This article throws light upon the top twelve roles of Flavonoids. Some of the roles are: 1. Flavonoids in Heart Disease 2. Flavonoids in Antioxidant Activity 3. Flavonoids in Lipid Lowering Activity and Heart Disease 4. Effects of Flavonoids in Blood Vessels 5. Flavonoids in Antithrombotic Activity 6. Flavonoids in Anti-diabetic Activity 7. Flavonoids in Antineoplastic Activity and others
Role # 1. Flavonoids in Heart Disease:
In order to study the role of dietary flavonoids in coronary heart disease prevention; qucertin, kaempaferol, myricetin, luteolin, apigenin are major phytonutrient which help in prevention of heart disease. Flavonoids have high propensity to transfer electrons, chelate ferrous ions, and scavenge reactive oxygen species.
Because of these properties, and also been considered as potential protectors against chronic cardio toxicity caused by the cytostatic drug doxorubicin. Doxorubicin is a very effective antitumor agent but its clinical use is limited by the occurrence of a cumulative dose related cardio toxicity, resulting in, for example, congestive heart failure (negative inotropic effect).
In a recent report, the cardio toxicity of doxorubicin on the mouse left atrium has been inhibited by flavonoids, 7-mono-hydro-xyethylrutoside and 7′, 3′, 4′-trihydroxyethylrutoside.
Role # 2. Flavonoids in Antioxidant Activity:
Plant polyphenolics, such as flavonoids are described as scavengers of reactive oxygen species (ROS), via inhibition of oxidoreductases. Flavonoids inhibit LPO in vitro at the initiation stage by acting as scavengers of superoxide anions and hydroxyl radicals.
It has been proposed that flavonoids terminate chain radical reactions by donating hydrogen atoms to the per-oxy radical forming a flavonoid radical; this flavonoid radical reacts with free radicals terminate the propagation chain reaction.
In addition to their anti-oxidative properties, some flavonoids act as metal chelating agents and inhibit the superoxide-driven Fenton reaction, which is an important source of active oxygen radicals. The flavones and catechins seem to be the most powerful flavonoids for protecting the body against reactive oxygen species (ROS).
Body cells and tissues are continuously threatened by the damage caused by free radicals and ROS which are produced during normal oxygen metabolism or are induced by exogeneous damage.
Free radicals and ROS have been implicated in a large number of human diseases. Quercetin, kaempferol, morin, myricetin and rutin, by acting as antioxidants, exhibited beneficial effects such as anti-inflammatory, anti-allergic, antiviral, as well as anticancer activity.
They have also been suggested to play a protective role in liver diseases, cataracts, and cardiovascular diseases. Quercetin and silybin, acting as free radical scavengers, were shown to exert a protective effect in liver reperfusion ischemic tissue damage.
The scavenging activity of flavonoids has been reported in some research papers to be in the order:
Myrcetin > quercetin > rhamnetin > morin > diosmetin > naringenin > apigenin > catechin > 5, 7-dihydroxy-3′, 4′, 5′-trimethoxy- flavone > robinin > kaempferol > flavones.
Morin, myricetin, kaempferol and quercetin have also been suggested as stabilizers for fish oil as an alternative to synthetic antioxidants.
Role # 3. Flavonoids in Lipid Lowering Activity and Heart Disease:
Many of plant flavonoids are responsible for the anti-lipid-emic activity; the lipid lowering studies have observed in in vitro and in vivo. Oxidative modification of low-density lipoproteins (LDL) by free radicals is an early event in the pathogenesis of atherosclerosis.
The rapid uptake of oxidatively modified LDL via scavenger receptor leads to the formation of foam cells. Oxidized LDL also has a number of other atherogenic properties. A number of mechanisms are likely to contribute to inhibition of LDL oxidation by flavonoids.
Flavonoids may directly scavenge some radical species by acting as chain breaking antioxidants. In addition, they may recycle other chain-breaking antioxidants such as a-tocopherol by donating a hydrogen atom to the tocopheryl radical.
Transition metals such as iron and copper are important pro-oxidants, and some flavonoids can chelate divalent metal ions, hence preventing free radical formation.
The ability of quercetin, and the quercetin glycosides, to protect LDL against oxidative modification has shown a significant protective effect. Influence of flavonoids on blood coagulation has been studied, the anticoagulant action of heparin was antagonized by T. hircanicum extracted.
The ability of different flavonoids to inhibit the pro-coagulant activity of adherent human monocyties has been studied recently and hinokiflavone, a bioflavonoid has been found to be very effective in inhibiting the interleukin-1â induced expression of tissue factor on human monocytes.
