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Flavonoids (or bioflavonoids) are a class of phytonutrients (i.e., nutrients produced by plants) grouped together because of their basic molecular structure. There are many points of attachment to that basic structure and many possibilities for what may be attached at those points. Thus, there are many unique molecules that fall into the classification of “flavonoid.” In fact, more than 5000 flavonoids have been identified.
Flavonoids, themselves a subclass of polyphenols, can be divided into subclasses, again based on specific features of their molecular structure. The following list shows the subclasses and some of their food sources.[i]
Flavonoid subclass Some specific examples Typical rich food sources
Flavanol Catechin, EGCG* Teas, red grapes and red wine
Flavanones Hesperidin, naringenin Citrus fruits
Flavones Luteolin Green leafy spices (e.g., parsley)
Isoflavones Daidzen, genistein Soybeans, soy foods
Flavonols Quercetin, myricetin Onions, apples, walnuts, kale
Anthocyanidins Cyanidin, delphinidin Red, purple, and blue berries
Tannins Gallic acid, ellagic acid Apples, berries, chocolate, red wine, nuts, oolong and black teas, coffee (including proanthocyanidins)
*EGCG = epigallocatechin-3-gallate
Flavonoids have a wide variety of functions in plants, such as attracting pollinators or repelling pests or providing pigment that protects against UV radiation. These compounds have the potential to impact human health in either positive or negative ways. Studies of populations that consume diets rich in fruits and vegetables or specific foods particularly high in flavonoids suggest that flavonoids may be protective against certain degenerative diseases, such as heart disease or cancer. However, epidemiological studies cannot isolate the factors in those foods responsible for a perceived health benefit or detriment. For example, do the flavonoids in red wine account for the relatively low incidence of heart disease among the French, or is it the alcohol in the wine, or is it the fact that the French traditionally take time to enjoy their food and wine and thereby have moments of relief from stress?
Flavonoids have been credited with strengthening blood vessels, providing relief for allergy symptoms, inhibiting tumor growth, preventing oxidation of LDL-cholesterol (and hence, atherosclerosis), preventing cataracts and macular degeneration, and protecting skin from aging. Because flavonoids are strong antioxidants in the test tube, it has been presumed that all these protections result from the quenching of free radicals in the body by flavonoids. However, the Linus Pauling Institute has reported that dietary flavonoids are generally not absorbed from the intestine in the forms found in plants and cannot be found in the blood at high enough levels to function relevantly as antioxidants.[ii] Ingested flavonoids are modified in the intestine and, after absorption, are further modified in the liver before entering the blood.[iii] The forms that enter the blood are chemically distinct from their parent compounds and likely have different physiological behavior. This does not mean that flavonoids are without effects on human health. However, many claims of the beneficial effects of flavonoids have been based on test-tube or cell culture studies and their results cannot legitimately be carried over to humans consuming those flavonoids, whether in foods or as supplements. As of this writing in 2008, there is very little solid research defining the health effects resulting from the consumption of flavonoids. This is a complicated area of study because of the vast number of different starting compounds and the even greater number of possibly active metabolites. Below, some purported uses of citrus-derived flavonoid supplements and the evidence supporting them are discussed.
Citrus fruits and their peels contain a number of different types of flavonoids: hesperidin (abundant in oranges and lemons), naringin and naringenin (abundant in grapefruit), limonene (abundant in lemons and oranges), luteolin (abundant in lemons and oranges), tangeretin (abundant in peels of lemons, grapefruit, and oranges), diosmin (abundant in lemons and oranges), rutin, and quercetin.
Citrus fruits are known for their ability to overcome scurvy. While vitamin C overcomes the symptoms of scurvy, which include bleeding gums and internal bleeding, other compounds in citrus, namely the flavonoids, are also thought to strengthen blood vessel walls and thereby prevent bleeding and bruising. Little high quality research has been published about this reputed benefit of eating citrus fruits or taking citrus bioflavonoid supplements. However, there is much research about a micronized (finely ground) combination of 90% diosmin and 10% hesperidin (sold as the drug Daflon 500™), which has been used successfully for treating various conditions resulting from weakened or poorly functioning blood or lymphatic vessels, such as venous insufficiency (a condition in which blood is not returned to the heart as it should be and accumulates in the veins), venous ulcers (ulcers on the leg or foot that can result from venous insufficiency), hemorrhoids, and easy bruising.[iv],[v],[vi] Although the micronized form of these citrus flavonoids may be more readily absorbed and in greater concentration than the same flavonoids as they come in citrus fruits and citrus bioflavonoid supplements, the successful application of Daflon lends support to the traditional use of the fruits and supplements for maintaining healthy blood vessels.
