Flavonoids (or bioflavonoids) are a large group of polyphenolic compounds, ubiquitously present in foods of plant origin. Some flavonoids (e.g. quercetin, rutin) are available as dietary supplements.
Bioflavonoids are a group of polyphenolic anti-oxidants, which often occur as glycosides. Flavonoids can be further subdivided into five main groups: flavonols (e.g. kaempferol, quercetin and myricetin) flavones (e.g. apigenin and luteolin) flavonones (e.g. hesperetin, naringenin, erio-dictyol) flavan-3-ols (e.g. (+)-catechin, (+)-gallo-catechin, (–)-epicatechin, (–)-epigallo-catechin) anthocyanins (e.g. cyanidin, delphinidin, malvidin, pelargonidin, peonidin, petunidin) proanthocyanidins.
More than 4000 flavonoids have been identified, and many have been studied in the laboratory and in animal studies, but apart from quercetin, few have been studied in humans. Most flavonoids are colourless but some are responsible for the bright colours of many fruit and vegetables. Flavonoids are distinguished from the carotenoids (see Carotenoids), which are the red, yellow and orange pigments found in fruit and vegetables. Unlike carotenoids, flavonoids are water-soluble.
Flavonoids appear to display several effects.1
act as scavengers of free radicals, including superoxide anions, singlet oxygen, and lipid peroxyl radicals (they have antioxidant properties);
sequester metal ions;
inhibit in vitro oxidation of LDL cholesterol; inhibit cyclo-oxygenase, leading to lower platelet aggregation, decreased thrombotic tendency and reduced anti-inflammatory activity;
inhibit histamine release;
improve capillary function by reducing fragility of capillary walls and thus preventing abnormal leakage; and
inhibit various stages of tumour development (animal studies only).
The activities of flavonoids are dependent on their chemical structure.
No proof of a dietary need exists.
Estimates of dietary flavonoid intake vary from 10 to 100 mg daily, depending on the popula-tion studied, the technique used and the number and identity of flavonoids measured. If all flavonoids are included, intake may be several hundreds of milligrams a day, particularly if red wine is consumed in large amounts.
Table 1 Flavonoid content of selected foods (mg/100 g)
|Chocolate bar, dark||–||–||–||53.49||–||170|
|Chocolate bar, milk||–||–||–||13.45||–||70|
|Lemon juice, raw||–||0||18.33||–||–||–|
|Onions, red, raw||37.87||0||–||–||13.14||–|
|Tea, black, brewed||3.86||0||–||73.44||13.34|
|Tea, green, brewed||5.21||0.34||–||132.43|
|Wine, table red||1.64||0||–||11.9||9.19||61.63|
|Wine, table white||0.06||0||–||1.38||0.06||0.81|
|USDA database: http://www,nal.usda.gov/fnic/foodcomp|
|–, not analysed to date|
Flavonoids are found in the white segment or ring of fruit (especially citrus fruit) and vegetables, and also in tea and red wine. In the UK, tea, apples and onions seem to be major sources. Flavonoid content of foods varies widely (see Table 1). Cherry tomatoes contain higher concentrations than normal-sized tomatoes, and Lollo Rosso lettuce more than iceberg lettuce.1 The flavonoid content of red wine may also vary widely, depending on the source, growing conditions and harvesting of the grapes.2 Chocolate is also a good source of flavonoids (including flavonols, flavanols, catechins, epicatechins and proanthocyanidins).
Flavonoids have been investigated for a potential role in the prevention of CVD, cancer and cataracts. The totality of evidence suggests a role for flavonoids in prevention of CVD, cancer and possibly other chronic diseases.3,4
Epidemiological studies have suggested that consumption of fruit and vegetables may protect against CVD. That such a benefit could occur as a result of dietary antioxidant vitamins is well known, but the presence of flavonoids in these foods may also account for these findings.
Bioflavonoids may help to reduce the risk of heart disease (possibly by helping to dilate the coronary arteries and by preventing atherosclerosis). The Zutphen study from the Netherlands5 demonstrated a reduced risk of CHD and a reduced incidence of myocardial infarction in men aged 65–84 years associated with increased ingestion of dietary flavonoids. The major dietary sources of flavonoids in this study were tea (61%), onions (13%) and apples (10%). Flavonoid intake was inversely associated with CHD mortality, with a 68% reduction in risk for intake >19 mg daily. There was, however, no correlation between flavonoid intake and CHD incidence among those with no history of myocardial infarction. The researchers later updated their results,6 extending follow-up to 10 years. Similar results for CHD mortality were found, but a smaller risk reduction and a borderline significant trend (P = 0.08) for the incidence of CHD existed.
