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FREE RADICAL FIGHTER
Antioxidants are vitamins, minerals, and other nutrients that protect and repair cells from damage caused by free radicals. Many experts believe this damage plays a part in a number of chronic diseases, including hardening of the arteries (atherosclerosis), cancer, and arthritis. Free radicals can also interfere with your immune system. So, fighting off damage with antioxidants helps keep your immune system strong, making you better able to ward off colds, flu, and other infections.
Antioxidants are compounds that neutralize the cellular-damaging effects of free radicals. Free radicals are produced naturally in your body, but when you exercise hard, your body pumps out more free radicals. Environmental factors such as pollution, the sun, cigarette smoke, and herbicides can also spawn free radicals. The danger is that free-radical damage may lead to cancer. Antioxidants interact with and stabilize free radicals and may prevent some of the damage that free radicals otherwise might cause. As an active person, more antioxidants may help you slow the aging process, ward off cancer and stress, and promote good health.
Flavonoids (or bioflavonoids) are a class of plant secondary metabolite compounds found in fruits, vegetables, and certain beverages that have diverse beneficial biochemical and antioxidant effects. Flavonoids were referred to as Vitamin P (possibly because of the effect they had on the permeability of vascular capillaries) from the mid 1930s to early 50s, but the term has since fallen out of use. Their dietary intake is quite high compared to other dietary antioxidants like vitamins C and E. The antioxidant activity of flavonoids depends on their molecular structure, and structural characteristics of certain flavonoids found in hops and beer confer surprisingly potent antioxidant activity exceeding that of red wine, tea, or soy.
Flavonoids is the universal term given to some 4,000 compounds that make up the colorful pigment in fruits, vegetables and herbs. Flavonoids can also be found in legumes, grains and nuts, and they can act as effective antivirals, anti-inflammatories, antihistamines and antioxidants. Flavonoids are useful for reducing cancer risk and serve to prevent or treat a wide variety of conditions.
FLAVONOID FUNCTIONS & CLASSIFICATIONS
Flavonoids are polyphenolic compounds that are ubiquitous in nature and are categorized, according to chemical structure, into flavonols, flavones, flavanones, isoflavones, catechins, anthocyanidins and chalcones. Over 4,000 flavonoids have been identified, many of which occur in fruits, vegetables and beverages (tea, coffee, beer, wine and fruit drinks). The flavonoids have aroused considerable interest recently because of their potential beneficial effects on human health-they have been reported to have antiviral, anti-allergic, antiplatelet, anti-inflammatory, antitumor, anti-diarrheal and antioxidant activities.
Flavonoids are widely distributed in plants fulfilling many functions. Flavonoids are the most important plant pigments for flower coloration producing yellow or red/blue pigmentation in petals designed to attract pollinator animals in higher plants. Flavonoids are involved in UV filtration, symbiotic nitrogen fixation and floral pigmentation. They may act as a chemical messenger or physiolgical regulator, they can also act as cell cycle inhibitors. Flavonoids secreted by the root of their host plant help Rhizobia in the infection stage of their symbiotic relationship with legumes like peas, beans, clover, and soy. Rhizobia living in soil are able to sense the flavonoids and this triggers the secretion of Nod factors, which in turn are recognized by the host plant and can lead to root hair deformation and several cellular responses such as ion fluxes and the formation of a root nodule. In addition, some flavonoids have inhibitory activity against organisms that cause plant disease e.g. Fusarium oxysporum.
According to the IUPAC nomenclature, they can be classified into flavones, isoflavonoids and neoflavonoids. These three classes are all ketone-containing compounds, and as such are flavonoids and flavonols. This class was the first to be termed bioflavonoids. The terms flavonoids and bioflavonoids have also been more loosely used to describe non-ketone polyhydroxy poolyphenol compounds which are more specifically termed flavanoids, flavan-2-ols (or catechins). The three cycle or heterocycles in the flavonoid backbone are generally called ring A, B and C. Ring A usually shows a phloroglucinol substitution pattern.
Antioxidants are compounds that protect cells against the damaging effects of reactive oxygen species, such as singlet oxygen, superoxide, peroxyl radicals, hydroxyl radicals and peroxynitrite. An imbalance between antioxidants and reactive oxygen species results in oxidative stress, leading to cellular damage. Oxidative stress has been linked to cancer, aging, atherosclerosis, ischemic injury, inflammation and neurodegenerative diseases (Parkinson's and Alzheimer's). Flavonoids may help provide protection against these diseases by contributing, along with antioxidant vitamins and enzymes, to the total antioxidant defense system of the human body. Epidemiological studies have shown that flavonoid intake is inversely related to mortality from coronary heart disease and to the incidence of heart attacks.
The recognized dietary antioxidants are Vitamin C, Vitamin E, Selenium, and Carotenoids. However, recent studies have demonstrated that flavonoids found in fruits and vegetables may also act as antioxidants. Like alpha-tocopherol (vitamin E), flavonoids contain chemical structural elements that may be responsible for their antioxidant activities. A recent study by Dr. van Acker and his colleagues in the Netherlands suggests that flavonoids can replace vitamin E as chain-breaking antioxidants in liver microsomal membranes. The contribution of flavonoids to the antioxidant defense system may be substantial considering that the total daily intake of flavonoids can range from 50 to 800 mg. This intake is high compared to the average daily intake of other dietary antioxidants like vitamin C (70 mg), vitamin E (7 to 10 mg) or carotenoids (2 to 3 mg). Flavonoid intake depends upon the consumption of fruits, vegetables, and certain beverages, such as red wine, tea, and beer. The high consumption of tea and wine may be most influential on total flavonoid intake in certain groups of people.
