Greater binding affinity to plasma proteins and thus, possibly, lower flavonoid bioavailability has been linked to structural characteristics, such as methylation and galloylation.

On the contrary, glycosylation reduced binding affinity to plasma proteins, suggesting that aglycones might have a limited bioavailability compared to glycosylated flavonoids.

While glucuronidation is thought to facilitate the excretion of flavonoids from the body, glucuronides show little affinity to plasma proteins and might thus be able to diffuse to target tissues where deglucuronidation can take place 8.

In general, the bioavailability of flavonoids is low due to limited absorption, extensive metabolism , and rapid excretion. Isoflavones are thought to be the most bioavailable of all flavonoid subclasses, while anthocyanins and galloylated catechins are very poorly absorbed 8 , Yet, given the wide variability in structures within subclasses, it is difficult to generalize the absorbability and bioavailability of flavonoids based only on their structural classification.

In addition, 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 Peak plasma concentrations measured after the consumption of anthocyanins, flavanols, and flavonols including those from tea are generally lower than 1 μM 2.

A recent quantitative analysis of 88 polyphenolic metabolites not limited to flavonoids identified in human blood and urine found median peak concentrations of 0.

Flavonoids are effective scavengers of free radicals in the test tube in vitro 24, However, even with very high flavonoid intakes, plasma and intracellular flavonoid concentrations in humans are likely to be to 1, times lower than concentrations of other antioxidants , such as ascorbate vitamin C , uric acid, and glutathione.

Moreover, most circulating flavonoids are actually flavonoid metabolites , some of which have lower antioxidant activity than the parent flavonoid 5. 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 29, 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 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, such as proliferation , differentiation , inflammatory responses, apoptosis programmed cell death , and survival.

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 effects of flavonoids, including antiinflammatory, antidiabetic, anticancer, and neuroprotective activities, are related to their ability to modulate cell-signaling pathways Intracellular concentrations of flavonoids required to affect cellular signaling 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 31, Effective signal transduction requires proteins known as kinases that catalyze the phosphorylation of target proteins, which become either activated or inhibited.

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 prevent the transcription of target genes.

Results of numerous studies in cell culture suggest that flavonoids may affect chronic disease by selectively inhibiting kinases 27 , 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 Each flavonoid subclass contains many types of chemicals with varying biological activities and potential health benefits such that the activity of a specific flavonoid cannot easily be generalized.

Some examples of major biological activities of flavonoids are highlighted below. Flavonoids have been shown to 1 reduce inflammation by suppressing the expression of pro-inflammatory mediators ; 2 down-regulate the expression of vascular cell adhesion molecules, which contribute to the recruitment of inflammatory white blood cells from the blood to the arterial wall 38, 39 ; 3 increase the production of nitric oxide NO by endothelial nitric oxide synthase eNOS , thus improving vascular endothelial function 40 ; 4 inhibit angiotensin-converting enzyme , thus inducing vascular relaxation 41 ; 5 inhibit platelet aggregation 42 ; and 6 oppose smooth muscle cell proliferation and migration occurring during atherogenesis Flavonoids have been found to interfere with the digestion, absorption, and metabolism of carbohydrates reviewed in Flavonoids have been found to 1 scavenge free radicals that can damage macromolecules, including DNA 46, 47 ; 2 interfere with biotransformation enzymes and efflux transporters, possibly preventing the activation of procarcinogenic chemicals and promoting their excretion from the body 48, 49 ; 3 regulate proliferation , DNA repair, or activation of pathways leading to apoptosis programmed cell death in case of irreversible DNA damage 50 ; and 4 inhibit tumor invasion and angiogenesis 51, Flavonoids are thought to 1 promote neurogenesis, synaptic growth, and neuron survival in the learning and memory-related brain regions e.

Several prospective cohort studies conducted in the US and Europe have examined the relationship between some measure of dietary flavonoid intake and cardiovascular disease CVD or mortality.

A recent meta-analysis of 14 prospective studies published between and reported that higher intakes in each flavonoid subclass were significantly associated with a reduced risk of cardiovascular events However, several serious limitations highlighted in a recent publication by Jacques et al.

suggested caution when interpreting these results In particular, most of the prospective studies in these meta-analyses did not include all flavonoid subclasses nor calculate intakes using the latest and more complete versions of the USDA databases for the flavonoid content of foods Another major concern is the lack of adjustment regarding the overall quality of the diet.

