN flavonoids.e. i. Flavonoids prevent synthesis of PGs that suppress T-cells. 45]. and also The figure (X) represents the effect of flavonoids in the treatment of flavonoids (e. blood coagulation. and DAG stimulates PKC. and raise the alarm in the cell. The immune cells communicate with chemical signals called cytokines site. which encodes the PG COX that produces the eicosanoids. This substance induces the expression of the COX gene. and smooth muscle contraction [16].e. 53] inhibit cytosolic and tyrosine kinase [40]. and repair processes. It is both a free radical generating and free-radical producing process [50]. Kaempferol. chemotaxis.. [50]. 3. tea Jan-Mar 2011 Vol 1 Issue 1 30 Internationale Pharmaceutica Sciencia . et al: A Review of Phytochemistry and Pharmacology of Flavonoids the side chain hydroxyl group of serine in the active site of COX [16]. rutin when administered intraperitoneally (25-100 mg/kg) inhibited dose-dependent gastric damage produced by ethanol in rats [43]. synthesis Flavonoids inhibit the activity of PKC at ATP-binding Flavonoids [16].

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]. against which the lymphocytes are directed. They inhibit 31 Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 . which are uncoordinated with the mechanical requirements defined by the stress gradients. which. granulocytes. 5. Flavonoids in treatment of thrombosis: Flavonoids are used as antithrombotic due to their ability to scavenge free radicals. et al: A Review of Phytochemistry and Pharmacology of Flavonoids (-) COX (-) iNOS (-) cytosolic kinase (-) tyrosine kinase (-) neutrophil degranulation (-) protein kinase C (+) Promote IFN synthesis head of the bone. 4. quercetin. the enhanced osteoclastic activity leads to the destruction of the heads of the long bones in the joints. An additional effect of the flavonoids may be to activate cytotoxic Tlymphocytes.. Flavonoids in treatment of thrombosis: Etiology of Thrombosis: Arachidonic acid released by in inflammatory conditions is metabolized by platelets to form prostaglandin.Guardia et al.g. These spikes cause tissue lesions. Kaempferol. Apigenin. e. It acts as a growth hormone on T-lymphocytes. macrophages. but the antigen. 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. Flavonoids do activate cytotoxic Tlymphocytes. Effect of flavonoids on rheumatic disease: Etiology of Rheumatic disease: Autoimmunity and inflammation is an important component of rheumatoid arithritis. 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.. which kill cells presenting the harmful foreign antigen. and pain [16]. bleeding. reported rutin to be most effective plant flavonoids for the treatment of inflammation in chronic phase [54]. hesperidin is known to possess antiinflammatory and analgesic effects. inflammation. Platelet aggregation further contributes to atherosclerosis and acute platelet thrombus formation. Osteoclasts resembles macrophages because both produce and secrete IL-1 and are phagocytic. is a mitogen to T and B-lymphocytes. Since rheumatic disease is associated with painful joints.Bimlesh Kumar. such a destruction is followed by repair processes. IL-1 is produced by macrophages. and blood vessel endothelial cells. endoperperoxides and thromboxane A2 thus contributing to platelet activation and aggregation. myricetin. If osteoclasts respond to IL-2 secreted from immune cells. luteolin. it is believed that the antigen specificity of the T-cells is directed against an epitope characteristic of the cartilage in a joint. then. fisetin are reported to possess COX and LOX inhibitory activities [43]. In rheumatic arithritis. 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]. in turn. Guardia et al. quercetin are known to possess antiinflammatory activity [43].. FLAVONOIDS Activate Cytotoxic T-lymphocytes [16] Fig X: Effect of flavonoids on Inflammation Citrus flavonoids. which are induced to proliferate and secrete IL-2. a part of chondroitin sulphate. Activated platelets adhering to vascular endothelium generate lipid peroxides and oxygen free radicals which inhibit endothelial function of prostacyclin and nitric oxide [40]. remains unidentified shown in fig (XI)..

