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Tropical Journal of Pharmaceutical Research
Pharmacotherapy Group, Faculty of Pharmacy, University of Benin, Benin City, Nigeria
ISSN: 1596-5996 EISSN: 1596-9827
Vol. 7, Num. 3, 2008, pp. 1089-1099

Tropical Journal of Pharmaceutical Research, Vol. 7, No. 3, September, 2008, pp. 1089-1099

Review Article

Flavonoids as Nutraceuticals: A Review

AR Tapas*1, DM Sakarkar1, and RB Kakde2

1Department of Pharmaceutical Chemistry, Sudhakarrao Naik Institute of Pharmacy, Pusad-445204, Dist.-Yavatmal
2(Maharashtra INDIA), University Department of Pharmaceutical Sciences, R.T.M. Nagpur University, Nagpur440033, Maharashtra, INDIA.
*Corresponding author: Email:; Tel:+91 07233 247308; +91 09325377391

Code Number: pr08030


Phenolic compounds form one of the main classes of secondary metabolites. They display a large range of structures and are responsible for the major organoleptic characteristics of plant-derived foods and beverages, particularly color and taste properties. They also contribute to the nutritional qualities of fruits and vegetables. Among these compounds, flavonoids constitute one of the most ubiquitous groups of plant phenolics. Owing to their importance in food organoleptic properties and human health, a better understanding of their structures and biological activities indicates their potentials as therapeutic agents and also for predicting and controlling food quality. Due to the variety of pharmacological activities in the mammalian body, flavonoids are more correctly referred as “nutraceuticals”.

Keywords: Bioflavonoids, Structure-Classification, Nutraceuticals, Antimicrobial activities, Anti-oxidant activity, Metabolic effects


Phenolic compounds constitute one of the main classes of secondary metabolites. They display a large range of structures and they are responsible for the major organoleptic characteristics of plant-derived foods and beverages, particularly color and taste properties and they also contribute to the nutritional qualities of fruits and vegetables. The most important natural pigments are carotenoids which are tetrapyrrole derivatives of naturally occurring phenolic compounds ubiquitously distributed in plant kingdom. Among these compounds, flavonoids constitute one of the most ubiquitous groups of all plant phenolics. So far, over 8,000 varieties of flavonoids have been identified1 .

Until ~50 years ago, information on the working mechanisms of flavonoids was scare. But it has been widely known for centuries that compounds of plant origin possess broad spectrum of biological activity2 . In 1930, Szent-Gyorgyi isolated a new substance from oranges and classified it as vitamin P but later, it became clear that this substance was actually a flavonoid3 . Flavonoids drew greater attention from researchers with the discovery of the French Paradox, i.e., the decrease incidence of cadio-vascular disease observed in the Mediterranean population which was associated with red wine consumption, and a greater amount of saturated fat the average diet than in other countries3 .


Flavonoids occur as aglycones, glycosides and methylated derivatives4 . In plants, flavonoids aglycones (i.e., flavonoids without attached sugar) occur in a variety of structural forms. All contain fifteen carbon atoms in their basic nucleus: two six-membered rings linked with a three carbon unit which may or may not be a part of a third ring5 . For convenience, the rings are labeled A, B, and C (see Fig. 1). The individual carbon atoms are based on numbering system which uses ordinary numerals for the A and C and “primed” numerals for B-ring (1). Primed modified numbering system is not used for chalcones (2) and the isoflavones derivatives (6): the pterocarpans and the rotenoids6 . The different ways to close this ring associated with the different oxidation degrees of ring A provide the various classes of flavonoids.

The six-membered ring condensed with the benzene ring is either a γ-pyrone (flavones (1) flavonols (3)) or its dihydroderivative (flavanones (4) and flavan-3-ols (5)). The position of the benzenoid substituent divides the flavonoids into two classes: flavonoids (1) (2-position) and isoflavonoids (6) (3-position). Most flavonoids occur naturally associated with sugar in conjugated form and, within any one class, may be characterized as monoglycosidic, diglycosidic, etc. The glycosidic linkage is normally located at position 3 or 7 and the carbohydrate unit can be L-rhamnose, D glucose, glucorhamnose, galactose or arabinose8 .


