IngredientsBioflavonoids — also referred to simply as flavonoids — are a large and structurally diverse family of plant-derived polyphenolic secondary metabolites. Dietary flavonoids are emerging as multifunctional bioactive compounds, and they encompass considerable structural diversity with characteristic chemistry, dietary sources, and bioavailability profiles. The term "bioflavonoids" is used interchangeably with "flavonoids" in the nutritional supplement literature, though strictly speaking, "bioflavonoids" historically referred to a subset of flavonoids identified for their activity on capillary function.
Flavonoids are mainly found in plant cell vacuoles in the form of C-glycosides or O-glycosides. The basic molecular structure of flavonoids depends upon their basic C6–C3–C6 skeleton, labeled as the A, B, and C rings. Based on the degree of unsaturation and the substitution pattern, different flavonoid classes are distinguished: flavones, flavonols, flavanones, flavan-3-ols, anthocyanins, dihydroflavonols, and isoflavones, as well as the biogenetic intermediate chalconoid forms.
In natural sources, they may occur in free forms (aglycones), as glycosylated or acylated derivatives, and as oligomeric and polymeric structures such as the flavan-3-ol-derived condensed tannins (or proanthocyanidins). Several thousand flavonoids have been identified in plant sources, and the number of compounds increases when considering the flavonoid-derived products that can be formed during the processing and storage of foodstuffs, and the metabolites and conjugates produced in the human organism after their intake.
Concerns about their extensive bioactive benefits, including anti-inflammatory, antioxidant, anti-viral, antifungal, antibacterial, antihypertensive, cardioprotective, anti-ulcer, anti-diabetic, anti-Alzheimer, anti-depression, and anti-cancer effects, have received great attention and support from numerous studies. Till now, more than 9,000 flavonoids have been reported, and their daily intake varies between 20 mg and 500 mg, mainly from dietary sources including apples, grapes, berries, tea, tomatoes, and onions.
Hydroxylated polyphenols, also called flavonoids, are richly present in vegetables, fruits, cereals, nuts, herbs, seeds, stems, and flowers of numerous plants. Flavonoids are found in the roots, stems, leaves, and fruits of many plant taxa. They are related to plant growth and development, pigment formation, and protection against environmental stress.
The most commercially significant botanical sources for bioflavonoid supplements include:
In 1936, Nobel Prize winner Dr. Albert Szent-Györgyi and co-workers reported that a flavonoid preparation from paprika and citrus peel could restore complete health to scorbutic guinea pigs when vitamin C alone did not. Albert Szent-Györgyi was also the one who discovered vitamin C. Szent-Györgyi suggested these compounds were crucial for integrity of the small blood vessels and as treatment for skin purpura. He and his co-workers at first referred this class of plant compounds to as "vitamin P."
He later carried out further studies of citrus fruits, identifying vitamin P (a complex compound of flavonoids) and postulating its use in strengthening capillaries. A deficiency disease linked to the lack of vitamin P, however, has never been established, and the designation "vitamin" was eventually withdrawn. His persistent studies of biological oxidation led to the recognition of the catalytic function of the C4-dicarboxylic acids, the discovery of "cytoflav" (flavin), and a recognition of the biological activity and probable vitamin nature of flavanone (vitamin P).
The 1930s saw early biochemical identification of anti-capillary-permeability factors (the "Szent-Györgyi era") leading to descriptive naming as "vitamin P." During the 1940s–1960s, structural elucidation of hesperidin, naringin, and rutin was achieved via chromatography and spectroscopy. In the 1970s–1990s, pharmacology studies established antioxidant and venotonic properties, and formulation science produced Micronized Purified Flavonoid Fraction (MPFF) for chronic venous insufficiency.
The earliest studies of flavonoid pigments date to Robert Boyle in 1664, which described the effects of acids and bases on the color of extracts from plant flowers and other pigmentation tissues.
Traditional medicinal recipes are major sources of flavonoids and other polyphenols aside from medicinal plants. Humans have long used traditional medicines since ancient times, especially in Asian countries. In many of these traditions, plants rich in flavonoids were employed for a wide variety of purposes, even though the specific chemical constituents were not identified until the modern era.