Effect of flavonoids on cancer-related pathways: Etiology of Cancer: Cancer is a growth of diseases caused by disturbance in growth metabolism [52]. Flavonoids have emerged as potential chemopreventive candidates for cancer treatment due to their ability to induce apoptosis[55]. dedifferentiation and loss of function. kaempferol (fig XIV) and galangin. Flavonoids like quercetin. kaempferol and myricetin are known to possess antiaggregatory properties [40. Inhibit angiogenesis. Alter carcinogen metabolism Metastasis Tumour Prevent further DNA damage. including singlet oxygen and various free radicals. et al: A Review of Phytochemistry and Pharmacology of Flavonoids cyclooxygenase and lipooxygenase pathway. Flavonoids in treatment of Cancer: Flavonoids for a long time have been part of the herbal treatment by lay practitioners. differentiation. invasiveness and metastasis that differ it from normal cells [51]. and the flavones apigenin (fig XVI) have been reported to inhibit cytochrome P450 enzymes of the CYP1A family. Quercetin is abundantly found in 32 Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 . The main antiaggregatory effect is by the inhibition of thromboxane A2 formation. angiogenesis and metastasis [55] as shown in fig (XIII).Bimlesh Kumar. but they were recognised only recently as effector substances. 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. which is the most abundant P450 enzyme in the liver and beneficial in metabolizing a significant number of carcinogens and medications [16]. O The flavonols quercetin (fig XV). 43]. 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. Induces apoptosis cell cycle arrest Inhibit angiogenesis ROS scavenging . apoptosis. Fig (XVII): Naringin Quercetin (fig XIV) and naringin (fig XVII) have also been shown to inhibit CYP3A4. 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]. Normal cell Initiated cell Prevent further DNA damage Induces apoptosis Preneoplasts Prevent further DNA damage. which are possibly involved in DNA damage and tumor promotion. Cancer cells manifest to varying degree of uncontrolled proliferation. 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. proliferation.

.. such as glutathione reductase. In other in vitro models. 56]. In addition. glutathione S-reductase. animal and in vitro detoxifying and antioxidant studies have shown that tea catechins increase the several enzymes. multiple mechanisms have been identified for the anti-neoplastic effects of flavonoids. 55]. quercetin). stimulate neuronal regeneration and induce neurogenesis. it 33 Synaptic Activit Synaptic plasticity Fig XX: Overview of functions of flavonoids on memory system[57] Jan-Mar 2011 Vol 1 Issue 1 Internationale Pharmaceutica Sciencia . to act as novel brain-stem stimulants Studies suggest that flavonoids. tea flavonoids inhibit signal transduction pathways mediated by epidermal growth factor and platelet-derived growth factor. enhance existing neuronal function. Early indications regarding the ability of flavonoids to impact upon brain function were reported in the 1950s. isoflavonoids. flavonoids have also been to affect cell-signaling and cell cycle progression. However. 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]. 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. it has been postulated that their effects in the brain is mediated by an ability to protect vulnerable neurons. luteolin (fig XIX) and quercetin have been shown to cause cell cycle arrest and apoptosis by a p53-dependent mechanism [52].Bimlesh Kumar. Activation of Finally. with flavones reported [14]. Researches revealed that isoflavones results in positive effects on neuro-cognitive functions which is apparent in post-menoupausal women. including antioxidant. 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. 55. It has been found that flavonoids subclasses flavonols. this anti-proliferative effect has been related to the antiestrogenic properties of certain flavonoids (e. anti-inflammatory and antiproliferative activities. Instead. Ghasemzadeh et al.g. 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. Indeed. glutathione peroxidase. inhibition of bioactivating enzymes. the biological actions of flavonoids to their ability to exert antioxidant actions. Effect of flavonoids on memory: Flavonoids in treatment of memory cognition: Historically. Genistein (fig XVIII) and quercetin inhibit protein tyrosine kinase which is also involved in cell proliferation [16. favorably affecting downstream events such as angiogenesis. 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. flavanols. catalase. 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]. and induction of detoxifying enzymes [52]. and quinone reductase [16. In estrogen-dependent tumor cells or animal models. For example. 7. long-term potentiation and memory. apigenin. and thus exerts a dose-dependent inhibitory effect on cell proliferation activity of [55]. flavanones. studies have shown that some flavonoids components such as quercetin had mechanism. 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.