“Nutraceutical” is a term coined in 1979 by Stephen DeFelice9 . It is defined “as a food or a parts of food that provide medical or health benefits, including the prevention and treatment of disease.” Nutraceuticals may range from isolated nutrients, dietary supplements, and diets to genetically engineered “designer” food, herbal products, and processed products such as cereals, soups, and beverages. A nutraceutical is any nontoxic food extract supplement that has scientifically proven health benefits for both the treatment and prevention of disease10 .

The increasing interest in nutraceuticals reflects the fact that consumers hear about epidemiological studies indicating that a specific diet or component of the diet is associated with a lower risk for a certain disease. The major active nutraceutical ingredients in plants are flavonoids. As is typical for phenolic compounds, they can act as potent antioxidants and metal chelators. They also have long been recognized to possess antiinflammatory, antiallergic, hepatoprotective, antithrombotic, antiviral, and anticarcinogenic activities, as discussed in the subsections that a follow:

Antioxidant activity

The best-described property of almost every group of flavonoids is their capacity to acts as antioxidants. 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 damage11,12 . Free radicals and ROS have been implicated in a large number of human diseases13,14 . Quercetin, kaempferol, morin, myricetin and rutin, by acting as antioxidants, exhibited beneficial effects such as anti-inflammatory, antiallergic, 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 damage15,16 . The scavenging activity of flavonoids has been reported to be in the order: Myrcetin > quercetin > rhamnetin > morin > diosmetin > naringenin > apigenin > catechin > 5,7-dihydroxy-3’,4’,5’-trimethoxy flavone > robinin > kaempferol > flavone17 .

Antimicrobial activity

Flavonoids and esters of phenolic acids have also been investigated for their antibacterial, antifungal and antiviral activities.

Antibacterial activity

Antibacterial activity has been displayed by a number of flavonoids. Quercetin has been reported to completely inhibit the growth of Staphylococcus aureus. Most of the flavonones having no sugar moiety showed antimicrobial activities whereas none of the flavonols and flavonolignans tested showed inhibitory activity on microorganisms23 .

Antifungal activity

A number of flavonoids isolated from the peelings of tangerine orange, when tested for fungistatic activity towards Deuterophoma tracheiphila were found to be active; nobiletin and langeritin exhibited strong and weak activities, respectively, while hesperidin could stimulate fungal growth slightly. Chlorflavonin was the first chlorine-containing flavonoid-type antifungal antibiotic produced by strains of Aspergillus candidus24 .

Antiviral activity

Naturally occurring flavonoids with antiviral activity have been recognized since the 1940s but only recently have attempts been made to make synthetic modifications of natural compounds to improve antiviral activity. Quercetin, morin, rutin, dihydroquercetin (taxifolin), apigenin, catechin, and hesperidine viruses

The antiviral activity appears to be associated with the nonglycosidic compounds, and hydroxylation at the 3-position is apparently a prerequisite for antiviral activity. It has been found that flavonols are more active than flavones against Herpes simplex virus type 1 and the order of importance was galangin>kaempferol>quercetin26 . Recently, a natural plant flavonoid polymer of molecular weight 2,100 daltons was found to have antiviral activity against two strains of type 1 Herpes simplex virus and type 2 Herpes simplex viruses27 . Because of the worldwide spread of HIV since the 1980s, the investigation of the antiviral activity of flavonoids has mainly focused on HIV28 . There have appeared several recent reports on the anti-AIDS activity of flavonoids. Out of twenty eight flavonoids tested, the flavans were generally more effective than flavones and flavonones in the selective inhibition of HIV-1 and HIV-2 or similar immunodeficiency virus infections29 .