Consumption of red grapefruit for 30 days by hyperlipidemic subjects who had undergone coronary bypass surgery reduced serum triglycerides by 20% and LDL-cholesterol by 17%. White grapefruit was about half as effective, and the control group (no grapefruit) showed no changes in blood lipids.[vii] While the study did not identify the specific compound(s) responsible for the changes, a study of isolated citrus flavonoids did show a similar effect: citrus flavonoids (270 mg), combined with 30 mg of tocotrienols and taken for 12 weeks, reduced total cholesterol by 20% to 30% and improved the HDL/total cholesterol ratio in hypercholesterolemic subjects (i.e., subjects with total cholesterol greater than 230 mg/deciliter).[viii]
Naringin and naringenin, both found in grapefruit, inhibited the development of oral cancer in hamsters whose cheek pouches were painted with both a carcinogen and a solution containing the two flavonoids.[ix] A study in mice showed that fortification of the diet with naringin reduced radiation damage to DNA in bone marrow, lowering the risk of leukemia.[x] Feeding diosmin and hesperidin to rats either before or after giving a carcinogen in drinking water for 8 weeks reduced cancer incidence by about 75%.[xi] Results of animal studies, of course, are not translatable to human conditions, but with this kind of success suggesting a role of flavonoids in cancer prevention, human studies will likely follow eventually.
Rutin and hesperidin have been shown to lessen bone loss in rats and mice whose ovaries were removed to simulate conditions of menopause. [xii], [xiii]
Rutin is quercetin with a disaccharide attached. (See Customer Literature File :”Quercetin” for more information about quercetin.) Rutin is found in buckwheat, apricots, cherries, prunes, citrus fruit rind, noni, black tea, and apple peel. Although a large portion of ingested rutin may be converted to quercetin before absorption, a study in mice showed that rutin and not quercetin could prevent colitis in mice given a colitis-inducing drug, suggesting that the two compounds can have different effects.[xiv]
In humans, rutin has been shown to be effective in treating chronic venous insufficiency (CVI). Patients with CVI who took 1500 to 2000 milligrams of rutin daily over 5 years showed reductions in swelling and capillary filtration rate to near normal levels and no deterioration of the venous system in the legs. Furthermore, ulcerations, a common occurrence with CVI, were prevented.[xv]
Naringenin, in high concentration in grapefruit, is an inhibitor of the enzyme cytochrome P450 3A4, an enzyme involved in the metabolism of drugs and estrogen. One study of postmenopausal women showed a higher risk of breast cancer among women consuming 1/4 of a grapefruit or more per day than among women who ate no grapefruit.[xvi] The effect of moderate grapefruit consumption is not known. More evidence is needed to validate these findings.
High consumption of grapefruit can result in increased blood levels of drugs that are metabolized by liver cytochrome P450 3A4. Grapefruit can also cause increases or decreases in the absorption of various drugs. If you take prescription medications, you should ask your prescribing physician or a pharmacist about drug-grapefruit interactions before taking supplementary naringenin or consuming large quantities of grapefruit or grapefruit juice.
[i] Beecher GR. Overview of dietary flavonoids: Nomenclature, occurrence and intake. J Nutr 2003; 133:3248S-3254S.
[ii] “Flavonoids,” Linus Pauling Institute website, June 2008 (2 July 2008), http://lpi.oregonstate.edu/infocenter/phytochemicals/flavonoids/.
[iii] Kroon PA et al. How should we assess the effects of exposure to dietary polyphenols in vitro? Am J Clin Nutr 2004; 80:15-21.
[iv] Guilou JJ et al. Benefit of a 1-month treatment with a micronized, purified flavonoidic fraction on venous ulcer healing. A randomized, double-blind, controlled versus placebo trial. Int J Microcirc Clin Exp 1997; 17 Suppl 1:21-26.
[v] Ramelet AA. Clinical benefits of Daflon 500 mg in the most severe stages of chronic venous insufficiency. Angiology 2001; 52 Suppl 1:S49-S56.
[vi] Lyseng-Williamson KA & Perry CM. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs 2003; 63(1):71-100.
[vii] Gorinstein S et al. Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. J Agric Food Chem 2006; 54(5):1887-1892.
[viii] Roza JM et al. Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects. Altern Ther Health Med 2007; 13(6):44-48.
[ix] Miller EG et al. Inhibition of oral carcinogenesis by citrus flavonoids. Nutrition and Cancer 2008; 60(1):69-74.
[x] Jagetia GC et al. Naringin, a citrus flavonone, protects against radiation-induce chromosome damage in mouse bone marrow. Mutagenesis 2003; 18:337-343.
[xi] Tanaka T et al. Chemoprevention of 4-nitroquinoline 1-oxide-induced oral carcinogenesis in rats by flavonoids diosmin and hesperidin, each alone and in combination. Cancer Res 1997; 57(2):246-252.
[xii] Horcajada-Molteni MN et al. Rutin inhibits ovariectomy-induced osteopenia in rats. J Bone Min Res 2000; 15:2251-2258.
[xiii] Chiba H et al. Hesperidin, a citrus flavonoid, inhibits bone loss and decreases serum and hepatic lipids in ovariectomized mice. J Nutr 2003; 133:1892-1897.
[xiv] Kwon KH et al. Dietary rutin, but not its aglycone quercetin, ameliorates dextran sulfate sodium-induced experimental colitis in mice: attenuation of pro-inflammatory gene expression. Biochem Pharmacol 2005; 69(3):395-406.
[xv] Belcaro G et al. 5-year control and treatment of edema and increased capillary filtration in venous hypertension and diabetic microangiopathy using O-(beta-hydroxyethyl)-rutosides: a prospective comparative clinical registry. Angiology 2008; 59 Suppl 1:14S-20S.
[xvi] Monroe KR et al. Prospective study of grapefruit intake and risk of breast cancer in postmenopausal women: the Multiethnic Cohort Study. Br J Cancer 2007; 97(3):440-445.
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