Another part of the Zutphen study7 investigated a cohort of men aged 50–69 years, following them up for 15 years. Dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence after adjustment for potential confounders, including antioxidant vitamins. The relative risk of stroke for the highest versus the lowest quartile of flavonoid intake was 0.27. A lower stroke risk was also observed for the highest quartile of beta-carotene intake, but vitamins C and E were not associated with stroke risk. Black tea contributed about 70% to flavonoid intake. The relative risk for daily consumption of 4.7 cups or more of tea versus less than 2.6 cups of tea was 0.31 (95% CI, 0.12 to 0.84).
However, the Caerphilly study in Wales showed no reduced risk of heart disease with increasing flavonoid consumption.8 This investigation involved 1900 men aged 45–59 who were studied for up to 14 years. Tea provided 82% of the flavonoid intake, and was strongly and positively associated with risk of CHD.
Baseline flavonoid intake was estimated in 16 cohorts of the Seven Countries Study,9 and mortality from CHD, cancer and all causes was investigated after 25 years of follow-up. Average intake of flavonoids was inversely associated with mortality from CHD and explained about 25% of the variance in CHD rates in the 16 cohorts. Flavonoid intake was not independently associated with mortality from other causes, including cancer.
Two studies used data from American cohorts of men and women. One study investigated the relationship between flavonoid intake and CHD risk in 34 789 men aged 40–75 in 1986 with a follow-up of 6 years.10 The main sources of flavonoids were tea and onions. Flavonoid intake > 40 mg daily was not associated with reduced CHD risk. The Iowa Womens’ Health Study11 investigated 34 492 post-menopausal women aged 55–69 for subsequent risk of CHD over a 10-year follow-up period. Compared to women in the lowest quintile (<5.8 mg daily) of flavonoid intake, those in the highest quintile (18.7 mg daily) had a significant 32% reduced risk of CHD death.
The association of tea intake with aortic atherosclerosis has also been investigated in a Dutch study.12 In a prospective study of 3454 men and women aged 55 and older, who were free of CVD at baseline, tea intake was inversely correlated with severe (but not mild or moderate) aortic atherosclerosis.
A meta-analysis of seven prospective cohort studies published before 2001 included 2087 fatal CHD events. Comparison of those in the top third with those in the bottom third of dietary flavonol intake yielded a combined risk ratio of 0.8 (95% CI, 0.69 to 0.93) after adjustment for known CHD risk factors and other dietary components. The authors concluded that high dietary intakes of flavonols from a small number of fruits and vegetables, tea and red wine may be associated with reduced risk of CHD mortality in free-living populations.13
A prospective study in 38 445 women (free of CVD and cancer) with a mean follow-up period of 6.9 years found no significant linear trend for CVD and important vascular events across quintiles of flavonoid intake. No indi-vidual flavonol or flavone was associated with CVD. Broccoli and apple consumption were associated with non-significant reductions in CVD risk. A small proportion of women (1185) consuming four or more cups of tea a day had a reduction in the risk of important vascular events but with a non-significant linear trend. In this study flavonoid intake was not strongly associated with risk of CVD.14
In the SU.VI.MAX study (an 8-year trial evaluating the effect of antioxidant supplementation on the incidence of major chronic disease), flavonoid-rich food in women was inversely associated with systolic blood pressure. No such relationship was seen in men. Women in the highest tertile of flavonoid-rich food consumption were at lower risk for CVD (OR 0.31; 95% CI, 0.14 to 0.68), while a positive tendency was observed in men. In this study, a high consumption of flavonoid-rich food appeared to reduce cardiovascular risk in women.15
Chocolate has attracted attention for its possible role in preventing CVD. A systematic review of 136 publications, mainly short-term feeding trials, suggested that cocoa and choco-late may exert benefit on cardiovascular risk via lowering blood pressure, anti-inflammatory effects, anti-platelet function, raising HDL and decreasing LDL oxidation. An associated meta-analysis of flavonoid intake suggests that these compounds may lower cardiovascular mortality.16
Intervention trials have shown that flavonoids can reverse endothelial dysfunction. Endothelial dysfunction appears to be important in the pathogenesis of CVD so any improvement could reduce the risk of coronary events. However, there is considerable variation in the response in endothelial function to flavonoids and this may be related to inter-individual differences in flavonoid metabolism.17
Activity of flavonoids against malignant cells has been demonstrated in vitro,18–20 and there
is much current interest in the potential use of bioflavonoids in the prevention and treatment of cancer.
