Flavonoids were discovered by Albert Szent-Györgyi, one of the most important chemists from the start of the twentieth century. He received the Nobel prize in 1937 for his discovery and description of vitamin C. Szent-Györgyi discovered the flavonoids while he was working on the isolation of vitamin C .
The term ‘bioflavonoids’ or ‘flavonoids’ was first used by the German research scientists Geissmann en Hinreiner in 1952. They are also responsible for the classification system based on the structure of the ‘core’ of the basic flavonoid structure: the oxygen-containing pyran ring. To date, more than 5,000 naturally occurring flavonoids have been isolated from a variety of plants . Flavonoids are the largest group of polyphenols (more than 8,000 polyphenols are known) [2-4].
Sources and deficiencies
Nearly all types of fruits, vegetables, herbs and spices (including ginkgo) are sources of flavonoids. Flavonoids are also encountered in other types of food, such as dried beans (responsible for the colour of red and black beans) and grains (flavonoids usually colour them yellow). In general, the most colourful parts of our food, such as the skins/rinds of fruits, contain the highest concentrations of flavonoids. An exception to this rule is the white pulpy mass between the fruit and the rind of citrus fruits, which is very rich in bioflavonoids, whereas the rind and the fruit itself contain significantly lower concentrations. Factors that contribute to flavonoid deficiency are insufficient consumption of vegetables and fruits, as well as daily consumption of industrially processed vegetables and fruits. Symptoms that indicate insufficient intake of flavonoids are: very easy bleeding (gums, nose), easy bruising (bruises take a long time to disappear) and also easy swelling after injury. Another indication of flavonoid deficiency could be immune weakness, which becomes apparent when one easily catches a cold or another infection.
Structure, nomenclature and classification
The flavonoids are a very large and varied group of plant substances. However, they all share the same basic chemical structure: two aromatic rings (A- and B-ring) are attached to the sides of an oxygen-containing pyran ring (C-ring). Since a phenol group is always bound to one of the benzene rings, the flavonoids, together with the phenolic acids and the non-flavonoid polyphenols, belong to the larger group of polyphenols.
Six sub-classes can be distinguished, in which there are many bonds that are unique for the individual substances. These substances differ from each other in the number of hydroxyl groups they contain, how they are ordered in three dimensions and the extent to which these groups are ‘taken’. This results in a large variety of flavonoids, which usually have a broad range of different biochemical and physiological properties [3,4].
Flavonoids usually occur in nature in the form of glycosides, which means that they are bound to sugar molecules such as glucose, rhamnose and arabinose. Flavanols (catechins and proanthocyanidines) are the only exception – they are not bound to sugar molecules (aglycon) .
Flavons are less common in fruits and vegetables than flavonols are. The flavons in our food are usually glycosides of luteolin and apigenin. Parsley and celery are the only important dietary sources of flavons that are currently known [6-8].
Flavonols, in particular quercetin, but also kaempferol, myricetin, fisetin, isorhamnetin, pachypodol and rhamnazin are very common in the plant kingdom. Nonetheless, their amounts in our diet are usually very small. Daily intake of flavonols is estimated at a mere 20–35 mg per day. The richest sources are onions (up to 1.2 g/kg), cauliflower, kale, leek, broccoli and blueberries.
Our food contains flavonols in their glycosylated form. Often, the associated sugar group is either glucose or rhamnose, but other sugars may be present as well (including galactose, arabinose, xylose, glucuronic acid). The most important representatives of this group are quercetin and kaempferol.
Quercetin is probably the commonest flavonoid. Many of our more common foodstuffs contain flavonoids, including apples, onions, (green) tea, berries and cabbages, but also seeds, nuts, flowers, bark and leaves, red grapes, raspberries and garlic. Many of our medicinal plants owe a great deal of their medicinal properties to their high quercetin content. Quercetin is an aglycon; rutin is its associated glycoside. In food supplements, the group of flavonols is usually represented by quercetin or rutin, but it is also available as an extract of medicinal plants such as Ginkgo biloba. Sylimarine, a mixture of flavonolignans from Silybum marianum (milk thistle), also belongs to this group, as does phloridzin from apples.