Many medicinal properties and traditional uses of plants are attributed to the presence of bioflavonoids among their secondary metabolites. In Traditional Chinese Medicine (TCM), plants such as Nelumbo nucifera (sacred lotus), Citrus aurantium (bitter orange), and numerous others were used for their anti-inflammatory, hemostatic, and tonic properties. Nelumbo nucifera has been used as an important ingredient for traditional medicines since ancient times, especially in Asian countries.
In Ayurvedic medicine, flavonoid-rich botanicals such as turmeric (Curcuma longa), ashwagandha, and amla (Phyllanthus emblica) were employed for a range of indications. In European herbalism, flavonoid-rich plants including chamomile (Matricaria chamomilla), elderflower (Sambucus nigra), and hawthorn (Crataegus spp.) were used as preparations for heart complaints, inflammation, fevers, and respiratory conditions.
Fructus aurantii is widely used in clinical practice as an expectorant and digestant herb in traditional Chinese medicine and has been proven to have a variety of pharmacological functions. The bark, leaves, and fruits of citrus species were used throughout Asia and the Mediterranean for digestive complaints, fevers, and skin conditions — preparations that would later be found to be concentrated sources of flavanone glycosides.
Flavonoids possess numerous medicinal properties such as antioxidant, anti-cancer, anti-microbial, neuroprotective, and anti-inflammation. Studies show that flavonoids activate antioxidant pathways that render an anti-inflammatory effect. They inhibit the secretions of enzymes such as lysozymes and β-glucuronidase and inhibit the secretion of arachidonic acid, which reduces inflammatory reactions.
The antioxidant mechanism of flavonoids is structural and depends on the pattern of hydroxylation of the phenyl rings. Like other similar antioxidant flavonoids, quercetin is considered to be a free-radical scavenger of highly reactive species such as peroxynitrite and the hydroxyl radical. While the class of flavonoid is not determinant for antioxidant activity, the hydroxyls at positions 5 and 7 on the A ring and at position 4 on the B ring are important. Specifically, hydroxyls at position 3 on the B ring reduce flavonoid activity. Thus, changes into the basic flavonoid structure could increase, decrease, or even not alter flavonoid antioxidant activity.
Flavonoids exhibit pleiotropic effects and can modulate inflammatory regulatory nodes. The anti-inflammatory effect of flavonoids can be mediated in many ways: a) antioxidant effects, b) inhibition of inflammation-related gene expression, c) interactions with signaling pathways, d) interactions with inflammation-inducing proteins.
Key pathways that flavones regulate in controlling inflammation include NF-κB, STAT, and Nrf2, and they have a potential impact on chronic inflammatory diseases (CID) such as obesity and cancer. Flavonoids function as antioxidants and exert anti-inflammatory effects in the cardiovascular system by modulating classical inflammatory response pathways, such as the TLR4-NF-κB, PI3K-AKT, and Nrf2/HO-1 signalling pathways.
Flavonoids have been shown to have strong anti-inflammatory effects and can inhibit the development of inflammation by inhibiting the production of inflammatory mediators such as prostaglandins and leukotrienes.
The mechanisms of flavonoids in cancer prevention include complementary and overlapping mechanisms of action: antioxidant activity and scavenging free radicals, modulation of carcinogen metabolism, regulation of gene expression on oncogenes and tumour-suppressor genes in cell proliferation and differentiation, induction of cell cycle arrest and apoptosis, modulation of enzyme activities in detoxification, oxidation and reduction, anti-inflammatory properties, and action on other possible targets.
There is an increasing body of evidence from randomised, controlled clinical trials suggesting that flavonoids may be beneficial for the vascular system, particularly with regard to the prevention of endothelial dysfunction. Endothelial function can be described as arterial vasomotor responses mediated by the release of vasodilatory and vasoconstricting chemicals from the endothelium. An imbalance in these endothelium-derived relaxing and contracting factors results in endothelial dysfunction, most commonly characterised by the impaired release of the vasodilator, nitric oxide (NO).
Flavonoids have been reported to demonstrate antidiabetic effects through various molecular mechanisms of action. Glycogen phosphorylase inhibitory activity has been investigated for several structural requirements. Glycogen phosphorylase is one of the enzymes that catalyses the breakdown of glycogen into glucose in the liver, and its inhibition has been shown to modulate the glucose level associated with type 2 diabetes.