9. STRESS + GLUTAMATE NA 5. showed that quercetin at a dose of 10.o.. 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]. Maher et al.HT BDNF CRF release Hypothalamus NMDA receptor α2 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] Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 34 . impairs cognitive function by suppressing pAkt and pCaMKII thus decreasing pCREB expression in hippocampus [49]. 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]. 20..Bimlesh Kumar. et al: A Review of Phytochemistry and Pharmacology of Flavonoids Jung et al. 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. 40 mg/kg p. reported fisetin to facilitate memory by activating ERK and inducing cAMP response elementbinding protein phosphorylation [58]. 8. 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).

7. 6. Considering the [7]. tranquilizers. sedative. Effect of flavonoids on antimicrobial activity: Flavonoids have been used extensively since centuries for the treatment of various diseases. It has been reported to possess inhibitory actions against Aspergillus tamarii. and thus they bind to the benzodiazepine binding site with resulting depressant actions in mice anticonvulsant.. 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. Flavonoid glycosides form the newest group within the growing family of flavonoids with activity on the CNS [7]. Candida albicans. Aspergillus flavus. fluorescens. Many flavone derivatives were found to be ligands for the GABAA receptors in the CNS.4’-trimethoxyflavone are effective against Aspergillus flavus [10].. Pencillium digitatum.5’-dihydroxy-8. Nobiletin and langeritin isolated from peelings of tangerine orange showed fungistatic action towards Deuterophoma tracheiphila while [43]. [63]. Staphylococcus nervous.4’-trihydroxy-3’. enteric. 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.4’- These were the also found to possess sedative action. linarin) does not appear to be critical for activity.7. Yi et al. from reported bacteria coli. Cladosporium sphaerospermum. Rattanachaikunsopon et al. guajava possess Bacillus four quercetin-3-O-arabinoside Psidium bacteriostatic action action against all foodborne pathogenic Escherichia Pseudomonas including Listeria stearothermophilus. that these quercetin. Quercetin has been reported to completely inhibit growth of Staphylococcus aureus [43]. 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. Staphylococcus epidermis. 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> gossypin≌2S-naringin. Galangin is a flavonol commonly found in 35 stimulate fungal growth slightly Quercetin. Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 . (methylenedioxy) flavan isolated from Termanalia bellerica possess antifungal activity against Candida albicans. leaves and morin-3-O-arabinoside.e. Propolis has been used referred even in old testament for its healing properties. monocytogenes. Saccharomyces cerevisiae [62]. Penicillium italicum [10].2’.4’-trihydroxy-8-methyl-6-(3-methyl-[2-butenyl])2S-flavonone texana isolated from shrub Eysenhardtia and flavonoids 7-hydroxy-3’. resulting in flavone derivatives with planar configuration (i.5’-dimethoxyflavone and 5. It was further suggested that dietary flavonoids possess a therapeutic potential in disorders especially where monoaminergic system is involve [61]. The antimicrobial activity of propolis has been attributed to its high flavonoids content. propolis. Salmonella Staphyloccus aureus.Bimlesh Kumar. Vibrio cholera Flavonones having sugar moiety showed antimicrobial activity while none of the flavonols and flavonolignans showed inhibitory activity on microorganisms. 10. naringenin are reported to be inhibitors of Bacillus subtilis. Brochothrix thermosphacta. Escherichia coli. isolated morin-3-Olyxoside. 5.