Because isoflavons are structurally related to oestrogens, they are sometimes called plant hormones or phyto-oestrogens. Although they are non-steroidal, they do have hydroxyl groups in positions 7 and 4 in a configuration that is analogous to that of the hydroxyl groups in the oestradiol molecule. This gives them the property to bind to oestrogen receptors. Isoflavons are exclusively found in legumes, in particular in soy beans. The three most important isoflavons are genistein, daidzein and glycitein. They occur both as aglycons and glycosides, depending on how the soy beans are processed. It is still a matter to scientific debate which of these forms has the highest biological availability .
The group of flavanones is a relatively small group of flavonoids, which only occurs in high concentrations in citrus fruits. Citrus fruits contain flavanones in glycosylated form, such as hesperidin in oranges (glycoside of hesperetin), naringenin in grapefruits (glycoside of naringin) and eriodictyol in lemons (glycoside of eriocitrin). Tomatoes can contain small amounts of flavanones, as can aromatic plants such as mint. Food supplements contain these flavonoids in the form of ‘citrus bioflavonoids’.
Anthocyanidins are a group of pigments that are responsible for the pink, red, blue and purple colours of certain foodstuffs. In general, the colour intensity corresponds to the amount of anthocyanidins the food contains. This amount increases when the fruit ripens. Anthocyanidins can be found in our diet, for instance in red wine, certain grains and some vegetables (aubergines, cabbage, beans, onions, radish), while fruits are the richest source. Wine contains 200–350 mg anthocyanidins per litre and these anthocyanidins are converted into several complex compounds when the wine matures [10,11]. The highest concentrations of anthocyanidins in food supplements can be found in the extracts of Vaccinium myrtillus (blueberry), Rubus fruticosus (bramble), Rubus idaeus (raspberry), Ribes nigrum (blackberry) and Sambucus nigra (elderberry).
In contrast to other classes of flavonoids, flavanols occur in our food in unglycosylated form. Flavanols often occur along organic acids, mainly gallic acid, as flavanol gallate esters. Cocoa is a rich source of flavanols. Many manufacturers of chocolate remove the flavanols from their products as they have a bitter taste. Most consumers are unaware of this, as this type of information does not have to be included on the packaging .
All flavanols consist of one, or more, flavan-3-ol units. A generally accepted classification of this group is detailed below.
- Monomers: there are two stereo-isomers of flavan-3-ol: catechin and epicatechin. Catechins can be found in several types of fruit (in particular fresh apricots). They also occur in red wine, although green tea and cocoa are the richest sources [13,14]. In addition, medicinal plants such as Camellia sinensis (green tea) may be rich in catechins. The last three are the best sources of this group of flavonoids and are generally used in food supplements.
- Di- and trimers: these are oligomeric proanthocyanidins (OPC), which are also referred to as procyanidins (in France, for instance). The group (oligomeric) proanthocyanidins is one of the most important groups of flavonoids in plants. They are compounds of dimers and trimers of catechins and epicatechins which may be bound to each other in several ways, resulting in a great variety. OPC occurs in particular in berries (blueberries, chokeberries (Aronia), cranberries), grape skin and seeds, pomegranates and dark chocolate. Grape seeds are a good source of OPC in food supplements. Pycnogenol is a registered brand name of an OPC product that is extracted from the bark of the maritime pine (Pinus pinaster). Pycnogenol contains somewhat less procyanidins than grape seeds do.
Proanthocyanidins should not be confused with the previously mentioned anthocyanidins. However, they may be converted into each other enzymatically, causing a red colour to appear: '''PRO'''anthocyani'''DI'''nes (no colour) ---> anthocyanins (red). This process is partly responsible for the fact that leaves change their colour in autumn.