The ability of (+)-catechin to inhibit LDL oxidation induced by copper and several cell lines including mouse macrophages, human monocyte-derived macrophages, and vascular endothelial cells isolated from human umbilical cords have been investigated.
As expected, LDL modified by cells or copper-induced oxidation was endocytosed and degraded by human macrophages more quickly than native LDL. However, in the presence of (+) – catechin, the rate of endocytosis and degradation by macrophages was similar to that of native LDL.
Role # 4. Effects of Flavonoids in Blood Vessels:
Flavonoids quercetin and rutin are used in capillary fragility and phlebosclerosis and displayed pharmaceutical importance. The activities of certain flavonoids in inhibiting capillary permeability and Arthus phenomenon were found to be in the following order, hesperitin > rutin > quercetin > naringenin > kaempferol > isoquercitol.
It has been suggested that flavonoids, which contain free hydroxyl groups at 3, 3′ and 4′ positions exert beneficial physiological effects on capillaries.
Tangeratin, hesperidin, quercetin, and rutin have been found to reduce aggregation of horse erythrocytes; the decrease in blood cell aggregation produced by most of the flavonoids may explain the reported valuable effects of these compounds on abnormal capillary permeability and fragility, the reduction of disease symptoms and their protection against various traumas and stresses.
The flavonoids O-(â- hydroxyethyl) rutoside, (+) catechol, trihydroxyethylrutoside increased the negative charge density of the blood vessel wall in vitro and were markedly antithrombogenic. Quercetin also has been reported to inhibit aggregation of human platelets by several authors.
Other antiaggregatory flavonoids reported were 3-methyl quercetin, toxerutin, fisetin, dihydroquercetin and flavone. Nobeletin and sinensetin decreased erythrocyte aggregation and sedimentation in vitro and might be useful in dietary control of high blood viscosity syndrome; Patuletin reduced the capillary permeability and was also reported to have antispasmodic and hypotensive effects.
Orally administered flavonoids weakly inhibit the vascular permeability and prevent pulmonary haemorrhage. Acacetin at 25-100 mg/kg oral dose to mice reduced capillary fragility and at 50-100 mg/ kg it reduced vascular permeability.
Role # 5. Flavonoids in Antithrombotic Activity:
Several flavonoids are responsible for the antithrombotic activity; platelet aggregation plays a pivotal role in the physiology of thrombotic diseases. Activated platelets adhering to vascular endothelium generate lipid peroxides and oxygen free radicals which inhibit the endothelial formation of prostacyclin and nitrous oxide.
It was shown in the 1960s that tea pigment can reduce blood coagulability, increase fibrinolysis, and prevent platlet adhesion and aggregation. Selected flavonoids such as quercetin, kaempferol and myricetin were shown to be effective inhibitors of platelet aggregation in dogs and monkeys.
Flavonols are particularly antithrombotic because they directly scavenge free radicals, thereby maintaining proper concentration of endothelial prostacyclin and nitric oxide. Few study showed that flavonoids are powerful antithrombotic agents in vitro and in vivo because of their inhibition of the activity of cyclooxygenase and lipoxigenase pathways.
Role # 6. Flavonoids in Anti-Diabetic Activity:
Flavonoid, quercetin plays significant role in administration of insulin secretion, and shows anti-diabetic activity. Vessel and coworkers reported that quercetin brings about the regeneration of pancreatic islets and probably increases insulin release in strptozotocin-induced diabetic rats.
In another study, quercetin stimulate insulin release and enhanced Ca2+ uptake from isolated islets cell which suggest a place for flavonoids in noninsulin-dependent diabetes.
Role # 7. Flavonoids in Antineoplastic Activity:
Various flavonoids have exhibited antineoplastic activity and detailed studies have revealed that quercetin exerted a dose-dependent inhibition of growth and colony formation.
The flavonoids, kaempferol, catechin, toxifolin and fisetin, also suppress the cell growth. On screening the antileukaemic efficacy of naturally occurring and synthetic flavonoids on human promyelocytic leukaemic HL-60 cells, genistein, an isoflavone was found to have strong effect.
Cirrus flavonoids (tangeretin) also exhibit anti-invasive activity, but appear to act by a different mechanism. They show a poor affinity for the extracellular matrix and do not bind enzymes to laminin. In vitro studies have been made on the anti-proliferative effect of citrus flavonoids quercetin, taxifolin, nobletin and tangeretin on human squamous cell carcinoma.