Consumers with higher flavonoid intakes are likely to have a greater consumption of fruit and vegetables and overall healthier diets than those with poor flavonoid intakes.

Additionally, none of the studies excluded potential bias due to constituents of flavonoid-rich foods that are known to either lower e.

In the Framingham Offspring Cohort study that followed 2, adults for a mean of Yet, adjusting for confounding factors , including fruit and vegetable intake and overall diet quality, attenuated these relationships such that they were no longer statistically significant.

An analysis of a larger prospective study of the EPIC-Norfolk cohort 24, participants that considered confounding by many dietary factors vitamin C , dietary fiber , fat, saturated fat, potassium , sodium, and alcohol found no significant association between flavanol intake and CVD-related or all-cause mortality A number of large prospective studies and small-scale, randomized controlled trials have investigated the effects of flavonoids on established biomarkers of CVD, including those involved in oxidative stress , inflammation , abnormal blood lipid profile, endothelial dysfunction, and hypertension ; some of these studies are highlighted below.

Interestingly, a food-based analysis revealed that intakes of foods rich in anthocyanins, e. Higher intakes of polymeric flavanols i. Intake levels of total flavonoids and flavanol monomers i. Although tea is a major source of flavanols, tea consumption was not correlated with the composite inflammation score or any components of this score in this study Cocoa is another source of flavanols, in particular - -epicatechin and procyanidins, that may provide cardiovascular benefits Indeed, a recent randomized , double-blind , placebo -controlled study in healthy adults ages, years suggested that short-term benefits of cocoa flavanol consumption on cardiovascular health, including improvements in lipoprotein profile i.

Supplementation of dyslipidemic patients for 12 or 24 weeks with a mixture of 17 anthocyanins improved cholesterol clearance via the HDL-mediated reverse cholesterol transport from extra-hepatic tissues back to the liver and lowered LDL-cholesterol compared to a placebo in two randomized controlled trials 72, However, a week, randomized, double-blind, placebo-controlled study in 52 healthy postmenopausal women found that daily consumption of mg of elderberry anthocyanins as cyanidinglucoside had no effect on inflammation markers, markers of vascular health, lipid profile, and glycemia; all of these measures were in normal range of concentrations at baseline The vascular endothelial cells that line the inner surface of all blood vessels synthesize an enzyme , endothelial nitric oxide synthase eNOS , whose function is essential to normal vascular physiology.

Specifically, eNOS produces nitric oxide NO , a compound that regulates vascular tone and blood flow by promoting the relaxation vasodilation of all types of blood vessels, including arteries NO also regulates vascular homeostasis and protects the integrity of the endothelium by inhibiting vascular inflammation , leukocyte adhesion, platelet adhesion and aggregation, and proliferation of vascular smooth muscle cells In the presence of cardiovascular risk factors e.

Endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities and is considered to be an early step in the development of atherosclerosis. Measures of brachial flow-mediated dilation FMD , a surrogate marker of endothelial function, have been found to be inversely associated with risk of future cardiovascular events Preclinical studies have demonstrated the benefits of berry fruits, extracts, or purified anthocyanins on vascular function.

Anthocyanin supplementation to diabetic mice was found to improve diabetes -induced vascular dysfunction by promoting NO-mediated endothelium-dependent vasodilation through the upregulation of adipocyte -derived adiponectin In a randomized trial of participants with hypercholesterolemia, supplemental anthocyanins increased FMD values by Several small-scale, intervention studies have also examined the effect of flavanol-rich food and beverages, including tea, red wine, purple grape juice, cocoa, and chocolate, on endothelium-dependent vasodilation.

A meta-analysis of nine intervention studies in a total of participants estimated that the acute ingestion of 2 to 3 cups of tea mL — containing about mg of flavonoids in green tea and mg in black tea — significantly increased brachial FMD see also the article on Tea Also, using a similar protocol, the authors showed that dark chocolate intake blunted acute endothelial dysfunction-induced by a glucose load challenge in 12 healthy volunteers Other benefits of dark chocolate consumption included reductions in arterial stiffness measured through pulse wave analysis and serum concentrations of markers of oxidative stress and vasoconstriction 8-isoprostaglandin F2α and endothelin Another recent clinical trial found improvements in endothelium-dependent vasodilation in response to acute consumption of one bar 40 g of dark chocolate containing Oral administration of pure flavanol - -epicatechin to healthy volunteers showed NO -dependent vasodilatory effects similar to those observed following flavanol-rich cocoa ingestion Administration of - -epicatechin also improved acetylcholine-induced endothelial-dependent vasodilation of thoracic aorta rings from rats with salt-induced hypertension Endothelial nitric oxide production also inhibits the adhesion and aggregation of platelets, one of the first steps in atherosclerosis and blood clot formation A number of clinical trials that examined the potential for high flavonoid intakes to decrease various measures of platelet function outside of the body ex vivo have reported mixed results.