- Tetramers and higher: polymeric proanthocyanidins (tannins). Tannins frequently occur in food, including in tea, cocoa, coffee, fruits, fruit juices, red wine, vinegar, and vegetables. When tannins come into contact with mucous membranes they form complexes with proteins (cross-linking) both in the saliva itself and in the epithelial cells of the mucosa. Subsequently, the mucosa becomes more solid and less permeable. This mechanism is responsible for the adstringent quality of fruits (including grapes, peach, persimmon, apple, pear and berries) and beverages (including wine, cider, tea and beer). It is also responsible for the bitter quality of chocolate . The adstringent effect changes as the fruit ripens (or the beverage, such as wine or cider, matures) and disappears when the fruit is ripe . As tannins are large polar molecules, they are not easily absorbed by the skin or in the gastro-intestinal tract. The pharmacological effects of tannins can for the most part be explained by the local effects they have on these organs, such as the adstringent effect on the lumen of the gastro-intestinal tract. Tannins may also be broken down into their monomers and oligomers.
When describing the characteristics of flavonoids it is tempting to focus on a number of characteristic properties of specific individual flavonoids or their sub-groups. The sheer number of flavonoids and their wide variety of qualities would make this a gargantuan undertaking. Therefore, this monograph focuses on a few characteristic properties of the flavonoids as a group. However, it should be noted that the properties below do not necessarily apply to all of the flavonoids known to exist. Instead, the information below applies to flavonoids that are commonly found in a flavonoid complex.
- Antioxidative capacity: flavonoids have a direct antioxidative (in vitro) effect which is much more powerful than that of other vitamins, including vitamin C, vitamin E or glutathione. Their antioxidative capacity is probably related to their polyphenol structure [20,21]. It remains open to scientific debate as to what extent this strong antioxidative capacity plays any role in the human body [22,23]. An important measure of antioxidative capacity is the co-called ORAC value (see below).
ORAC (Oxygen Radical Absorbance Capacity) is an in vitro test that makes it possible to compare the antioxidative capacity of foodstuffs and supplements. The ORAC value gives an indication of the ability of foodstuffs to scavenge free radicals. The ORAC value can be measured in the lipid fraction (lipophilic) or in the water fraction (hydrophilic). The sum of both fractions provides the most accurate approximation of antioxidative capacity. More often than not, only the hydrophilic fraction is determined (where this is the case, this is mentioned in the table below). The ORAC value can be used to choose products which contribute significantly to the antioxidative capacity of the human body.
A few typical ORAC values:
- Blueberries 6552 µmol TE/100 g (H & L)
- Plums 6259 µmol TE/100 g (H & L)
- Blackberries 5347 µmol TE/100 g (H & L)
- Raspberries 4882 µmol TE/100 g (H & L)
- Strawberries 3577 µmol TE/100 g (H & L)
- Cherries 3365 µmol TE/100 g (H & L)
- Broccoli (uncooked) 3083 µmol TE/100 g (H & L)
- Raisins 3037 µmol TE/100 g (H & L)
- Oranges 1819 µmol TE/100 g (H & L)
- Spinach (uncooked) 1515 µmol TE/100 g (H & L)
- Alfalfa 1510 µmol TE/100 g (H only)
- Red grapes 1260 µmol TE/100 g (H only)
- Onions (uncooked) 1034 µmol TE/100 g (H & L)
- Aubergine 933 µmol TE/100 g (H & L)
- Carrots 666 µmol TE/100 g (H & L)
- Pumpkin 483 µmol TE/100 g (H & L)
- Cauliflower 620 µmol TE/100 g (H only)
Source: Agricultural Research Service (ARS) 2007
- Protection of capillaries, haemostatic (anti-hemorrhagic) effects: many flavonoids have strengthening effects on the vascular wall. Being more susceptible to bleeding is one of the characteristic symptoms of a flavonoid deficiency.