Effect on gastrointestinal system

Antiulcer activity

exert significant anti-inflammatory activity in the animal model of both acute and chronic inflammation when given orally or topically34,35 . Hesperidin, a citrus flavonoid, possesses significant anti-inflammatory and analgesic effects36 . Recently apigenin, luteolin and quercetin have been reported to exhibit anti-inflammatory activity37 .

A number of reports have been published which demonstrate that flavonoids can modulate arachidonic acid metabolism via the inhibition of cyclo-oxygenase (COX) and lipooxygenase activity (LO). Also, it has been speculated that the anti-inflammatory and antiallergic properties of flavonoids are the consequence of their inhibitory actions on arachidonic acid metabolism38 . Among Some recent studies have indicated that flavonoids possess antiulcerogenic activity. Flavonoid glycosides of Ocimum basilicum (Labiatae) decreased ulcer index, and inhibited gastric acid and pepsin secretions in aspirin-induced ulcers in rats30 . Quercetin, rutin, and kaempferol administered intraperitoneally (25-100 mg/kg) inhibited dose-dependent gastric damage produced by acidified ethanol in rats31 .

Hepatoprotective activity

The liver is subject to acute and potentially lethal injury by several substances including phalloidin (the toxic constituent of the mushroom, Amanita phalloides), CCl4 , galactosamine, ethanol, and other compounds. Flavonoids have also been found to possess hepatoprotective activity. In a study carried out to investigate the flavonoid derivatives silymarin, apigenin, quercetin, and naringenin, as putative therapeutic agents against microcrystin LR-induced hepatotoxicity, silymarin was found to be the most effective one32 . The flavonoid, rutin and venoruton, showed regenerative and hepatoprotective effects in experimental cirrhosis33 .

Anti-inflammatory activity

The anti-inflammatory activity of flavonoids in many animal models have been reported. 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 activities39, 40 .

Antidiabetic effects

Flavonoids, especially quercetin, has been reported to possess antidiabetic activity. Vessal et al reported that quercetin brings about the regeneration of pancreatic islets and proprably increases insulin release in strptozotocin-induced diabetic rats41 . Also in another study, Hif and Howell reported that quercetin stimulate insulin release and enhanced Ca2+ uptake from isolated islets cell which suggest a place for flavonoids in noninsulin-dependent diabetes42, 43 .

Effect on cardiovascular system

Vasorelaxant agent

The consumption of flavonoids may prevent endothelial dysfunction by enhancing the vasorelaxant process leading to a reduction of arterial pressure44,45 . Endothelial dysfunction represents a critical event in the development of cardiovascular diseases and the major complication of atherosclerosis and arterial thrombus formation46 .

The consumption of flavonoids can prevent a number of cardiovascular diseases including hypertension and atherosclerosis47,48 . Recently, many experimental studies have shown that these polyphenolic compounds may reduce the arterial pressure in rats and enhance the vasorelaxant process. The endothelium-dependent relaxation induced by flavonoids has been well documented. Furthermore, Also investigators have

The rapid uptake of oxidatively-modified LDL via a scavenger receptor leads to the formation of foam cells. Flavonoids may directly scavenge some radical species by acting as a chain braking antioxidant51 . The ability of quercetin and the quercetin glycosides to protect LDL against oxidative modification has shown a significant protective demonstrated that Anthocyanin delphinidin exerts a significant endothelium dependent vasorelaxation49,50 .

Antiatherosclerotic effects

Oxidative modification of low-density lipoproteins (LDL) by free radicals is an early event in the pathogenesis of atherosclerosis. effect52 . Furthermore, a Japanese study reported an inverse correlation between flavonoid intake and total plasma cholesterol concentrations53 .

Antithrombogenic effects

Platelet aggregation plays a pivotal role in the physiology of thrombotic disesases. 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 aggregation54 . Selected flavonoids such quercetin, kaempferol and myricetin were shown to be effective inhibitors of platelet aggregation in dogs and monkeys55 . Flavonols are particularly antithrombotic because they directly scavenge free radicals, thereby maintaining proper concentration of endothelial prostacyclin and nitric oxide56 . One study showed that flavonoids are powerful antithrombotic agents in vitro and in vivo because of their inhibition of the activity of cyclooxegenase and lipoxigenase pathways57 .