A recent systematic review of these intervention studies suggested that consumption of flavanol-rich cocoa and grape seed extract was generally found to improve platelet function by inhibiting platelet adhesion, activation, and aggregation Interestingly, in a cross-over, controlled study, the acute consumption of a flavanol-rich cocoa beverage mg of total - -EC and procyanidins exhibited additive anti-platelet effects to aspirin 81 mg in healthy volunteers In contrast, the results of interventions using apigenin-rich soup, quercetin-rich supplements or onion soups, isoflavone-rich soy protein isolates, black tea, wines, berries, or grape juices have given inconsistent results reviewed in A meta-analysis of 20 short-term, randomized controlled trials , including a total of mainly healthy participants, found that consumption of flavanol-rich dark chocolate and cocoa products significantly reduced systolic blood pressure by 2.

However, heterogeneity across studies was high, and risk of bias was significant A greater blood pressure-reducing effect was observed in a subanalysis of studies using flavanol-free rather than flavanol-low control groups Another meta-analysis of 22 trials highly heterogeneous found reductions in diastolic blood pressure Additionally, green tea flavanols have been shown to lower blood pressure especially in pre- hypertensive subjects.

A pooled analysis of 13 randomized controlled trials in 1, subjects found a 2. The inhibition of angiotensin-converting enzyme ACE , a key regulator of arterial blood pressure, may partly explain how flavanol-rich food and beverages might exert blood pressure-lowering effects Some intervention trials have also examined the effect of the flavonol quercetin on blood pressure in human subjects.

In a recent six-week, cross-over, randomized, double-blind, placebo-controlled trial, daily ingestion of mg of quercetin decreased 24 h-ambulatory blood pressure — but not systolic blood pressure in the resting state — in hypertensive but not in pre-hypertensive participants There was no change in biomarkers of lipid metabolism , inflammation , oxidative stress , or endothelial function, including total, HDL -, LDL - cholesterol , serum CRP , soluble adhesion molecules, plasma oxidized LDL, urinary 8-isoprostaglandin F2α, serum endothelin-1, serum ACE, and plasma endogenous NOS inhibitor.

Additional trials may help establish whether the blood pressure-lowering effect of some flavonoids could be translated into long-term benefits for cardiovascular health. The association between flavonoid consumption and risk for type 2 diabetes mellitus has been examined in a recent European, multicenter, nested case-control study — the "EPIC-InterAct" project — that included 16, diabetes-free participants and 12, diabetics.

Specifically, the risk of diabetes was inversely correlated with the intake of flavanols monomers and dimers only and flavonols 98, Recent meta-analyses of randomized controlled trials have examined the possible health effects of green tea flavanol monomers catechins on glucose metabolism and have provided conflicting results.

A meta-analysis of seven trials in pre-diabetic and diabetic patients found no effect of green tea or green tea extracts on fasting plasma glucose , fasting serum insulin , or measures of glycemic control glycated hemoglobin, HbA1c and insulin sensitivity HOMA-IR Finally, a third meta-analysis of 25 trials found that ingestion of green tea extracts for at least two weeks could lower fasting blood glucose in both the presence or absence of caffeine Dark chocolate is another good source of flavanols such that the effects of cocoa flavanols have been examined in individuals at-risk or with established type 2 diabetes.

In a day, cross-over , randomized controlled study, the daily consumption of g of dark chocolate bars containing Daily supplementation with flavonoid-enriched chocolate containing mg of flavanols and mg of isoflavones for one year significantly improved insulin sensitivity and reduced a predicted risk of coronary heart disease CHD at 10 years in 93 postmenopausal women treated for type 2 diabetes The EPIC-InterAct study did not find any association between dietary anthocyanin intake and risk of diabetes 98, Moreover, the consumption of berries, rich in anthocyanins, has been shown to trigger favorable glycemic responses in type 2 diabetics reviewed in In recent intervention studies , anthocyanins demonstrated beneficial effects on metabolic abnormalities in patients at-risk or diagnosed with diabetes.