- Chelation of metals: metal ions, such as iron and copper, are able to catalyse the production of free radicals. The capability of flavonoids to bind with metal ions (chelation) appears to contribute to their antioxidative strength in vitro . Whether this is also the case in vivo remains to be seen, as most copper and iron in animals is already bound to proteins. This limits the number of reactions producing free radicals that they can take part in .
- Influence on cell growth and proliferation: cell growth and proliferation are regulated by growth factors which initiate a cascade of processes when a growth factor docks onto a specific receptor in the cell membrane. Several in vitro studies indicate that flavonoids may influence cell growth and proliferation by inhibiting the phosphorylation of the receptor, or may even block it completely [25-27].
- Influence on gene expression: flavonoids have a regulating effect on gene expression. By phosphorylating certain signalling proteins, flavonoids are able to influence the activity of transcription factors (via kinase). Transcription factors are proteins that regulate the expression of several genes. This way, flavonoids play a significant role in a range of important processes in the cell, such as growth, proliferation and apoptosis (cell death) [3,4].
- Antibacterial and antiviral effects: under certain circumstances, flavonoids may have an antibiotic effect as they can disturb the function of micro-organisms, such as viruses and bacteria. The procyanidins in Vaccinium myrtillus (blueberry) and cranberry inhibit the working mechanisms of bacteria which are responsible for urinary tract infections. In addition, several flavanols from green tea have been shown to be effective against influenza [3,4].
- Antihistamine: flavonoids have an inhibitory effect on the release of histamine .
- Very easy bleeding (gums, nose)
- Immune weakness
- Cardiovascular diseases
- Allergic conditions
Scientists have not as yet agreed upon a general method of measurement for flavonoids. As a result, hard and reliable data on flavonoid intake are hard to come by. In relation to the Netherlands, the results of Hertog and colleagues are taken to be the most reliable . Their conclusion was that the average person ingests approximately 23 mg of flavonoids per day, whereas it would be advisable to take at least 100 mg per day .
Flavonoid intake varies widely among individuals, depending on whether or not their diets contain any important sources of flavonoids, including (green and white) tea, grapes, red wine, berries, citrus fruits, legumes , cocoa (chocolate products with a cocoa percentage of 70% or over), apples and onions [17,32].
- Rusznyak SP, Szent-Gyorgyi A. Vitamin P: ﬂavonols as vitamins. Nature. 1936;138:27.
- Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr. 2002;22:19-34.
- Flavonoids: Chemistry, Biochemistry and Applications. Andersen ØM, Markham KR, editor. CRC Publication; 2005.
- Grotewold E. The science of flavonoids. Springer; 2005.
- Williamson G. Common features in the pathways of absorption and metabolism of flavonoids. In: Davies AJ, Lewis DS, et al., editors. Phytochemicals: Mechanisms of Action Boca Raton: CRC Press; 2004. p. 21-33.
- King HGC. Phenolic compounds of commercial wheat germ J Food Sci. 1962;27:446-54.
- Feng Y, McDonald CE, Vick BA. C-glycosylflavones from hard red spring wheat bran Cereal Chem. 1988;65:452-6.
- Sartelet H, Serghat S, Lobstein A, et al. Flavonoids extracted from fonio millet (Digitaria exilis) reveal potent antithyroid properties. Nutrition. 1996;12(2):100-6.
- Manach C, Williamson G, Morand C, et al. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr. 2005;81(1 Suppl):230S-42S. GRATIS: http://www.ajcn.org/cgi/content/full/81/1/230S
- Clifford MN. Anthocyanins - nature, occurrence and dietary burden J Sci Food Agric. 2000;80(7):1063-72. GRATIS: http://www3.interscience.wiley.com/cgi-bin/fulltext/72502495/HTMLSTART
- Es-Safi NE, Cheynier V, Moutounet M. Interactions between cyanidin 3-O-glucoside and furfural derivatives and their impact on food color changes. J Agric Food Chem. 2002;50(20):5586-95.
- The devil in the dark chocolate. Lancet. 2007;370(9605):2070.