Animal and human studies have found that these compounds have poor oral bioavailability, which might be attributed to the loss of the compounds during the absorption and metabolism phases. In addition, these compounds also tend to have poor water solubility, low permeability, as well as poor stability profile.
Following the ingestion of flavonoids, sugar moieties (as in quercetin-3-glucoside) are cleaved from the phenolic backbone in the small intestine and absorbed there. Enzymes such as lactase phlorizin hydrolase (LPH) at the enterocyte membrane or cytosolic β-glucosidase (CBG) hydrolyze glycosylated flavonoids, and then aglycones enter epithelial cells by passive diffusion. However, flavonoids linked to a rhamnose moiety must reach the colon and be hydrolyzed by α-rhamnosidases secreted by the colon microbiota (such as Bifidobacterium dentium) in order to proceed to absorption.
Due to the low bioavailability of flavonoids, 90% of them persist in the colon. The gut microbiota exhibits great metabolic capacity for metabolizing the flavonoids via hydrolyzation, de-methylation, de-hydroxylation, and de-carboxylation, resulting in smaller metabolites, which are absorbed across the intestinal mucosa to benefit human health.
Fat intake will increase flavonoid bioavailability, while protein intake will reduce it. The metabolic behavior of the liver (Phase I and Phase II), such as the methylation, sulfation, or glucuronidation of flavonoids, also plays a critical role. It is worth noting that after being "processed" by microorganisms, the bioactivity of some flavonoids may even improve.
There are many factors affecting bioavailability, such as the chemical structure, sugar binding and metabolic enzymes of flavonoids, plasma protein binding, and the participation of intestinal microorganisms in various metabolic reactions.
Evidence level: Moderate (RCT data exist; heterogeneity limits conclusions)
Research has suggested a number of beneficial effects arising from the consumption of dietary flavonoids found in foods such as cocoa, apples, tea, citrus fruits, and berries, on cardiovascular risk factors such as high blood pressure and endothelial dysfunction. These effects are thought to have a significant impact upon both vascular and cerebrovascular health, ultimately with the potential to prevent cardiovascular and potentially neurodegenerative disease with a vascular component, for example vascular dementia.
Evidence presented includes the potential to reduce blood pressure in hypertensive individuals, as well as increasing peripheral blood perfusion and promoting cerebral blood flow (CBF) in both healthy and at-risk populations. However, there is great variation in the literature due to the heterogeneous nature of the randomised controlled trials conducted. As such, there is a clear need for further research and understanding within this area in order to maximise potential health benefits.
A double-blind, RCT conducted on 21 healthy adults (aged 21–55 years) investigated the effects of high-flavonoid (213 mg procyanidins and 46 mg of epicatechin) or low-flavonoid dark chocolate bar intake (46 g/day) showing an improvement in the flow-mediated dilation (FMD) of the brachial artery (1.3 ± 0.7%; p = 0.024) in high-flavonoid chocolate consumers compared to the control group after 2 weeks of treatment, while no differences were observed in blood pressure in both groups.
A 34,492-female population study showed that total flavonoid intake was associated with a decreased risk of CHD deaths in postmenopausal women. There is increasing evidence for the therapeutic effects of flavonoids on hypertension, atherosclerosis, and other diseases.
For quercetin specifically, recent studies have found a reduction in blood pressure when hypertensive (>140 mmHg systolic and >90 mmHg diastolic) animals and humans are supplemented with quercetin. Proposed mechanisms for the antihypertensive effect of quercetin include decreased oxidative stress, inhibition of angiotensin converting enzyme activity, improved endothelial function, direct action on the vascular smooth muscle, and/or modulation in cell signaling and gene expression.
Researchers have been debating whether discoveries made in vitro and in vivo with quercetin and other flavonols have any relevance in human clinical trials. The scientific community has established great interest in the characterization and validation of flavonoids in CVDs by exploring molecular processes and conducting dozens of new clinical trials. In a query of the ClinicalTrials.gov database in January 2022, only the keyword "quercetin" identified 101 clinical studies in which this flavonol was registered.
Evidence level: Moderate-to-Strong (multiple RCTs and a Cochrane meta-analysis)
Due to their antioxidant properties, flavonoids have been implicated as a therapy source for many diseases and conditions, including inflammation, vasculitis, venous insufficiency, and hemorrhoids.