Another six-week randomized trial in individuals with diabetes showed that daily supplementation with Cornelian cherry Cornus mas extracts containing mg of anthocyanins significantly lowered serum levels of HbA1c and triglycerides and increased serum insulin concentrations Further, supplemental anthocyanins up-regulated adiponectin expression and improved nitric oxide -mediated endothelium-dependent vasodilation within 12 weeks of treatment see also Cardiovascular disease Although various flavonoids have been found to inhibit the development of chemically-induced cancers in animal models of lung , oral , esophageal , gastric , colon , skin , prostate , , and mammary cancer , observational studies do not provide convincing evidence that high intakes of dietary flavonoids are associated with substantial reductions in human cancer risk reviewed in A meta-analysis of 13 case-control and 10 prospective cohort studies found little-to-no evidence to support a preventive role of dietary flavonoid intake in gastric and colorectal cancer A meta-analysis of 19 case-control studies and 15 cohort studies found that total flavonoid intake and intakes of specific flavonoid subclasses i.

The risk of lung cancer was not significantly associated with high flavonoid intakes , although an earlier meta-analysis of eight prospective studies with substantial heterogeneity across them suggested a protective role of flavonoids against lung cancer in smokers only Further, a prospective analysis of over 45, postmenopausal women from the Multiethnic Cohort Study found a reduced risk of endometrial cancer with the highest intakes of total isoflavones, daidzein, and genistein Additionally, limited evidence from observational studies suggests no relationship between total flavonoid intake and ovarian cancer To date, there is little evidence that flavonoid-rich diets might protect against various cancers, but larger prospective cohort studies are needed to address the association.

Because isoflavones are phytoestrogens , it is thought that they may interfere with the synthesis and activity of endogenous hormones , eventually influencing hormone-dependent signaling pathways and protecting against breast and prostate cancers In addition to the ethnicity and menopausal status, polymorphisms for hormone receptors and phase I biotransformation enzymes have been found to modify the association between isoflavone intake and breast cancer.

Another recent meta-analysis of 12 observational studies six prospective cohort studies , one nested case-control study , and five case-control studies investigated the chemopreventive effects of flavonoids except isoflavones The results suggested that intakes of flavonols and flavones may also be inversely associated with the risk of breast cancer.

Further, a pooled analysis of four case-control studies that stratified by menopausal status showed inverse associations between breast cancer and intakes of flavonols, flavones, or flavanols in postmenopausal women only.

A meta-analysis of 13 observational studies also suggested an inverse relationship between prostate cancer risk and consumption of soy products, especially tofu Yet, further analyses supported a protective role of soy food based only on case-control studies, which have inherent flaws such that associations may often be overestimated or underestimated.

In this study, no changes were reported in sex hormone concentrations in blood, suggesting that isoflavones may reduce prostate cancer incidence without interfering with hormone-dependent pathways. Additional investigations will be necessary to determine whether supplementation with specific flavonoids could benefit cancer prevention or treatment.

For more information on flavonoid-rich foods and cancer, see articles on Fruit and Vegetables , Legumes , and Tea. Therefore, the various properties of flavonoids, including their role in protecting vascular health, could have beneficial effects on the brain, possibly in the protection against cerebrovascular disorders , cognitive impairments, and subsequent stroke and dementias.

The cross-sectional data analysis of 2, participants ages, years from the Hordaland Health Study in Norway indicated that, when compared to non-consumers, consumers of flavonoid-rich chocolate, tea, and wine had better global cognitive function, assessed by a battery of six cognitive tests In addition, those with higher dietary flavonoid intakes at baseline experienced significantly less age-related cognitive decline over a year period than those with the lowest flavonoid intakes The daily consumption of the cocoa drink high in flavanols improved some, but not all, measures of cognitive process speed and flexibility and verbal fluency compared to baseline test scores and scores following low flavanol drink consumption.

A composite test score reflecting overall cognitive performance was found to be significantly greater in those given cocoa drinks high rather than low in flavanols. The study also reported reductions in cardiovascular risk markers i.