and the Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 36 . Antibacterial activity 2. or tend to decrease the incidence of cardiovascular diseases and their consequences. In the ischemic phase of AMI platelet aggregation. Antiviral activity 3. apigenin Quercetin Quercetin Quercetin Chloroflavonin Quercetin Chrysoeriol Chrysoeriol Chrysoeriol Quercetin. morin. Etiology of Cardiovascular Diseases: transformation of xanthine dehydrogenase into ROS producing xanthine oxidase (XO) play important role [16].Bimlesh Kumar. ROS can mediate the cardiac hypertrophy and patients with heart failure have an increased production of ROS. epicatechin Apigenin. Here again. kaempferol. CVS diseases include atherosclerosis. Oxidative stress is a condition of imbalance between endogenous oxidants and reactive oxygen/nitrogen species (RONS) with predominance of reactive species. Endothelial dysfunction with increased platelet aggregation facilitates procoagulation. rutin Galangin. Common consequences of AMI are heart failure and arrhythmias. Flavonoids in treatment of cardiovascular diseases: Cardiovascular diseases are today the principal cause of death in both developing and developed countries. Naringin+rutin.baicalin. an increase in cellular free redox active iron. Naringin+hespertin. Flavonoids in treatment of CVS: Studies ensure that long-term administration of flavonoids can decrease. may play an important role in the genesis of some arrhythmias. quercetin.rutin. Quercetrin. Atherosclerosis involves modification of LDL particles by oxidative stress with subsequent induction of inflammation which is caused by increased leucocyte adherence [16]. antimicrobial and antiviral activities of flavonoids [41] S. ROS. et al: A Review of Phytochemistry and Pharmacology of Flavonoids Table 4: Antibacterial.naringin. Fisetin. Antifungal activity 11. Echinacin Phaseolinisoflavan 1. Baicalin. Similarly. iso-liquiritigenin Fisetin Apigenin Apigenin Chrysin Chrysin Chrysin Rutin. hydroxyethylrutosine Quercetin Quercetin Rutin Datisetin Hydroxyethylrutoside Quercetin. coronary heart disease.quercetrin. Patients with arterial hypertension have an increased oxidative stress status [64]. No. and in particular the superoxide radical.naringin Apigenin Quercetin. Hesperitin. The major reason behind CVS diseases is oxidative stress. which may induce a thrombosis resulting in an acute myocardial infarction. arterial hypertension. and heart failure. rutin Quercetin Quercetin.apigenin Quercetin. the activation of neutrophils. 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.

Effect of flavonoids on diabetes mellitus: Etiology of diabetes mellitus: Diabetes mellitus is a serious chronic disease. stimulate Ca2+ uptake from isolated islet cells thus suggesting it to be effective even in non-insulin dependent diabetes [43]. 1. studied hepatoprotective studies on identified to be good inhibitors of aldose reductase The fig (XXIII) depicts the mechanism of flavonoids in diabetes mellitus. apigenin. As a result. Gulati et al. quercetin. then quercetin is producing hepatoprotection at a dose of 15 mg/ 100 g p. thus concluding that quercetin is a potent hepatoprotective agent [69].. 5. Sriram et al. Effect of flavonoids in treatment of hepatotoxicity: Role of flavonoids in treatment of hepatotoxicity: Flavonoids bind to subunit of DNAdependent RNA polymerase I. Regenerate pancreatic islets. 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. Rutin and venoruton are reported to show regeneration and hepatoprotective effects in experimental cirrhosis [43]. 12. decreased expression of iNOS and COX-2 Decrease in ROS burst. 7-monohydroxyethylrutoside and 7’. inhibition of NADPH oxidase. It was observed that hirustrin. 4.. protein synthesis gets increased leading to regeneration and production of hepatocytes [11]. Quercetin protects LDL against oxidative modifications effect. 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]. Li et al. avicularin. (+) insulin release. naringenin are Flavonoids have been reported to be potent therapeutic agents against microcrystin LR-induced hepatotoxicity. 4’-trihydroxyethylrutoside are reported to be cardioprotective [43]. 3. hirustin. it has been reported to 37 Internationale Pharmaceutica Sciencia Jan-Mar 2011 . 13.. myeloperoxidase. avicularin and quercetin.o.. Kim et al. flavonoids can ameliorate some of the consequences of diabetes mellitus [66]. 3’. No. trifolin. 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. et al: A Review of Phytochemistry and Pharmacology of Flavonoids Table 5: Proposed positive effects of flavonoids on CVS: S. reported fisetin to be a therapeutic agent for treatment of diabetes mellitus at a dose of 10 mg/kg [68].. isolated isovitexin. recovery of NO due to inhibition of superoxide production Flavonoid consumption prevent many cardiovascular diseases including hypertension and atherosclerosis. inhibition of leucocyte leucocyte adhesion. (-) Aldose reductase.. 2. inhibition of platelet aggregation Decrease in oxidative stress (direct ROS scavenging) inhibition of metalloproteinase Decrease in oxidative stress Vasodilatory properties. indicated that flavonoids in Ipmoea batalas leaf possesses antidiabetic activity against alloxaninduced diabetes at a dose of 100 mg/kg [67].Bimlesh Kumar. However. Also. [16]. (+) 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. thus activating the enzyme. Silymarin. quercetin possess hepatoprotective action against t-BHP in HepG2 Vol 1 Issue 1 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.o.