A Cochrane review and meta-analysis of phlebotonics for venous insufficiency, published in 2020, analyzed 56 randomized, double-blind, placebo-controlled trials involving 7,690 participants. Ten trials with Micronized Purified Flavonoid Fraction (MPFF) out of forty using flavonoids were included. Animal models and studies in patients indicate that MPFF has beneficial effects on a range of pathophysiological processes that contribute to the symptoms of CVD, including inflammation, micro-vessel permeability, valve and vessel wall remodelling, and reflux in microvalves.
These pharmaceutical medicines are primarily used to treat mild symptoms like pain or early stages of edema. There is a moderate amount of data to support their use in treating specific clinical indications of CVI, such as trophic abnormalities, cramping, restless legs, edema, and paresthesia; nevertheless, there is conflicting information about their effectiveness in treating venous ulcerations.
Evidence level: Preliminary (mainly preclinical; limited human data)
Currently, some flavonoids are being researched for their antioxidant ability concerning neuroprotection. These flavonoids can penetrate the blood–brain barrier and, depending on the specific flavonoid, retain adequate bioavailability in certain brain regions. Further data suggest that flavonoids could have a strong anti-inflammatory effect in the brain, which not only could be a robust therapeutic source for known neuroinflammatory diseases such as Alzheimer's Disease or Parkinson's Disease but also could be a therapeutic source for ischemic or hemorrhagic conditions such as stroke.
Many flavonoids are already being isolated, purified, and implemented in both in vitro and in vivo experiments. As these flavonoids proceed to clinical trials, it will be important to understand how they function as a therapy, primarily as antioxidants, and by other secondary mechanisms.
Evidence level: Moderate preclinically; modest human trial evidence
Flavonoids are known to have analgesic, anti-inflammatory, and antioxidant properties. Studies about flavonoids' effects on inflammatory diseases and pain have been increasing in the last decade as several groups are demonstrating the involvement of these phenolic compounds as anti-inflammatory, analgesic, and antioxidant molecules. The search for new therapeutic drugs with less or no side effects is a major reason leading to this growing interest in natural products for the treatment of inflammatory and painful conditions.
Different approaches to evaluate the anti-inflammatory activity of flavones, both in vitro and in vivo, showed a reduction in the production of pro-inflammatory mediators and inhibition of activation of the signaling pathway and nuclear factor. Regardless of the chosen model of arthritis, colitis, or gastric ulcer, flavones inhibited different signaling pathways, production of mediators, transcription factor activation, and ROS production.
Evidence level: Preliminary to moderate; growing human evidence for glucose and insulin outcomes
Flavonoids are naturally occurring polyphenolic secondary metabolites which have been reported to demonstrate a wide range of pharmacological properties, most importantly antidiabetic and anti-inflammatory effects. The relationship between hyperglycemia and inflammation and vascular complications in diabetes is now well established. Flavonoids possessing antidiabetic properties may alleviate inflammation by reducing hyperglycemia through different mechanisms of action.
Evidence level: Preclinical and epidemiological; direct clinical evidence is still limited
The molecular mechanisms underlying the multiple pharmacological effects of flavonoids, especially cancer chemoprevention, continue to be reviewed. Possible strategies have been discussed to develop anticancer therapy by combining flavonoid nutraceuticals with conventional chemotherapeutic agents. Numerous pharmacokinetic challenges such as bioavailability and drug-drug interactions are still fundamental questions concerning future clinical application.
Evidence from in vitro and in vivo models, supported by clinical data, demonstrates flavonoids' capacity to regulate oxidative stress, inflammation, metabolic syndrome, adipogenesis, cell proliferation, apoptosis, autophagy, and angiogenesis. However, well-powered human intervention trials specifically investigating cancer endpoints remain sparse and are primarily observational or surrogate-marker-based.
Evidence level: Moderate (supported by multiple small-to-moderate RCTs and meta-analyses)
Among the best-studied individual bioflavonoids for blood pressure, quercetin has the most robust human trial dataset. The average western diet supplies 15–40 mg of quercetin a day, and higher dietary levels (>33 mg/day) have been associated with decreased risk of CVD. Because few controlled randomized trials have been performed, little data exist to provide a solid scientific basis for many of the treatment claims made for quercetin.