The data could be replicated in cognitively healthy older people ages, years , suggesting that cocoa flavanols might enhance some aspects of cognitive function during healthy aging Because cerebral blood flow is correlated with cognitive function in humans, these preliminary data suggest that cocoa flavanol consumption could exert a protective effect against dementia Yet, in other randomized controlled trials , the lack of an effect of cocoa flavanols on blood pressure, cerebral blood flow, mental fatigue, and cognitive performance in healthy young and old adults suggested that benefits may only be seen in very demanding cognitive exercises Some randomized controlled studies also reported improvements in measures of cognitive function in healthy and cognitively impaired subjects with other flavonoid subclasses, including anthocyanins , flavanones , , and isoflavones , Although some flavonoids and flavonoid-rich foods may enhance cognitive function in the aging brain, it is not yet clear whether their consumption could lower the risk of cognitive impairments and dementia in humans.

For more detailed information on flavanol-rich tea and cognitive function, see the article on Tea. The main dietary sources of flavonoids include tea , citrus fruit, citrus fruit juices, berries, red wine, apples, and legumes.

Individual flavonoid intakes may vary considerably depending on whether tea, red wine, soy products, or fruit and vegetables are commonly consumed reviewed in 2. Information on the flavonoid content of some flavonoid-rich foods is presented in Tables 2 These values should be considered approximate since a number of factors may affect the flavonoid content of foods, including agricultural practices, environmental conditions, ripening, storage, and food processing.

For additional information about the flavonoid content of food, the USDA provides databases for the content of selected foods in flavonoids 60 and proanthocyanidins For more information on the isoflavone content of soy foods, see the article on Soy Isoflavones or the USDA database for the isoflavone content of selected foods 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 US.

The anthocyanin content of these products may vary considerably. Standardized extracts that list the amount of anthocyanins per dose are available. Numerous tea extracts are available in the US 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 tea flavanol dimers and polymers , respectively.

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 for more information on tea flavanols, see the article on Tea.

Citrus bioflavonoid supplements may contain glycosides of hesperetin hesperidin , naringenin naringin , and eriodictyol eriocitrin. Hesperidin is also available in hesperidin-complex supplements, with daily doses from mg to 2 g The peels and tissues of citrus fruit e.

Although dietary intakes of these naturally occurring flavones are generally low, they are often present in citrus bioflavonoid complex supplements. Some tea preparations may also include baicaleinglucuronide The flavonol aglycone, quercetin, and its glycoside rutin are available as dietary supplements without a prescription in the US.

Other names for rutin include rutoside, quercetinrutinoside, and sophorin Citrus bioflavonoid supplements may also contain quercetin or rutin. A mg soy isoflavone supplement usually includes glycosides of the isoflavones: genistein genistin; 25 mg , daidzein daidzin; 19 mg , and glycitein glycitin; about 6 mg.

Smaller amounts of daidzein, genistein, and formononetin are also found in biochanin A-containing supplements derived from red clover No adverse effects have been associated with high dietary intakes of flavonoids from plant-based food. This lack of adverse effects may be explained by the relatively low bioavailability and rapid metabolism and elimination of most flavonoids.

Higher doses up to In a recent randomized , double-blind , controlled study in healthy adults, the daily intake of 2 g of cocoa flavanols for 12 weeks was found to be well tolerated with no adverse side effects 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 The total number of adverse events and the number of serious adverse events were not different between the treatment and placebo groups However, the use of green tea extracts was directly associated with abnormally high liver enzyme levels in 7 out of the 12 women who experienced serious adverse events.

Also, the incidence of nausea was twice as high in the green tea arm as in the placebo group The safety of flavonoid supplements in pregnancy and lactation has not been established ATP-binding cassette ABC drug transporters, including P-glycoprotein, multidrug resistance protein MRP , and breast cancer-resistant protein BCRP , function as ATP -dependent efflux pumps that actively regulate the excretion of a number of drugs limiting their systemic bioavailability 8.

ABC transporters are found throughout the body, yet they are especially important in organs with a barrier function like the intestines, the blood-brain barrier, blood-testis barrier, and the placenta , as well as in liver and kidneys There is some evidence that the consumption of grapefruit juice inhibits the activity of P-glycoprotein Genistein, biochanin A, quercetin, naringenin, hesperetin, green tea flavanol - -CG, - -ECG, and - -EGCG, and others have been found to inhibit the efflux activity of P-glycoprotein in cultured cells and in animal models Thus, very high or supplemental intakes of these flavonoids could potentially increase the toxicity of drugs that are substrates of P-glycoprotein, e.

Many anthocyanins and anthocyanidins, as well as some flavones apigenin, chrysin , isoflavones biochanin A, genistein , flavonols kaempferol , and flavanones naringenin , have been identified as inhibitors of BRCP-mediated transport, theoretically affecting drugs like anticancer agents mitoxantrone, topotecan, thyrosine kinase inhibitors , antibiotics fluoroquinolones , β-blockers prazosin , and antiarthritics sulfasalazine.