Flavonoids extracted from Scutelluria baicalensis (baicalein, baicalin and woogonin) exerted in vitro a concentration-dependent inhibition of the proliferative response of cultured rabbit vascular smooth muscle cells upon exposure to 5% calf serum.
Aside from quercetin and baicalein, epigallocatechin gallate and green tea extract were also reported to inhibit tumor growth by inhibiting mitosis. Some flavonoids (quercetin, epigallocatechin) and green tea extract inhibit tumor growth both by inhibiting some phase of the cell cycle and by blocking or competing for hormone receptor sites.
Rutin, on the contrary, does not bind to estrogen binding sites and does not inhibit the growth of hormone-depending tumors. Quercetin, but not rutin, was also reported to be effective in inhibiting of in vitro bromodeoxyuridine incorporation by cells from transitional cell carcinoma of the bladder.
The flavonoids tricin and kaempferol-3-O-P-D-glucopyranoside derived from the traditional Chinese medicinal plant Wikstroemia Mica, demonstrated anti-leukaemic activity in the P-388 leukemic mice. Furthermore, epidemiological studies indicated that diets containing linseed and soy (rich in iso-flavonoids and lignans) may protect against colon, breast and prostatic cancer.
Role # 8. Flavonoids in Osteoclast genesis:
Flavonoids are found to have an inhibitory effect on osteoclastic bone resoption in vitro. Flavonoid quercertin was found to increase calcium content in the diaphyseal tissues of rat femoral culture system in vitro, although such an effect was not seen with culture of myricetin, kaempferol, isorhamnetin, curcumin, hesperidin, or astaxanthin.
Among various flavonoids, quercetin had unique effect on bone calcification, although the effect of flavonoids on osteoblastic cells remains a matter of some controversy.
Quercetin has been shown to increase osteogenic differentiation of human adipose tissue-derived stromal cells; reverse transcription-polymerase chain reaction (RT-PCR) and real time PCR analysis show that quercetin treatment induces an increase in the gene expression of osteopontin, bone morphogenic protein 2, alkaline phosphatase and Runx 2, which are a marker protein of osteoblastic cells .
Meanwhile, quercetin has been reported to accelerate the tumor necrosis factor-alpha induced growth inhibition and apoptosis in osteoblastic MC3T3-E1 cells.
Role # 9. Flavonoids as Anti-Inflammatory Agent:
Most of the flavonoids shown anti-inflammatory properties and these have been studied both in vitro and in vivo. Flavone/flavonol glycosides as well as flavonoid aglycons have been reported to Flavones/flavonols kaempferol, quercetin, myricetin, fisetin were reported to possess LO and COX inhibitory activities.
Hesperidin, a citrus flavonoid possesses significant anti-inflammatory and analgesic effects.
Recently, apigenin, luteolin and quercetin have been reported to exhibit anti-inflammatory activity. Quercetin, gallic acid ethyl ester and some as yet unidentified flavonoids might account for the anti-nociceptive action reported for the hydro-alcoholic extract of Phyllanthus caroliniensis.
Nepetin, a flavonoid obtained from Nepeta hindostana, was investigated in both acute and chronic models of inflammation in rats and found to possess significant activity in both proliferative and exudative phases of inflammation. Apigenin and luteolin from Chamomilla recutita were found to significantly inhibit the oedema caused by croton oil.
This activity may have been due to a direct inhibition of arachidonic acid metabolism or to other mechanisms such as inhibition of histamine release or promotion of scavenging activity.
Studies on the in vivo anti-inflammatory activity of the flavonoids, particularly hypolaetin-8-P-D-gluco-side, sidertoflavone (isolated from the Spanish Sideritis mugronensis) and the flavonol glycosides gossypin and hibifolin (isolated from traditional Indian medicinal plants), showed a dose-dependent inhibition of both paw oedema and leucocyte accumulation in the peritoneum in the carrageen- an-induced models of oedema and peritonitis.
Other studies were carried out on the anti-inflammatory activities of quercetin and quercitrin. In an ex vivo system utilizing the carrageen announced pleurisy model in rats, quercetin reduced in a dose related manner the induced contractions of both prostaglandin E, and leukotriene B, and leukocyte migration in the exudate.
Quercetin also reduced LTB4, synthesis in cells stimulated with ionophore A23 both ex-vivo and in vitro. Quercitrin exhibited similar but less activity than quercetin, recently it was reported that quercitrin decreased colonic damage and the incidence of diarrhea and normalized colonic fluid transport in rats with chronic experimental colitis.