The oxidation of low-density lipoprotein (LDL) has been recognized to play an important role in atherosclerosis. Immune system cells called macrophages recognize and engulf oxidized LDL, a process that leads to the formation of atherosclerotic plaques in the arterial wall. LDL oxidation can be induced by macrophages and can also be catalyzed by metal ions like copper. Several studies have shown that certain flavonoids can protect LDL from being oxidized by these two mechanisms.
(Listed in order of decreasing potency.)
Quercetin (a flavonol in vegetables, fruit skins, onions) Xanthohumol (a prenylated chalcone in hops and beer) Isoxanthohumol (a prenylated flavanone in hops and beer) Genistein (an isoflavone in soy)
Chalconaringenin (a non-prenylated chalcone in citrus fruits) Naringenin (a non-prenylated flavanone in citrus fruits)
The capacity of flavonoids to act as antioxidants depends upon their molecular structure. The position of hydroxyl groups and other features in the chemical structure of flavonoids are important for their antioxidant and free radical scavenging activities. Quercetin, the most abundant dietary flavonol, is a potent antioxidant because it has all the right structural features for free radical scavenging activity.
Recently, chalcone and flavanone flavonoids with prenyl or geranyl side chains have been identified in hops and beer by Dr. Fred Stevens and Dr. Max Deinzer at Oregon State University. Hops are used in beer for flavor. Xanthohumol (a chalcone) and isoxanthohumol and 6-prenylnaringenin (flavanones) are the major prenyl-flavonoids found in beer. Although the antioxidant activities of these compounds have not been studied, these flavonoids may be responsible for the antioxidant activity of lager beer, which is higher than that of green tea, red wine, or grape juice as reported earlier by Dr. Joe A. Vinson from the University of Scranton in Pennsylvania. Xanthohumol is found only in beer but in small concentrations.
To assess the antioxidant activity of the prenylated flavonoids, we-in collaboration with LPI researchers-evaluated the capacity of these flavonoids to inhibit the oxidation of LDL by copper. The antioxidant properties of the prenylflavonoids were compared to those of quercetin (a flavonol), genistein (the major isoflavone in soy), chalconaringenin (a non-prenylated chalcone), naringenin (a non-prenylated flavanone), and vitamin E. The possible interaction of xanthohumol, the major prenylchalcone in beer, with vitamin E to inhibit LDL oxidation induced by copper was also examined.
Research results showed that the prenylchalcones and prenylflavones are effective in preventing LDL oxidation initiated by copper and that the prenylchalcones generally have greater antioxidant activity than the prenylflavanones. Xanthohumol, the major prenylchalcone in hops and beer, is a more powerful antioxidant than vitamin E or genistein. However, xanthohumol was less potent than quercetin. The potency of xanthohumol as an antioxidant is markedly increased when combined with an equivalent amount of vitamin E.
As reported in the Journal of Agricultural and Food Chemistry, it was found that the prenyl group plays an important role in the antioxidant activity of certain flavonoids. A flavonoid chalcone (chalconaringenin) and a flavanone (naringenin) with no prenyl groups act as pro-oxidants, i.e. they promote rather than limit the oxidation of LDL by copper. However, adding a prenyl group to these flavonoid molecules counteracted their pro-oxidant activities.
Research reveals that there are unique flavonoids in hops and beer that may be potentially useful in the preventionof human disease attributed to free radical damage. The observation that prenyl groups are important in conferring antioxidant activity to certain flavonoids may lead to the discovery or synthesis of novel prenylated flavonoids as preventive or therapeutic agents against human diseases associated with free radicals. The encouraging results with xanthohumol suggest that this prenylchalcone should be further studied for its antioxidant action and protective effects against free radical damage in animals and humans. Preliminary studies have shown that xanthohumol is absorbed from the digestive tract in rats, and more studies are needed to evaluate the bioavailability of these interesting flavonoids in people.
Further studies are also needed to establish the safety of xanthohumol or other flavonoids for use as dietary supplements since high doses of these compounds may produce adverse effects in humans, according to recent findings by Dr. Martyn Smith, professor of toxicology, University of California at Berkeley.
Nutrition Basics: Bioflavonoids Information
FLAVONOID USES, HEALTH BENEFITS, & SCIENTIFIC EVIDENCE
Research generally supports the healing potential of Flavonoids; however, few have been studied. The following Flavonoids have been researched and are listed as the most important to date. Genistein, found in soybeans and some other legumes, can lessen hot flashes and help prevent hormone-related cancers; quercetin, found in apples and onions, helps reduce the risk for cataracts and macular degeneration, fibromyalgia, gout and rheumatoid arthritis; PCO’s (procyanidolic oligomers), found in pine bark and grape seed extract and red wine, helps reduce the risk of heart disease and stroke; and rutin and hesperidin, found in citrus fruits, is effective in repairing hemorrhoids and varicose veins. Another valuable Flavonoid is EGCG (epigallocatechingallate), a polyphenol found in green tea, and thought to be the most effective cancer battling compound to date.
Flavonoids are a large family of compounds synthesized by plants that have a common chemical structure. The basic structure of a flavonoid is shown above. Flavonoids may be further divided into subclasses. Over the past decade, scientists have become increasingly interested in the potential for various dietary flavonoids to explain some of the health benefits associated with fruit- and vegetable-rich diets.