Finally, flavonols quercetin, kaempferol, myricetin , flavanones naringenin , flavones apigenin, robinetin , and isoflavones genistein have been reported to inhibit MRP, potentially affecting MRP-mediated transport of many anticancer drugs, e.

Theoretically, high intakes of flavonoids e. Cytochrome P CYP enzymes are phase I biotransformation enzymes involved in the metabolism of a broad range of compounds, from endogenous molecules to therapeutic agents. The most abundant CYP isoform in the liver and intestines is cytochrome P 3A4 CYP3A4 ; the CYP3A family catalyzes the metabolism of about one-half of all marketed drugs in the US and Canada One grapefruit or as little as mL 7 fluid ounces of grapefruit juice have been found to irreversibly inhibit intestinal CYP3A4 The most potent inhibitors of CYP3A4 in grapefruit are thought to be furanocoumarins, particularly dihydroxybergamottin, rather than flavonoids.

All forms of the fruit — freshly squeezed juice, frozen concentrate, or whole fruit — can potentially affect the activity of CYP3A4.

Some varieties of other citrus fruit Seville oranges, limes, and pomelos that contain furanocoumarins can also interfere with CYP3A4 activity. Specifically, the inhibition of intestinal CYP3A4 by grapefruit consumption is known or predicted to increase the bioavailability and the risk of toxicity of more than 85 drugs.

Because drugs with very low bioavailability are more likely to be toxic when CYP3A4 activity is inhibited, they are associated with a higher risk of overdose with grapefruit compared to drugs with high bioavailability.

Some of the drugs with low bioavailability include, but are not limited to, anticancer drugs everolimus ; anti-infective agents halofantrine, maraviroc ; statins atorvastatin, lovastatin, and simvastatin ; cardioactive drugs amiodarone, clopidogrel, dronedarone, eplenorone, ticagrelor ; HIV protease inhibitors saquinavir , immunosuppressants cyclosporine, sirolimus, tacrolimus, everolimus ; antihistamines terfenadine ; gastrointestinal agents domperidone ; central nervous system agents buspirone, dextromethorphan, oral ketamine, lurasidone, quetiapine, selective serotonin reuptake inhibitors [sertraline] ; and urinary tract agents darifenacin reviewed in Because of the potential for adverse drug interactions, some clinicians recommend that people taking medications with low bioavailability i.

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. Flavonoids can also inhibit intestinal heme iron absorption Interestingly, ascorbic acid greatly enhances the absorption of iron see the article on Iron and is able to counteract the inhibitory effect of flavonoids on nonheme and heme iron absorption , , To maximize iron absorption from a meal or iron supplements, flavonoid-rich food and beverages and flavonoid supplements should not be consumed at the same time.

Originally written in by: Jane Higdon, Ph. Linus Pauling Institute Oregon State University. Updated in June by: Victoria J. Drake, Ph. Updated in November by: Barbara Delage, Ph.

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J Cardiovasc Pharmacol. Hanhineva K, Torronen R, Bondia-Pons I, et al. Impact of dietary polyphenols on carbohydrate metabolism. Int J Mol Sci. Babu PV, Liu D, Gilbert ER.

Recent advances in understanding the anti-diabetic actions of dietary flavonoids. Delgado ME, Haza AI, Arranz N, Garcia A, Morales P. Erba D, Casiraghi MC, Martinez-Conesa C, Goi G, Massaccesi L. Isoflavone supplementation reduces DNA oxidative damage and increases O-β-N-acetyl-D-glucosaminidase activity in healthy women.

Nutr Res. Moon YJ, Wang X, Morris ME. Dietary flavonoids: effects on xenobiotic and carcinogen metabolism. Schwarz D, Kisselev P, Roots I.

CYP1A1 genotype-selective inhibition of benzo[a]pyrene activation by quercetin. Eur J Cancer. Suh Y, Afaq F, Johnson JJ, Mukhtar H. Ravishankar D, Watson KA, Boateng SY, Green RJ, Greco F, Osborn HM.

Exploring quercetin and luteolin derivatives as antiangiogenic agents. Eur J Med Chem. Santos BL, Oliveira MN, Coelho PC, et al.