- Arts IC, van De Putte B, Hollman PC. Catechin contents of foods commonly consumed in The Netherlands. 2. Tea, wine, fruit juices, and chocolate milk. J Agric Food Chem. 2000;48(5):1752-7.
- Arts IC, van de Putte B, Hollman PC. Catechin contents of foods commonly consumed in The Netherlands. 1. Fruits, vegetables, staple foods, and processed foods. J Agric Food Chem. 2000;48(5):1746-51.
- Santos-Buelga C, Scalbert A. Proanthocyanidins and tannin-like compounds: nature, occurrence, dietary intake and effects on nutrition and health. Journal of the Science of Food and Agriculture. 2000;80(7):1094-117.
- Tanaka T, Takahashi R, Kouno I, et al. Chemical evidence for the de-astringency (insolubilization of tannins) of persimmon fruit J Chem Soc [Perkin 1]. 1994;:3013-22.
- Manach C, Scalbert A, Morand C, et al. Polyphenols: food sources and bioavailability. Am J Clin Nutr. 2004;79(5):727-47. GRATIS: http://www.ajcn.org/cgi/content/full/79/5/727
- Setchell KD, Brown NM, Lydeking-Olsen E. The clinical importance of the metabolite equol-a clue to the effectiveness of soy and its isoflavones. J Nutr. 2002;132(12):3577-84. GRATIS: http://jn.nutrition.org/cgi/content/full/132/12/3577
- Yuan JP, Wang JH, Liu X. Metabolism of dietary soy isoflavones to equol by human intestinal microflora--implications for health. Mol Nutr Food Res. 2007;51(7):765-81.
- Heijnen CG, Haenen GR, van Acker FA, et al. Flavonoids as peroxynitrite scavengers: the role of the hydroxyl groups. Toxicol In Vitro. 2001;15(1):3-6.
- Chun OK, Kim DO, Lee CY. Superoxide radical scavenging activity of the major polyphenols in fresh plums. J Agric Food Chem. 2003;51(27):8067-72.
- Lotito SB, Frei B. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: Cause, consequence, or epiphenomenon? Free Radic Biol Med. 2006;41(12):1727-46.
- Frei B, Higdon JV. Antioxidant activity of tea polyphenols in vivo: evidence from animal studies. J Nutr. 2003;133(10):3275S-84S. GRATIS: http://jn.nutrition.org/cgi/content/full/133/10/3275S
- Mira L, Fernandez MT, Santos M, et al. Interactions of flavonoids with iron and copper ions: a mechanism for their antioxidant activity. Free Radic Res. 2002;36(11):1199-208.
- Hou Z, Lambert JD, Chin KV, et al. Effects of tea polyphenols on signal transduction pathways related to cancer chemoprevention. Mutat Res. 2004;555(1-2):3-19.
- Williams RJ, Spencer JP, Rice-Evans C. Flavonoids: antioxidants or signalling molecules? Free Radic Biol Med. 2004;36(7):838-49.
- Lambert JD, Yang CS. Mechanisms of cancer prevention by tea constituents. J Nutr. 2003;133(10):3262S-7S. GRATIS: http://jn.nutrition.org/cgi/content/full/133/10/3262S
- Kawai M, Hirano T, Higa S, et al. Flavonoids and related compounds as anti-allergic substances. Allergol Int. 2007;56(2):113-23. GRATIS: http://ai.jsaweb.jp/fulltext/056020113/056020113_index.html
- Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovasc Drugs. 2004;4(5):281-97.
- Hertog MG, Hollman PC, Katan MB, et al. Intake of potentially anticarcinogenic flavonoids and their determinants in adults in The Netherlands. Nutr Cancer. 1993;20(1):21-9.
- EwaldFjelkner-Modig EC, Johansson K, et al. Effect of processing on major flavonoids in processed onions, green beans, and peas. In: Food Chem. 1999. p. 231-5.
- Slimestad R, Fossen T, Vågen IM. Onions: a source of unique dietary flavonoids. J Agric Food Chem. 2007;55(25):10067-80.