COMMON DIETARY FLAVONOIDS FLAVONOID SUBCLASS DIETARY FLAVONOIDS SOME COMMON FOOD SOURCES Anthocyanidins Cyanidin Delphinidin Malvidin Pelargonidin Peonidin Petunidin Red, blue, and purple berries. Red and purple grapes. Red wine. Flavonols Monomers (Catechins):
Catechin Epicatechin Epigallocatechin Epicatechin Gallate Epigallocatechin Gallate
Dimers & Polymers:
Theaflavins Thearubigins Proanthocyanidins Catechins: Teas (particularly green and white), chocolate, grapes, berries, apples. Theaflavins, Thearubigins: Teas (particularly black and oolong). Proanthocyanidins: Chocolate, apples, berries, red grapes, red wine. Flavanones Hesperetin Naringenin Eriodictyol Citrus fruits and juices, e.g., oranges, grapefruits, lemons. Flavonols Quercetin Kaempferol Myricetin Isorhamnetin Widely Distributed: Yellow onions, scallions, kale, broccoli, apples, berries, teas. Flavones Apigenin Luteolin Parsley, thyme, celery, hot peppers. Isoflavones Daidzein Genistein Glycitein Soybeans, soy foods, legumes.
METABOLISM & BIOAVAILABILITY
Flavonoids connected to one or more sugar molecules are known as flavonoid glycosides, while those that are not connected to a sugar molecule are called aglycones. With the exception of flavanols (catechins and proanthocyanidins), flavonoids occur in plants and most foods as glycosides. Even after cooking, most flavonoid glycosides reach the small intestine intact. Only flavonoid aglycones and flavonoid glucosides (bound to glucose) are absorbed in the small intestine, where they are rapidly metabolized to form methylated, glucuronidated, or sulfated metabolites.
Bacteria that normally colonize the colon also play an important role in flavonoid metabolism and absorption. Flavonoids or flavonoids metabolites that reach the colon may be further metabolized by bacterial enzymes, and then absorbed. A person's ability to produce specific flavonoid metabolites may vary and depends on the milieu of the colonic microflora. In general, the bioavailability of flavonoids is relatively low due to limited absorption and rapid elimination.
Bioavailability differs for the various flavonoids: Isoflavones are the most bioavailable group of flavonoids, while flavanols (proanthocyanidins and tea catechins) and anthocyanins are very poorly absorbed. Since flavonoids are rapidly and extensively metabolized, the biological activities of flavonoid metabolites are not always the same as those of the parent compound. When evaluating the data from flavonoid research in cultured cells, it is important to consider whether the flavonoid concentrations and metabolites used are physiologically relevant. In humans, peak plasma concentrations of soy isoflavones and citrus flavanones have not been found to exceed 10 micromoles/liter after oral consumption. Peak plasma concentrations measured after the consumption of anthocyanins, flavanols and flavonols (including those from tea) are generally less than 1 micromole/liter.
Direct Antioxidant Activity
Flavonoids are effective scavengers of free radicals in the test tube (in vitro). However, even with very high flavonoid intakes, plasma and intracellular flavonoid concentrations in humans are likely to be 100 to 1,000 times lower than concentrations of other antioxidants, such as ascorbate (vitamin C), uric acid, or glutathione. Moreover, most circulating flavonoids are actually flavonoid metabolites, some of which have lower antioxidant activity than the parent flavonoid. For these reasons, the relative contribution of dietary flavonoids to plasma and tissue antioxidant function in vivo is likely to be very small or negligible.
Metal ions, such as iron and copper, can catalyze the production of free radicals. The ability of flavonoids to chelate (bind) metal ions appears to contribute to their antioxidant activity in vitro. In living organisms, most iron and copper are bound to proteins, limiting their participation in reactions that produce free radicals. Although the metal-chelating activities of flavonoids may be beneficial in pathological conditions of iron or copper excess, it is not known whether flavonoids or their metabolites function as effective metal chelators in vivo.
Effects on Cell-Signaling Pathways
Cells are capable of responding to a variety of different stresses or signals by increasing or decreasing the availability of specific proteins. The complex cascades of events that lead to changes in the expression of specific genes are known as cell-signaling pathways or signal transduction pathways. These pathways regulate numerous cell processes, including growth, proliferation, and death (apoptosis). Although it was initially hypothesized that the biological effects of flavonoids would be related to their antioxidant activity, available evidence from cell culture experiments suggests that many of the biological effects of flavonoids are related to their ability to modulate cell-signaling pathways. Intracellular concentrations of flavonoids required to affect cell-signaling pathways are considerably lower than those required to affect cellular antioxidant capacity. Flavonoid metabolites may retain their ability to interact with cell-signaling proteins even if their antioxidant activity is diminished. Effective signal transduction requires proteins known as kinases that catalyze the phosphorylation of target proteins at specific sites. Cascades involving specific phosphorylations or dephosphorylations of signal transduction proteins ultimately affect the activity of transcription factors - proteins that bind to specific response elements on DNA and promote or inhibit the transcription of various genes. The results of numerous studies in cell culture suggest that flavonoids may affect chronic disease by selectively inhibiting kinases. Cell growth and proliferation are also regulated by growth factors that initiate cell-signaling cascades by binding to specific receptors in cell membranes. Flavonoids may alter growth factor signaling by inhibiting receptor phosphorylation or blocking receptor binding by growth factors.