Flavonoids suppress human glioblastoma cell growth by inhibiting cell metabolism, migration, and by regulating extracellular matrix proteins and metalloproteinases expression. Chem Biol Interact. Sokolov AN, Pavlova MA, Klosterhalfen S, Enck P. Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behavior.

Neurosci Biobehav Rev. Vauzour D, Vafeiadou K, Rodriguez-Mateos A, Rendeiro C, Spencer JP. The neuroprotective potential of flavonoids: a multiplicity of effects. Wang X, Ouyang YY, Liu J, Zhao G. Flavonoid intake and risk of CVD: a systematic review and meta-analysis of prospective cohort studies.

Br J Nutr. Wang ZM, Zhao D, Nie ZL, et al. Flavonol intake and stroke risk: a meta-analysis of cohort studies. Jacques PF, Cassidy A, Rogers G, Peterson JJ, Dwyer JT.

Dietary flavonoid intakes and CVD incidence in the Framingham Offspring Cohort. US Department of Agriculture. USDA Database for the Proanthocyanidin Content of Selected Foods. August, USDA Database for the Isoflavone Content of Selected Foods, release 2.

September USDA Database for the Flavonoid Content of Selected Foods, release 3. May Vogiatzoglou A, Mulligan AA, Bhaniani A, et al. Associations between flavanol intake and CVD risk in the Norfolk cohort of the European Prospective Investigation into Cancer EPIC-Norfolk.

Cassidy A, Rogers G, Peterson JJ, Dwyer JT, Lin H, Jacques PF. Different flavonoids have variable effects on xenobiotic metabolism in the skin by targeting phase I or phase II components of the cellular detoxification pathway.

The flavonols myricetin and quercetin can inhibit aryl hydrocarbon hydrolase a phase I enzyme activity when applied topically to mouse skin, potentially preventing the metabolic activation of procarcinogens 54 and the formation of DNA adducts On the other hand, flavonoids that induce phase II enzymes could facilitate the inactivation of CYP-generated metabolites.

Oral administration of silibinin, the active component of silymarin, for 15 days significantly induced phase II enzyme activity glutathione S-transferase and quinone reductase in mouse skin compared to vehicle-treated control mice Onion extract, rich in the flavonoids quercetin and kaempferol, has been used to reduce scar formation, particularly keloid scars.

Cho et. MMPs are enzymes secreted by epidermal keratinocytes and dermal fibroblasts in response to various stimuli, including UVR, oxidative stress , and inflammatory cytokines.

UVR induces three MMPs: MMP-1 collagenase , MMP-3, stromelysin , and MMP-9 gelatinase that cleave and degrade skin collagen and contribute to photoaging In the case of wound healing, a balance between MMP-1 and tissue inhibitor matrix metalloproteinase-1 TIMP-1 enzymatic activity affects the amount of extracellular matrix including collagen formed at the wound site.

Thus, quercetin may influence extracellular matrix deposition during wound healing in order to reduce hypertrophic scarring. Flavonoids, especially rutin and its derivatives, can benefit skin by influencing blood vessel permeability and fragility 5.

Their protective effect on blood vessels may reduce the formation of telangiectasias small dilated blood vessels near the surface of the skin and petechiae small red spots caused by broken capillaries or blood vessels.

It appears that flavonoid binding of metals leads to inhibition of enzymes involved in blood clotting and inflammation , which in turn influence capillary permeability and platelet aggregation 5. However, clinical experimentation is lacking and more human studies are needed to conclusively establish a role for specific flavonoids on blood vessel health.

The majority of information on flavonoids and skin health relates to photoprotective effects of green tea polyphenols, catechins, and genistein. Both oral supplementation and topical administration of the flavanol subclass in particular have demonstrated photoprotective effects in humans. Experimentation with topically applied flavonoids typically test purified compounds or concentrated plant extracts dissolved in organic solvent; although they show promise as photoprotective agents, delivery is an issue that can influence how commercially available formulations penetrate and function in human skin.

Flavonoids exert a wide range of influence due to their specific and nonspecific affinity for a diversity of proteins throughout the cell. The precise mechanisms by which flavonoids protect skin from the damaging effects of UVR are still being investigated, but there is evidence that flavonoids physically block UV penetration, influence DNA repair, reduce oxidative damage , attenuate the inflammatory response, preserve immune function, and induce cytoprotective pathways.