59 41 41 69. Cyt P450 Cyt P3A4 Tyrosine kinase P53 dependent Glutathione reductase. fisetin Quercetin. (+)-Cyandidanol-3. hesperidin. rutin Trihydroxyethylrutoside. Quercetin Apigenin. No. luteolin Tangeratin. 52 16. it is not possible for humans to suffer acute toxic effects from the consumption of flavonoids.e. Cancer 5. with the exception of a rare occurrence of allergy.55. 2. phytochemicals on an individual basis but are less toxic to normal cells [40]. Kaempferol. apigenin. They are gaining interest due to their wide variants and number of members. 15]. apigenin. Memory dysfunction Depression Cardiovascular diseases Diabetes mellitus Antiallergic Hepatoprotective Thrombosis Internationale Pharmaceutica Sciencia Jan-Mar 2011 Vol 1 Issue 1 38 . 3. catechin Hesperidin. Linarin Quercetin 7-monohydroxyethylrutoside. this family of compounds possess a diverse range of activities in mammalian cells. is very large and probably not surpassed by any other drug in current use [16]. kaempherol-3-Oglucoside and quercetin-3-O-glucoside isolated from Equisetum arvense.4’-trihydroxyrutoside Fisetin Quercetin Quercetin Rutin. O-( hydroxyethyl)rutoside. used in Oh et al. whereas isovitexin and trifolin possess no protective effect [70]. So. 71 71 71 41 4. luteolin Kaempferol. catalase. Apigenin Quercetin. Toxicological Profile of flavonoids: Flavonoids are widely distributed in edible plants and beverages toxic and have been previously traditional medicines. 41 58. citrin Disodium cromoglycate Quercetin Avicularin. a study regarding assessment of its required done these Table 6: Diseases treated with Flavonoids S. 54 43 16 16 16. to the short residence time of flavonoids in the intestine. glutathione peroxidise. [10]. et al: A Review of Phytochemistry and Pharmacology of Flavonoids cells. 2S-hesperidin. 2004 reported that among various flavonoids i. 55 49 49 58 61 7 43 68. naringin Genistein. 6. 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. 11. Galangin. However. Flavonoids are found to be toxic to cancer or immortalized cells Due to the low solubility of flavonoid aglycones in water. and to the low coefficient of absorption. luteolin. These are reported to be effective in pathogenesis of majority of disases.. 52 43. (+)-catechol Nobelitin. 43 54. CONCLUSION Flavonoids constitute a wide array of biological active compounds that are found abundantly in plant kingdom and dietary intake. 8. myricetin. in-vivo confirmation of their side effects would be necessary for full evaluation of their practical usefulness in the field of modern medicine. quercetin Catechins Genistein Quercetin Fisetin Naringenin. Given that the selectivity of flavonoids for eukaryotic enzymes toxicity appears is to vary to from be compound on to compound.Bimlesh Kumar. 9. hirustrin Onitin. 7. quercetin. Ulcer Rheumatoid arithritis Inflammation Disease Flavonoid Kaempferol.3’. therefore. 43 41 41. 1. The margin of safety for the therapeutic use of flavonoids in humans. meciadanol. catechins Sofalcone. sinesetin Target PAF Gastric H+/K+ ATPase PG synthesis Suppress inflammation by acting on COX COX and iNOS PG synthesis Na /K ATPase. so they are believed to be non[10. Quercetin Apigenin. 53 50. onitin and luteolin exhibited hepatoprotective activity against tacrine-induced cytotoxicity in human liver-derived Hep G2 cells [57]. luteolin. 10. rutin Quercetin. 51 46. quercetin. Antioxidant activity is the foundation of many actions which lead to its beneficial effects in majority of the diseases. 7’.rutin.

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