FLAVONOIDS & CANCER PREVENTION
Modulation of Cell-signaling pathways by flavonoids could help prevent cancer by:
Stimulating Phase II Detoxification Enzyme Activity: Phase II detoxification enzymes catalyze reactions that promote the excretion of potentially toxic or carcinogenic chemicals.
Preserving Normal Cell Cycle Regulation: Once a cell divides, it passes through a sequence of stages collectively known as the cell cycle before it divides again. Following DNA damage, the cell cycle can be transiently arrested at damage checkpoints, which allows for DNA repair or activation of pathways leading to cell death (apoptosis) if the damage is irreparable. Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer.
Inhibiting Proliferation & Inducing Apoptosis: Unlike normal cells, cancer cells proliferate rapidly and lose the ability to respond to cell death signals that initiate apoptosis.
Inhibiting Ttumor Invasion & Angiogenesis: Cancerous cells invade normal tissue aided by enzymes called matrix-metalloproteinases. To fuel their rapid growth, invasive tumors must develop new blood vessels by a process known as angiogenesis.
Decreasing Inflammation: Inflammation can result in locally increased production of free radicals by inflammatory enzymes, as well as the release of inflammatory mediators that promote cell proliferation and angiogenesis and inhibit apoptosis.
CANCER DISEASE PREVENTION
Although various flavonoids have been found to inhibit the development of chemically-induced cancers in animal models of lung, oral, esophageal, stomach, colon, skin, prostate, and mammary (breast) cancer, epidemiological studies do not provide convincing evidence that high intakes of dietary flavonoids are associated with substantial reductions in human cancer risk. Most prospective cohort studies that have assessed dietary flavonoid intake using food frequency questionnaires have not found flavonoid intake to be inversely associated with cancer risk. Two prospective cohort studies in Europe found no relationship between the risk of various cancers and dietary intakes of flavones and flavonols, catechins, or tea. In a cohort of postmenopausal women in the U.S., catechin intake from tea, but not fruits and vegetables, was inversely associated with the risk of rectal cancer, but not other cancers.
Two prospective cohort studies in Finland, where average flavonoid intakes are relatively low, found that men with the highest dietary intakes of flavonols and flavones had a significantly lower risk of developing lung cancer than those with the lowest intakes. When individual dietary flavonoids were analyzed, dietary quercetin intake, mainly from apples, was inversely associated with the risk of lung cancer; myricetin intake was inversely associated with the risk of prostate cancer.
Tea is an important source of flavonoids (flavanols and flavonols) in some populations, but most prospective cohort studies have not found tea consumption to be inversely associated with cancer risk. The results of case-control studies, which are more likely to be influenced by recall bias, are mixed. While some studies have observed lower flavonoid intakes in people diagnosed with lung, stomach, and breast cancer, many others have found no significant differences in flavonoid intake between cancer cases and controls. There is limited evidence that low intakes of flavonoids from food are associated with increased risk of certain cancers, but it is not clear whether these findings are related to insufficient intakes of flavonoids or other nutrients and phytochemicals found in flavonoid-rich foods.
Clinical trials will be necessary to determine if specific flavonoids are beneficial in the prevention or treatment of cancer; a few clinical trials are currently under way. See www.cancer.gov/clinicaltrials.
FLAVONOIDS & CARDIOVASCULAR DISEASE PREVENTION
Modulation of cell-signaling pathways by flavonoids could help prevent cardiovascular disease by:
Decreasing Inflammation: Atherosclerosis is now recognized as an inflammatory disease, and several measures of inflammation are associated with increased risk of myocardial infarction (heart attack).
Decreasing Vascular Cell Adhesion Molecule Expression: One of the earliest events in the development of atherosclerosis is the recruitment of inflammatory white blood cells from the blood to the arterial wall. This event is dependent on the expression of adhesion molecules by the vascular endothelial cells that line the inner walls of blood vessels.
Increasing Endothelial Nitric Oxide Synthase (eNOS) Activity: eNOS is the enzyme that catalyzes the formation of nitric oxide by vascular endothelial cells. Nitric oxide is needed to maintain arterial relaxation (vasodilation). Impaired nitric oxide-dependent vasodilation is associated with increased risk of cardiovascular disease.
Decreasing Platelet Aggregation: Platelet aggregation is one of the first steps in the formation of a blood clot that can occlude a coronary or cerebral artery, resulting in myocardial infarction or stroke, respectively. Inhibiting platelet aggregation is considered an important strategy in the primary and secondary prevention of cardiovascular disease.
Cardiovascular Disease Epidemiological Evidence
Several prospective cohort studies conducted in the U.S. and Europe have examined the relationship between some measure of dietary flavonoid intake and coronary heart disease (CHD) risk. Some studies have found that higher flavonoid intakes to be associated with significant reductions in CHD risk, while others have reported no significant relationship. In general, the foods that contributed most to total flavonoid intake in these cohorts were black tea, apples, and onions. One study in the Netherlands also found cocoa to be a significant source of dietary flavonoids. Of seven prospective cohort studies that examined relationships between dietary flavonoid intake and the risk of stroke, only two studies found that higher flavonoid intakes were associated with significant reductions in the risk of stroke, while five found no relationship. Although data from prospective cohort studies suggest that higher intakes of flavonoid-rich foods may help protect against CHD, it cannot be determined whether such protection is conferred by flavonoids, other nutrients and phytochemicals in flavonoid-rich foods, or the whole foods themselves.