Written in June by: Giana Angelo, Ph. Linus Pauling Institute Oregon State University. Reviewed in June by: Wilhelm Stahl, Ph. Institute of Biochemistry and Molecular Biology I Heinrich-Heine-University Düsseldorf Düsseldorf, Germany. This article was underwritten, in part, by a grant from Neutrogena Corporation , Los Angeles, California.

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Common cosmetic hydrophilic ingredients as penetration modifiers of flavonoids. Int J Cosmet Sci. Kitagawa S, Tanaka Y, Tanaka M, Endo K, Yoshii A. Enhanced skin delivery of quercetin by microemulsion.

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Neukam K, Stahl W, Tronnier H, Sies H, Heinrich U. Consumption of flavanol-rich cocoa acutely increases microcirculation in human skin. Eur J Nutr. Schroeter H, Heiss C, Balzer J, et al.

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Katiyar SK, Matsui MS, Elmets CA, Mukhtar H. Polyphenolic antioxidant - -epigallocatechingallate from green tea reduces UVB-induced inflammatory responses and infiltration of leukocytes in human skin. Photochem Photobiol. Katiyar SK, Perez A, Mukhtar H.

Green tea polyphenol treatment to human skin prevents formation of ultraviolet light B-induced pyrimidine dimers in DNA. Clin Cancer Res. Elmets CA, Singh D, Tubesing K, Matsui M, Katiyar S, Mukhtar H.

Cutaneous photoprotection from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol. Camouse MM, Domingo DS, Swain FR, et al. Topical application of green and white tea extracts provides protection from solar-simulated ultraviolet light in human skin.

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Dinkova-Kostova AT, Talalay P. Direct and indirect antioxidant properties of inducers of cytoprotective proteins. Mol Nutr Food Res. Liska DJ. The detoxification enzyme systems.

Altern Med Rev. Katiyar SK, Matsui MS, Mukhtar H. Ultraviolet-B exposure of human skin induces cytochromes P 1A1 and 1B1. Effects of solar radiation on cutaneous detoxification pathways.

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They are a vital part of many medicines and treatments for certain illnesses, and many manufacturers include them in cosmetics and anti-aging products.

This group of flavonoid has antioxidant properties and can help prevent vascular disease. Flavonol-rich foods and drinks include:. Flavones have antioxidative, anti-inflammatory, and anticancer properties.

Flavone-rich foods include:. Flavanones can effectively neutralize harmful cells in the body. They are generally found in citrus fruits.

Flavanone-rich foods include:. Isoflavonoids have properties that help treat and prevent various diseases and improve vascular health. Foods containing isoflavonoids include:. Also called flavanols and catechins, this subtype of flavonoid is commonly found in nutrient-rich foods.

Foods containing flavanols include:. Anthocyanins are the pigments that make up the colors in plants, fruits, and flowers. They may be beneficial for cardiovascular health. Foods rich in anthocyanins include:. Some people choose to take certain supplements to increase their flavonoid intake. This may be because a person is unsure whether they are getting enough flavonoids in their diet, or because they think this will improve their health.

For this reason, individuals should talk with a healthcare professional or dietitian before taking supplements. For more in-depth resources about vitamins, minerals, and supplements, visit our dedicated hub. Almost all flavonoids are antioxidants, meaning they can neutralize harmful atoms in the body known as free radicals.

This process can have a range of positive health effects. However, experts need to conduct more research into the potential benefits of antioxidants. According to a review , five subgroups of flavonoids have been found to help lower blood pressure. This can provide benefits such as improving heart health and protecting the kidneys.

Additionally, some research suggests that flavonoids may have a use in the prevention and treatment of cancer. Research into the safe use of flavonoids to treat cancer is ongoing. Flavonoids are a group of natural compounds found in fruits, vegetables, and other plants.

The antioxidative properties of flavonoids are vital in the research concerning their potential beneficial health effects.

Research is ongoing into the potential benefits of consuming flavonoids, but they are already an important component in many medicines and medical research. A person can typically maintain a sufficient intake of flavonoids by eating a nutritious, balanced diet that includes flavonoid-rich foods.

Antioxidants are in many healthful foods. Experts believe that they help the body fight harmful free radicals that can lead to various health….

Antioxidants are mostly found in plant foods. They are natural molecules that help neutralize harmful free radicals in our bodies.

Free radicals are…. What are micronutrients? Read on to learn more about these essential vitamins and minerals, the role they play in supporting health, as well as…. Adding saffron supplements to standard-of-care treatment for ulcerative colitis may help reduce inflammation and positively benefit patients, a new….

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