Bioflavonoids are consumed in the regular diet through fruits, vegetables, tea, cocoa, wine, and other plant-based foods. Daily intake varies between 20 mg and 500 mg, mainly from dietary supplements including apples, grapes, berries, tea, tomatoes, and onions.
Commercially, bioflavonoids are available as:
A key challenge is poor absorption: only about 2% of free-form quercetin is absorbed with water. Taking quercetin with a fat-containing meal increases absorption by roughly one-third. A quercetin glycoside is much more efficient than other forms of quercetin.
While flavonoid toxicity exists, they are relatively safe and non-invasive from natural origins. At dietary intake levels, bioflavonoids are not associated with adverse effects in the general population. At high supplemental doses, the evidence base is less comprehensive.
Flavonoids have a potential interaction with drug metabolism, particularly through the inhibition of the cytochrome P450 3A4 enzyme, the most versatile and abundant enzyme in the liver. CYP3A4 is responsible for metabolizing approximately 50% of clinically prescribed drugs across diverse therapeutic classes, raising concerns about potential adverse effects.
While the clinical significance of flavonoid-mediated CYP3A4 inhibition in dietary contexts is generally considered low due to moderate intake and complex interactions, it poses a potential concern for individuals consuming high doses of flavonoid supplements or concurrently taking medications metabolized by CYP3A4. This can lead to increased drug exposure, potentially triggering adverse reactions or reduced efficacy.
Flavonoids can cause interactions with certain medications. One of the ways in which flavonoids cause interactions is by inhibiting the enzymes responsible for drug metabolism, such as cytochrome P450 enzymes (CYP enzymes), the most significant of which is the CYP3A4 enzyme.
The grapefruit–drug interaction is perhaps the most clinically recognized flavonoid-related drug interaction. The components of grapefruit juice that are the most probable causes of the interactions are psoralen derivatives (furanocoumarins), but the flavonoid naringenin may also contribute. It was previously thought that flavonoids such as naringin or naringenin were the main biologically active components in grapefruit juice, but studies reported that naringenin had virtually no effect on the disposition of testosterone. A recent study demonstrated that the amounts of naringin and naringenin in grapefruit juice were too small to produce any inhibitory action on CYP3A4 activity. It now appears that furanocoumarin derivatives are responsible for the enzyme inhibitory action of grapefruit juice.
Researchers have identified over 85 drugs with which grapefruit reacts adversely. According to a review by the Canadian Medical Association, there is an increase in the number of potential drugs that can interact with grapefruit juice and of the number of fruit types that can interact with those drugs.
Natural compounds, i.e., flavonoids, play a vital role in the circulatory system, supporting blood vessels and promoting healthy blood flow. They may also, to some degree, raise vascular tone and affect platelet aggregation. These effects on platelet function mean that high-dose flavonoid supplementation used alongside anticoagulant or antiplatelet medications warrants attention, though robust clinical data on this specific interaction for isolated bioflavonoid supplements are not conclusive.
Natural ingredients in dietary supplements can influence the metabolism and absorption of drugs, leading to changes in the effectiveness or safety of prescribed therapy. The gut microbiome not only generates bioactive metabolites from flavonoid metabolism but also influences absorption and biological effects within the host organism. This finding offers new insights into personalized nutrition and the application of flavonoid compounds.
The toxicity and side effects of flavonoid preparations, as well as ways to improve the pharmacokinetics of flavonoids, need to be further explored. Flavonoids' biochemical properties are structure-dependent; however, they are yet to be thoroughly grasped. The vast structural diversity across over 9,000 known compounds means that safety data established for one flavonoid (e.g., quercetin) cannot be automatically generalized to another (e.g., naringenin or genistein).
Health conditions that Bioflavonoids may help support.
Bioflavonoids as a class (principally diosmin, hesperidin, rutin, troxerutin, and quercetin) are among the most evidence-supported natural treatments for hemorrhoids. A 2006 British Journal of Surgery meta-analysis confirmed bioflavonoid phlebotonics significantly reduce hemorrhoidal bleeding, pain, and itching. The American Society of Colon and Rectal Surgeons includes flavonoids in its Clinical Practice Guidelines for hemorrhoid management.
Body systems that Bioflavonoids may help support.
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