Vascular Endothelial Function
Vascular endothelial cells play an important role in maintaining cardiovascular health by producing nitric oxide, a compound that promotes arterial relaxation (vasodilation). Arterial vasodilation resulting from endothelial production of nitric oxide is termed endothelium-dependent vasodilation. Several clinical trials have examined the effect of flavonoid-rich foods and beverages on endothelium-dependent vasodilation. Two controlled clinical trials found that daily consumption of 4 to 5 cups (900 to 1,250 ml) of black tea for four weeks significantly improved endothelium-dependent vasodilation in patients with coronary artery disease and in patients with mildly elevated serum cholesterol levels compared with the equivalent amount of caffeine alone or hot water. Other small clinical trials found similar improvements in endothelium-dependent vasodilation in response to daily consumption of about 3 cups (640 ml) of purple grape juice or a high-flavonoid dark chocolate bar for two weeks. More recently, a 6-week cocoa intervention trial in 32 postmenopausal women with high cholesterol levels found significant improvements in endothelial function with daily cocoa supplementation. Improvements in endothelial function were also noted in conventionally medicated type 2 diabetics following flavanol-rich cocoa supplementation for 30 days. The flavanol epicatechin appears to be one of the compounds in flavanol-rich cocoa responsible for its vasodilatory effects. Interestingly, a recent randomized controlled trial in 44 older adults found that low doses of flavonoid-rich dark chocolate (6.3 grams per day for 18 weeks; equivalent to 30 calories) increased levels of plasma S-nitrosoglutathione, an indicator of nitric oxide production, compared to flavonoid-devoid white chocolate.
Endothelial nitric oxide production also inhibits the adhesion and aggregation of platelets, one of the first steps in blood clot formation. A number of clinical trials have examined the potential for high flavonoid intakes to decrease various measures of platelet aggregation outside of the body (ex vivo); such trials have reported mixed results. In general, increasing flavonoid intakes by increasing fruit and/or vegetable intake did not significantly affect ex vivo platelet aggregation, nor did increasing black tea consumption. However, several small clinical trials in healthy adults have reported significant decreases in ex vivo measures of platelet aggregation after consumption of grape juice (approximately 500 ml per day) for 7 to 14 days. Similar inhibition of platelet aggregation has been reported following acute or short-term consumption of dark chocolate and following acute consumption of a flavonoid-rich cocoa beverage. In addition, a placebo-controlled trial in 32 healthy adults found that 4-week supplementation with flavanols and procyanidins from cocoa inhibited platelet aggregation and function. The results of some controlled clinical trials suggest that relatively high intakes of some flavonoid-rich foods and beverages, including black tea, purple grape juice, and cocoa, may improve vascular endothelial function, but it is not known whether these short-term improvements will result in long-term reductions in cardiovascular disease risk.
FLAVONOIDS & NEURODEGENERATIVE DISEASE
Inflammation, oxidative stress, and transition metal accumulation appear to play a role in the pathology of several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Because flavonoids have anti-inflammatory, antioxidant, and metal-chelating properties, scientists are interested in the neuroprotective potential of flavonoid-rich diets or individual flavonoids. At present, the extent to which various dietary flavonoids and flavonoid metabolites cross the blood brain barrier in humans is not known. Although flavonoid-rich diets and flavonoid administration have been found to prevent cognitive impairment associated with aging and inflammation in some animal studies, prospective cohort studies have not found consistent inverse associations between flavonoid intake and the risk of dementia or neurodegenerative disease in humans. In a cohort of Japanese-American men followed for 25 to 30 years, flavonoid intake from tea during midlife was not associated with the risk of Alzheimer's or other types of dementia in late life. Surprisingly, higher intakes of isoflavone-rich tofu during midlife were associated with cognitive impairment and brain atrophy in late life.
A prospective study of Dutch adults found that total dietary flavonoid intake was not associated with the risk of developing Parkinson's disease or Alzheimer’s disease, except in current smokers whose risk of Alzheimer’s disease decreased by 50 percent for every 12 mg increase in daily flavonoid intake. In contrast, a study of elderly French men and women found that those with the lowest flavonoid intakes had a risk of developing dementia over the next five years that was 50 percent higher than those with the highest intakes. More recently, a study in 1,640 elderly men and women found that those with higher dietary flavonoid intake (greater than 13.6 mg per day) had better cognitive performance at baseline and experienced significantly less age-related cognitive decline over a 10-year period than those with a lower flavonoid intake (0 to 10.4 mg per day). Additionally, a randomized, double-blind, placebo-controlled clinical trial in 202 postmenopausal women reported that daily supplementation with 25.6 grams of soy protein (containing 99 mg of isoflavones) for one year did not improve cognitive function. However, a randomized, double-blind, placebo-controlled, cross-over trial in 77 postmenopausal women found that 6-month supplementation with 60 mg per day of isoflavones improved some measures of cognitive performance.
Although scientists are interested in the potential of flavonoids to protect the aging brain, it is not yet clear how flavonoid consumption affects neurodegenerative disease risk in humans.
FLAVONOID DOSAGE INFORMATION
FOOD SOURCES OF FLAVONOIDS
Dietary sources of flavonoids include tea, red wine, fruits, vegetables, and legumes. Individual flavonoid intakes may vary considerably depending on whether tea, red wine, soy products, or fruits and vegetables are commonly consumed. Although individual flavonoid intakes may vary, total flavonoid intakes in Western populations appear to average about 150 to 200 mg per day. Information on the flavonoid content of some flavonoid-rich foods is presented below.