In a Finnish study involving 9959 men and women (initially cancer-free) aged from 15 to 99, high dietary flavonoid intake was shown to reduce the risk of cancer.21 Researchers involved in the Iowa Women’s Health Study showed that in 35 000 post-menopausal women, those who drank more than two cups of tea a day were 32% less likely to have cancers of the mouth, oesophagus, stomach, colon and rectum. Risk of urinary tract cancer was reduced by 60%. In those who drank more than four cups of tea a day, the risk of cancer was lowered by 63%.22 Onions are high in flavonoids, which might explain the reduced risk of stomach cancer among those with a high intake of onions in a group of 120 852 men and women aged 55 to 69 years.23
A review of data from four cohort studies and six case-control studies examining associations between flavonoid intake and cancer risk found consistent evidence that flavonoids, especially quercetin, may reduce the risk of lung cancer.24
In the Nurses Health Study II, validated food frequency questionnaires from 90 630 women showed no associations between flavonols and breast cancer risk and there were no associations between individual flavonols such as kaempferol, quercetin and myricetin and breast cancer risk. However there was a significant inverse association between breast cancer and beans and lentils.25
There may be a role for flavonoids in preventing diabetes-related cataract formation. In diabetes mellitus, excess sorbitol or dulcitol is produced by the conversion of glucose by aldose reductase. The dulcitol cannot be further metabolised and therefore forms a hard crystalline layer in the lens, which forms the cataract. Flavonoids are potent inhibitors of the enzyme,26 but further studies are required before flavonoids could be recommended for cataract prevention.
Experimental studies have demonstrated that some flavonoids prevent ulcer formation,27 and that they may be useful in treating ulcers.
Flavonoids have been investigated for potential antiviral activity. In vitro tests have shown some activity against rhinovirus (responsible for 50% of common colds), but little activity against herpes simplex and influenza virus.28
Many claims have been made for the usefulness of bioflavonoids in a range of disorders, including haemorrhoids, allergy, asthma, menopausal symptoms and the prevention of habitual abortion, but scientific studies are required to investigate these claims. The suggestion has been made that flavonoids may reduce the occurrence of type 2 diabetes. However, a prospective study in 38 018 women aged over 45 and free of CVD, cancer and diabetes with an average 8.8-year follow-up found that total flavonols, flavones or individual compounds were associated with risk of type 2 diabetes, although apple and tea consumption was inversely associated with diabetes risk.29
As a dietary supplement, quercetin is promoted for prevention and treatment of atherosclerosis and hyperlipidaemia, diabetes, cataracts, hay fever, peptic ulcer, inflammation, prevention of cancer and for treating prostatitis. A preliminary, double-blind, placebo-controlled trial in chronic non-bacterial prostatitis showed that quercetin reduced pain and improved quality of life, but had no effect on voiding dysfunction.30 However, there is insufficient reliable information about the effectiveness of quercetin for other indications.
As a dietary supplement, rutin is used to reduce capillary permeability and treat symptoms of varicose veins. In combination with bromelain and trypsin, rutin is used to treat osteoarthritis. In one double-blind trial, 73 patients with osteoarthritis of the knee were randomly assigned to a combination enzyme product (containing rutin, bromelain and trypsin) or diclofenac. The enzyme product had a similar effect on reducing pain and mobility of the knee to diclofenac.31 However, there is insufficient reliable information about the effectiveness of rutin for other indications.
Pregnancy and breast-feeding
No problems have been reported.
None reported. However, there are no long-term studies assessing the safety of flavonoid supplements.
Flavonoids (e.g. quercetin, rutin) are available in the form of tablets and capsules.
The dose is not established; dietary supplements of quercetin and rutin provide around 500 mg in a single dose.
High dietary intakes of flavonoids have been linked with a reduced risk of CHD, cancer and cataracts. However, although a number of supplements (e.g. quercetin, rutin) are now available, there is currently only limited evidence that supplements are beneficial in any condition.
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