Cardioprotective effects

Recent interest in flavonoids has been stimulated by the potential health benefits arising from the antioxidant activity of these ployphenolic compounds. These are the result of their high propensity to transfer electrons, chelate ferrous ions, and scavenge reactive oxygen species58 . Because of these properties, flavonoids have been considered as potential protectors against chronic cardiotoxicity 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 cardiotoxicity, resulting in, for example, congestive heart failure (negative inotropic effect). In a recent report, the cardiotoxicity of doxorubicin on the mouse left atrium has been inhibited by flavonoids, 7monohydroxyethylrutoside and 7’,3’,4’trihydroxyethylrutoside (34)59,60, 61 .

Antineoplastic activity

A sufficient number of flavonoids have exhibited antineoplastic activity. Several recent reviews have highlighted this activity. Detailed studies62-64 have revealed that quercetin exerted a dose-dependent inhibition of growth and colony formation. The flavonoids, kaempferol, catechin, toxifolin and fisetin, also suppressed cell growth65, 66 . On screening the antileukaemic efficacy of 28 naturally occurring and synthetic flavonoids on human promyelocytic leukaemic HL-60 cells, genistein, an isoflavone was found to have strong effect67,68 .

Effect on central nervous system

Synthetic flavonoids, such as 6-bromoflavone and 6-bromo-3’-nitroflavones, were shown to displace [3H] flumazenil binding to membranes from rat cerebellum but not from spinal cord, indicating selectivity for the BZ-Omega receptor subtype, but the latter was more potent than 6-bromoflavone. Results from two conflict tests in rats showed that these synthetic flavonoids possess anxiolyticlike properties similar or superior to that of diazepam69 .

Toxicity of flavonoids

Flavonoids are ubiquitous in plant foods and drinks and, therefore, a significant quantity is consumed in our daily diet. The toxicity of flavonoids is very low in animals. For rats, the LD50 is 2-10 g per animal for most flavonoids. Similar doses in humans are quite unrealistic. As a precaution, doses less than 1mg per adult per day have been recommended for humans70 . Dunnick and Hailey reported that high doses of quercetin over several years might result in the formation of tumors in mice71. However, in other long-term studies, no carcinogenicity was found72 . Moreover, as described earlier, quercetin has been reported to be anti-mutagenic in vivo.

Tables 1, 2 and 3


Flavonoids comprise a vast array of biologically active compounds that are ubiquitous in plants, many of which have been used in traditional eastern medicine for thousands of years. They also constitute an unavoidable components of the diet. In the present review, we have reviewed detailed structural aspects and biological properties of flavonoids. The chemical and structural similarities of flavonoids with numerous biomolecules as well as their crucial role in plant-insect and plant-bacterial interactions make them an attractive class of phytoconstituents for biological activity. Their widespread occurrence, broad spectrum diversity and natural origin make them appropriate chemical scaffolds for novel therapeutic agents. Of the many actions of flavonoids, antioxidant and antiproliferative effects stand out. Given that certain substituents are known to be required or increase their actions, the therapeutic potential of selected flavonoids is fairly obvious. These natural compounds have several great advantages over other therapeutic agents for the following reasons:

i) Many diets are rich in these phenolics and are daily consumed.
ii) They rarely have any side effects.
iii) They have relatively long half-life
iv) They can be easily absorbed in the intestine after ingestion.

The study of flavonoids is complex because of the heterogeneity of different molecular structures and the scarcity of data on bioavailability. There is a need to improve analytic techniques to allow collection of more data on absorption and excretion. Data on the long-term consequences of chronic flavonoid ingestion are especially scarce. Finally, we think that natural, hemisynthetic and synthetic flavonoids alone or in combination with other preventive and/or therapeutic strategies will become effective future drugs against the most common degenerative diseases such as cancer, diabetes and cardiovascular complications.


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