Anthocyanin, Flavanol and Proanthocyanidin Content of Selected Foods
(mg/100g or 100 ml*)
Anthocyanin-Rich Foods Anthocyanins Flavanols Proanthocyanidins Blackberry 89 to 211 13 to 19 6 to 47 Blueberry 67 to 183 1 88 to 261 Grapes, Red 25 to 92 2 44 to 76 Raspberries (Red) 10 to 84 9 5 to 59 Strawberry 15 to 75 - 97 to 183 Red Wine 1 to 35 1 to 55 24 to 70 Plum 2 to 25 1 to 6 106 to 334 Red Cabbage 25 0 - Red Onion 13 to 25 - - Blood Orange Juice 3 to 10 - - Flavanol-Rich Foods Anthocyanins Flavanols Proanthocyanidins Green Tea - 24 to 216 - Black Tea - 5 to 158 4 Chocolate, Dark - 43 to 63 90 to 322 Apple, Red Delicious With Peel 1 to 4 2 to 12 89 to 148 Apricot - 10 to 25 8 to 13 Flavone-Rich Foods Anthocyanins Flavanols Proanthocyanidins Parsley, Fresh - - - Thyme, Fresh - - - Celery Hearts, Green - - - Celery - - - Oregano, Fresh - - - Chili Peppers, Green - - - Flavanone-Rich Foods Anthocyanins Flavanols Proanthocyanidins Lemon Juice, Fresh - - - Grapefruit Juice, Fresh - - - Orange Juice, Fresh - - - Grapefruit, Fresh - - - Orange, Fresh - - - Flavonol-Rich Foods Anthocyanins Flavanols Proanthocyanidins Onion, yellow - 0 - Kale - - - Leek - 0 - Broccoli - 0 - *per 100 grams (fresh weight) or 100 ml (liquids); 100 grams is equivalent to about 3.5 ounces; 100 ml is equivalent to about 3.5 fluid ounces.
Flavone, Flavonol & Flavanone Content of Selected Foods
(mg/100 g or 100 ml*)
Anthocyanin-Rich Foods Flavones Flavonols Flavanones Blackberry - 0 to 2 - Blueberry - 2 to 16 - Grapes, Red - 3 to 4 - Raspberries (Red) - 1 - Strawberry - 1 to 4 - Red Wine 0 2 to 30 - Plum 0 1 to 2 - Red Cabbage 0 to 1 0 to 1 - Red Onion 0 4 to 100 - Blood Orange Juice - - 10 to 22 Flavanol-Rich Foods Flavones Flavonols Flavanones Green Tea 0 to 1 3 to 9 - Black Tea 0 1 to 7 - Chocolate, Dark - - - Apple, Red Delicious With Peel 0 2 to 6 - Apricot 0 2 to 5 8 to 13 Flavone-Rich Foods Flavones Flavonols Flavanones Parsley, Fresh 24 to 634 8 to 10 - Thyme, Fresh 56 0 - Celery Hearts, Green 23 - - Celery 0 to 15 4 - Oregano, Fresh 2 to 7 0 - Chili Peppers, Green 5 13 to 21 - Flavanone-Rich Foods Flavones Flavanols Flavanones Lemon Juice, Fresh 0 0 to 2 2 to 175 Grapefruit Juice, Fresh 0 0 10 to 104 Orange Juice, Fresh 0 to 1 0 5 to 47 Grapefruit, Fresh - 1 55 Orange, Fresh - - 42 to 53 Flavonol-Rich Foods Flavones Flavonols Flavanones Onion, yellow 0 3 to 120 - Kale 0 30 to 60 - Leek 0 3 to 22 - Broccoli 0 4 to 13 - *per 100 grams (fresh weight) or 100 ml (liquids); 100 grams is equivalent to about 3.5 ounces; 100 ml is equivalent to about 3.5 fluid ounces.
These values should be considered approximate since a number of factors may affect the flavonoid content of foods, including agricultural practices, environmental factors, ripening, processing, storing, and cooking. For more information about the flavonoid content of foods, see the USDA databases for the flavonoid and proanthocyanidin content of selected foods. For information on the isoflavone content of soy foods, see the separate article on Soy Isoflavones or the USDA database for the isoflavone content of selected foods.
Flavonoid supplements are not needed to prevent deficiencies in people eating a healthy diet. If a supplement is needed the standard dosage is 1000 mg of citrus flavonoids taken 1 to 3 times per day, or 240 to 600 mg of Bilberry (standardized to 25 percent anthcyanosides) may be taken per day.
Anthocyanins: Bilberry, Elderberry, Black Currant, Blueberry, Red Grape, and Mixed Berry extracts that are rich in anthocyanins are available as dietary supplements without a prescription in the U.S. The anthocyanin content of these products may vary considerably. Standardized extracts that list the amount of anthocyanins per dose are available.
Flavanols: Numerous tea extracts are available in the U.S. as dietary supplements and may be labeled as tea catechins or tea polyphenols. Green Tea extracts are the most commonly marketed, but Black and Oolong Tea extracts are also available. Green tea extracts generally have higher levels of catechins (flavanol monomers), while black tea extracts are richer in theaflavins and thearubigins (flavanol polymers found in tea). Oolong tea extracts fall somewhere in between green and black tea extracts with respect to their flavanol content. Some tea extracts contain caffeine, while others are decaffeinated. Flavanol and caffeine content vary considerably among different products, so it is important to check the label or consult the manufacturer to determine the amounts of flavanols and caffeine that would be consumed daily with each supplement.