Other in vivo studies have been carried out on the anti-inflammatory and analgesic activities of flavonoids, such as those extracted from Citrus aurantium (hesperidin), Machaerium villosum (duartin) and from Cyclolobium clausseni (clausse-quinone).
Role # 10. Flavonoids in Hepatoprotective Activity:
A large number of flavonoids have also been found to possess hepato-protective activity; in a study carried out to investigate silymarin, apigenin, quercetin and naringenin as putative therapeutic agents against microcrystin LR- induced hepatotoxicity, silymarin was found to be the most effective natural compound for hepatic protection.
Rutin and venorutin showed regenerative and hepato-protective effects in experimental cirrhosis.
The results of several clinical investigations showed the efficacy and safety of flavonoids in the treatment of hepatobiliary dysfunction and digestive complaints, such as sensation of fullness, loss of appetite, nausea and abdominal pain.
Silymarin normalizes cell phospholipid synthesis without showing any demonstrable effect on undamaged cells where by counteracting fatty liver. Moreover, earlier findings on a hepato-protective effect and the prevention of NSAIDs-induced gastropathy may be confirmed.
Role # 11. Effect of Flavonoids on Hormones:
Flavonoids plays important role in regulatory activity of hormones, by binding to 1 7 beta-hydroxy steroid dehydrogenases, which regulates estrogen and androgen levels in humans and to 3 beta-hydroxy steroid dehydrogenase, which regulates progestin and androgen levels in males and females respectively.
Quercetin, myricetin, rutin, kaempferol affect the transport, metabolism and action of thyroid hormones. Quercetin myricetin, rutin, kaempferol, galangin, spirenoside and robinin are potent non-toxic ITH deiodinase inhibitors in microsomal membranes, and intact rat hepatocytes.
Myricetin, rutin, kaempferol are specific high affinity competitors for L- T4-binding to human TBPA, weaker antagonists in the T3- 5′-deiodinase reaction, and very poor inhibitors of T3 binding to the nuclear T3 receptor.
Further investigation needs the role of ITH de-iodination for tissue specific expression of thyroid hormone action as well advance the knowledge of specific interaction of flavonoids with anti-thyroidal agent with extra-thyroidal mechanism of action in the process of T4 bio-activation to the thyromimetically active T3.
Role # 12. Effect of Flavonoids on Enzymes:
The biochemical activities of flavonoids and their metabolites depend on their chemical structure and the relative orientation of various moieties on the molecule.
Flavonoids display a remarkable array of the effect of enzymes and inhibit a number of enzymes such as aldose reductase, xanthine oxidase, phosphodiesterase, Ca2+ ATPase, lipooxygenase and cyclooxygenase. Flavonols like quercetin, myricetin and kaempferol inhibit the activity of the adenosine deaminase of endothelial cells, while flavones are inactive.
Quercetin, morin, myricetin and kaempferol are effective in antagonizing bradykinin responses which is vasodilator compound. Effects of luteolin and quercetin on inhibition of tyrosine kinase on cell growth and metastasis; they have inhibitory properties on the 5′-nucleotides (5′-ribonucleotide phosphohydrolase) activity.
Flavonoids can inhibit intracellular Ca2+elevation by reducing phospholipase- C activity and they possess potent inhibitory effects on several enzyme systems such as protein kinase-C, protein tyrosine kinase, phospholipase A2 and others.
Silymarin acts a strong antioxidant by virtue of its ability to act as an acceptor of O2 or CCI3 radicals; by trapping O2 related free radicals silymarin hinders their interaction with polyunsaturated fatty acid and abolishes the enhancement of lipid peroxidation.
Apigenin inhibits phosphodiesterase (PDE) and the effect was greater on cAMP- PDE than cCMP-PDE levels by 40% and cGMP level remained unchanged. Some flavonoids are predominant inhibitors of either cyclo-oxygenase or lipoxygenase, others are equally effective against both enzymes.
Numerous reports of a high standard have appeared on the inhibition by flavonoids of a perplexing number and variety of enzymes, e.g. hydrolases (such as aglucuronidase), hyaluronidase, alkaline phosphatase, arylsulphatase, H+-ATPases of lysosomal and granular membranes, Na+/K+-ATPase of the plasma membrane, a-galactosidase, c-AMP phosphodiesterase, lipases, lyases (such as DOPA-decarboxylase), transferases (like catechol-O-methyltransferase), hydroxylases (like aryl hydroxylase), oxidoreductases (like aldose reductase) and kiriases (e.g. hexokinase).