Flavanones: Citrus Bioflavonoid supplements may contain glycosides of hesperetin (hesperidin), naringenin (naringin), and eriodictyol (eriocitrin). Hesperidin is also available in hesperidin-complex supplements.
Flavones: The peels of citrus fruits are rich in polymethoxylated flavones: tangeretin, nobiletin, and sinensetin. Although dietary intakes of these naturally occurring flavones are generally low, they are often present in Citrus Bioflavonoid supplements.
Flavonols: The flavonol aglycone, quercetin, and its glycoside rutin are available as dietary supplements without a prescription in the U.S. Other names for rutin include rutinoside, quercetin-3-rutinoside, and sophorin (114). Citrus Bioflavonoid supplements may also contain Quercetin or Rutin.
FLAVONOID SAFETY, CAUTIONS, & INTERACTIONS
No adverse effects have been associated with high dietary intakes of flavonoids from plant-based foods. This lack of adverse effects may be explained by the relatively low bioavailability and rapid metabolism and elimination of most flavonoids. Studies have shown the lowest intake of dietary flavonoids - particularly quercetin - was associated with the highest risk of developing a stroke. When taking supplements, always read and follow product dosage instructions carefully. If you have adverse effects, adjust dosage or discontinue use. Consult with your health care provider before taking supplements if you are pregnant, have health issues, or are taking prescribed medications. Supplements may interfere with or have interactions with medicines.
Some men taking Quercetin supplements (1,000 mg per day for one month) reported nausea, headache, or tingling of the extremities. Some cancer patients given intravenous quercetin in a phase I clinical trial reported nausea, vomiting, sweating, flushing, and dyspnea (difficulty breathing). Intravenous administration of Quercetin at doses of 945 mg/m2 or more was associated with renal (kidney) toxicity in that trial.
Nutrition Basics: Quercetin Bioflavonoid Information Quercetin Bioflavonoid Products
There have been several reports of hepatotoxicity (liver toxicity) following consumption of supplements containing tea (Camellia sinensis) extracts. In clinical trials of caffeinated Green Tea extracts, cancer patients who took 6 grams per day in 3 to 6 divided doses have reported mild to moderate gastrointestinal side effects, including nausea, vomiting, abdominal pain, and diarrhea. Central nervous system symptoms, including agitation, restlessness, insomnia, tremors, dizziness, and confusion, have also been reported. In one case, confusion was severe enough to require hospitalization. These side effects were likely related to the caffeine in the Green Tea extract. In a 4-week clinical trial that assessed the safety of decaffeinated Green Tea extracts (800 mg per day of EGCG) in healthy individuals, a few of the participants reported mild nausea, stomach upset, dizziness, or muscle pain.
Nutrition Basics: Green Tea Herb Information Nutrition Basics: Black Tea Herb Information
PREGNANCY & LACTATION
The safety of flavonoid supplements in pregnancy and lactation has not been established.
Inhibition of CYP 3A4 by Grapefruit Juice and Flavonoids
As little as 200 ml (7 fluid ounces) of grapefruit juice has been found to irreversibly inhibit the intestinal drug metabolizing enzyme, cytochrome P450 (CYP) 3A4. Although the most potent inhibitors of CYP3A4 in grapefruit are thought to be furanocoumarins, particularly dihydroxybergamottin, the flavonoids naringenin and quercetin have also been found to inhibit CYP3A4 in vitro. Inhibition of intestinal CYP3A4 can increase the bioavailability and the risk of toxicity of a number of drugs, including but not limited to HMG-CoA reductase inhibitors (atorvastatin, lovastatin, and simvastatin), calcium channel antagonists (felodipine, nicardipine, nisoldipine, nitrendipine, and verapamil), anti-arrhythmic agents (amiodarone), HIV protease inhibitors (saquinavir), immunosuppressants (cyclosporine), antihistamines (terfenadine), gastrointestinal stimulants (cisapride), benzodiazepines (diazepam, midazolam, and triazolam), anticonvulsants (carbamazepine), anxiolytics (buspirone) serotonin specific reuptake inhibitors (sertraline), and drugs used to treat erectile dysfunction (sildenafil). Grapefruit juice may reduce the therapeutic effect of the angiotensin II receptor antagonist, losartan. Because of the potential for adverse drug interactions, some clinicians recommend that people taking medications that undergo extensive presystemic metabolism by CYP3A4 avoid consuming grapefruit juice altogether to avoid potential toxicities.
Inhibition of P-glycoprotein by Grapefruit Juice and Flavonoids
P-glycoprotein is an efflux transporter that decreases the absorption of a number of drugs. There is some evidence that the consumption of grapefruit juice inhibits the activity of P-glycoprotein. Quercetin, naringenin, and the green tea flavanol, epigallocatechin gallate (EGCG), have been found to inhibit the efflux activity of P-glycoprotein in cultured cells. Thus, very high or supplemental intakes of these flavonoids could potentially increase flavonoid bioavailability, potentially increasing the toxicity of drugs that are substrates of P-glycoprotein. Drugs known to be substrates of P-glycoprotein include digoxin, antihypertensive agents, antiarrhythmic agents, chemotherapeutic (anticancer) agents, antifungal agents, HIV protease inhibitors, immunosuppressive agents, H2 receptor antagonists, some antibiotics, and others.
Anticoagulant and Antiplatelet Drugs
High intakes of flavonoids from purple grape juice (500 ml per day) and dark chocolate (235 mg per day of flavanols) have been found to inhibit platelet aggregation in ex vivo assays. Theoretically, high intakes of flavonoids (e.g., from supplements) could increase the risk of bleeding when taken with anticoagulant drugs, such as warfarin (Coumadin), and antiplatelet drugs, such as clopidogrel (Plavix), dipyridamole (Persantine), non-steroidal anti-inflamatory drugs (NSAIDs), aspirin, and others.
Flavonoids can bind nonheme iron, inhibiting its intestinal absorption. Nonheme iron is the principal form of iron in plant foods, dairy products, and iron supplements. The consumption of one cup of tea or cocoa with a meal has been found to decrease the absorption of nonheme iron in that meal by about 70 percent. To maximize iron absorption from a meal or iron supplements, flavonoid-rich beverages or flavonoid supplements should not be taken at the same time.
Studies in cell culture indicate that a number of flavonoids inhibit the transport of vitamin C into cells, and supplementation of rats with quercetin and vitamin C decreased the intestinal absorption of vitamin C. More research is needed to determine the significance of these findings in humans.
FLAVONOID SUPPLEMENT & RELATED PRODUCTS
QUALITY SUPPLIES & PRODUCTS
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CHRYSIN BIOFLAVONOID SUPPLEMENT PRODUCTS
Chrysin is chemically in the isoflavone family, usually extracted from passion flower plants.Chrysin happens to be a very good inhibitor of aromatase, the enzyme in the body that converts testosterone into estradiol, and androstenedione into estrone. When this enzyme is inhibited, testosterone (as well as androstenedione) will tend to accumulate to higher concentrations. Indeed, numerous studies have shown that levels of testosterone rise when the action of the aromatase enzyme is blocked. (For example, an average rise of 45-percent was recently reported in a study at Massachusetts General Hospital.) It therefore comes as no surprise that chrysin is popular among athletes and other people eager to increase their testosterone levels, often in conjunction with supplemental testosterone precursors.
HerbsPro: Chrysin, Jarrow Formulas, 500 mg, 30 Caps (1212)
5,7-Dihydroxyflavone Chrysin (5,7-Dihydroxyflavone) is a bioflavonoid found in the plant Passiflora coerula, a member of the Passionflower family. Body builders have used it as a testosterone boosting supplement. Chrysin is the most powerful of several flavonoids that have been tested and found to exhibit anti-estrogenic activity by inhibiting the aromatization process.
E-Vitamins: Chrysin-500, Jarrow Formulas, 500 mg, 30 Caps
5,7-Dihydroxyflavone Chrysin (5,7-Dihydroxyflavone) is a bioflavonoid found in the plant Passiflora coerula, a member of the Passionflower family. Body builders have used it as a testosterone boosting supplement. Chrysin is the most powerful of several flavonoids that have been tested and found to exhibit anti-estrogenic activity by inhibiting the aromatization process.
Kalyx: Chrysin (5,7-Dihydroxyflavone), Kalyx, 10 kg (22 lbs): GF
Amazon: Chrysin Supplement Products
Amazon: Flavonoid Supplement Health Products
Nutrition Basics: Bioflavonoids Information
AROMATHERAPY: ESSENTIAL OILS DESCRIPTIONS & USES
Allspice Leaf Oil Angelica Oil Anise Oil Baobab Oil Basil Oil Bay Laurel Oil Bay Oil Benzoin Oil Bergamot Oil Black Pepper Oil Chamomile (German) Oil Cajuput Oil Calamus Oil Camphor (White) Oil Caraway Oil Cardamom Oil Carrot Seed Oil Catnip Oil Cedarwood Oil Chamomile Oil Cinnamon Oil Citronella Oil Clary-Sage Oil Clove Oil Coriander Oil Cypress Oil Dill Oil Eucalyptus Oil Fennel Oil Fir Needle Oil Frankincense Oil Geranium Oil German Chamomile Oil Ginger Oil Grapefruit Oil Helichrysum Oil Hyssop Oil Iris-Root Oil Jasmine Oil Juniper Oil Labdanum Oil Lavender Oil Lemon-Balm Oil Lemongrass Oil Lemon Oil Lime Oil Longleaf-Pine Oil Mandarin Oil Marjoram Oil Mimosa Oil Myrrh Oil Myrtle Oil Neroli Oil Niaouli Oil Nutmeg Oil Orange Oil Oregano Oil Palmarosa Oil Patchouli Oil Peppermint Oil Peru-Balsam Oil Petitgrain Oil Pine-Long Leaf Oil Pine-Needle Oil Pine-Swiss Oil Rosemary Oil Rose Oil Rosewood Oil Sage Oil Sandalwood Oil Savory Oil Spearmint Oil Spikenard Oil Swiss-Pine Oil Tangerine Oil Tea-Tree Oil Thyme Oil Vanilla Oil Verbena Oil Vetiver Oil Violet Oil White-Camphor Oil Yarrow Oil Ylang-Ylang Oil Aromatherapy
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AROMATHERAPY: HERBAL & CARRIER OILS DESCRIPTIONS & USES
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