IngredientsFlavanones, also known as dihydroflavones, are an important class of flavonoids widely found in citrus fruits. They lack the double bond between carbons 2 and 3 in the C-ring of the flavonoid skeleton, which is present in flavones and flavonols, and they are the dominant subclass of flavonoids in Citrus spp. Flavanones and flavan-3-ols have the central heterocyclic ring saturated and, in this case, one or more chiral centers are present.
Almost all flavonoids present a C6-C3-C6 structure containing two benzene rings, A and B, connected by a heterocycle pyrene ring (C) that contains oxygen. Flavanones' general structure is characterized by the presence of a carbonyl group in the C4 position, the absence of substituents in the C3 position, and a double bond between C2 and C3. They contain only hydroxyl and methoxy groups and differ from one another in the number and/or position of such substituents.
Based on the degree of unsaturation and substitution pattern, flavanones are distinguished as one of the major flavonoid classes. In natural sources, they may occur in free forms (aglycones), as glycosylated or acylated derivatives, and as oligomeric and polymeric structures.
Several specific flavanones have been most extensively studied in scientific and clinical research. The main aglycones are naringenin in grapefruit, hesperetin in oranges, and eriodictyol in lemons. Flavanones mainly include hesperetin, naringenin, and eriodictyol. Hesperetin-7-O-glucoside, prunin, and isoquercitrin are flavonoid monoglucoside forms of hesperetin, naringenin, and quercetin, respectively. Hesperidin, naringin, and rutin are their corresponding flavonoid diglycosides.
Naringin is a natural dihydroflavonoid with the molecular formula C₂₇H₃₂O₁₄ and a relative molecular weight of 580.54 g/mol, chemically designated as 4′,5,7-trihydroxyflavanone-7-rhamnoglucoside. Naringenin is the aglycone of naringin, which forms a glycoside with neohesperidose at position 7. The chemical structure of naringenin consists of a flavanone skeleton with hydroxyl groups at positions 5′ and 7′ on ring A and at position 4′ on ring B, contributing to its strong antioxidant activity.
Hesperidin is a major flavanone composed of hesperetin (aglycone) conjugated by rutinose. The most abundant citrus flavonoids are flavanones, such as hesperidin, naringin, and neohesperidin.
Flavanones are extensively disseminated in around 42 larger plant families, especially in Compositae, Leguminosae, and Rutaceae. They are found in tomatoes and aromatic plants such as mint, but their major sources are citrus fruits, especially grapefruit. Flavanones may also be found, to a lesser extent, in aromatic plants such as mint.
Orange juice contains between 200 and 600 mg hesperidin per liter and 15–85 mg narirutin per liter; therefore, one glass of orange juice may contain between 40 and 140 mg flavanone glycosides. Since the highest flavanone content is found in the solid parts of citrus fruit, the whole fruit may contain up to five times more flavanone glycosides.
Flavanones are very abundant in citrus fruits and tomatoes. Isolated flavanones exhibit significant structural diversity, including diverse methoxy and hydroxy substitution patterns, formyl groups, and rare prenylated and C-benzylated derivatives.
Flavanones exist naturally as aglycone and glycoside forms. Flavanones are generally glycosylated by a disaccharide at position 7 (either a neohesperidose, which imparts a bitter taste, or a rutinose, which is flavorless). Flavanone-O-glycosides, flavone-O/C-glycosides and their derivatives were found to be the most abundant flavonoids in the genus Citrus.
In the commercial supplement space, flavanones are available as standardized citrus bioflavonoid extracts, as isolated hesperidin or naringin powders, as the aglycone forms hesperetin and naringenin, and in combination products such as the pharmaceutical preparation micronized purified flavonoid fraction (MPFF), which contains diosmin and hesperidin. Most studies tend to use 500 mg or more of supplemental hesperidin, and use the standard form of hesperidin if taking it as a daily preventative.
Flavonoid-enriched tissues of citrus such as peel, immature fruit, and flower are consumed as culinary seasonings and tea ingredients in China for centuries. Citrus fruit contains rich nutrients which are edible and of officinal value. Citrus flavanones are widely used in the treatment of cardiovascular and other diseases, and they are a foundational material of Chinese medicine.
An HPLC quantitative study on the five citrus flavonoids—naringin, hesperidin, neohesperidin, sinensetin, and nobiletin—across a wide range of Chinese citrus fruits and several Traditional Chinese Medicinal food ingredients in East China revealed a great diversity in flavonoid composition. C. aurantium, a major ingredient of several citrus-related TCM preparations, is a suitable source of naringin and neohesperidin and a good juice source for flavanone glycosides.
In traditional Chinese medicine, flavonoid-containing herbs have been used for a variety of medicinal purposes, including treatment or prevention of cardiovascular disease, cancer, and inflammation. This ancient practice reflects a deep-rooted understanding of using flavonoid-rich botanicals alongside other natural compounds to create synergistic healing effects.
Eysenhardtia platycarpa is used in traditional medicine for the treatment of kidney diseases, bladder infections, and diabetes mellitus. Many compounds have been isolated from this plant, such as flavones, flavanones, phenolic compounds, triterpenoid acids, chalcones, sugars, and fatty acids, among others. Flavonoids are evaluated to have drug-like nature since they possess different therapeutic activities, and can act as cardioprotective, antiviral, antidiabetic, anti-inflammatory, antibacterial, anticancer, and also work against Alzheimer's disease and others.
In flavonoid biosynthesis, one molecule of p-coumaroyl-CoA and three molecules of malonyl-CoA are used by the chalcone synthase (CHS) to generate a bicyclic chalcone as naringenin chalcone. Chalcones are substrates for chalcone isomerase (CHI), which carries out the B-ring closure at these compounds, rendering flavanones such as naringenin from citrus fruits. All flavonoid subfamilies derive from these 15-carbon flavanones.
Chalcone isomerase (CHI) catalyzes the conversion of chalcones into their corresponding flavanones via the rearrangement of the chalcone structure, specifically resulting in the intramolecular cyclization of chalcones into flavanones. From this biosynthetic intermediate position, flavone synthase (FNS) will generate flavones (as apigenin from celery), isoflavone synthase (IFS) will generate isoflavones (as genistein from soy), and flavanone-3-hydroxylase (F3H) will generate dihydroflavonols.
The principal bioactive flavanones studied in scientific literature include:
Several flavanones have been reported to exhibit potent biological activities, including antioxidant, cytotoxic, antiplasmodial, estrogenic, aromatase inhibitory, and α-glucosidase inhibitory properties.
The antioxidant activity of flavonoids depends on their stable roles in different matrices, as well as the position and number of hydroxyl groups in their structures. The mechanisms of antioxidant activity mainly comprise direct scavenging of reactive oxygen species (ROS). The radical-scavenging activity of flavonoids, commonly called their "antioxidant" activity, has been widely hypothesized as a mode of action to explain the many observed biological effects of these compounds.
Beneficial effects of citrus flavanones (e.g., radical scavenging and anti-inflammatory activity and modulation of microbiota) are considered to be related to their biochemical structure, such as the number and specific position of hydroxyl groups on the A and B ring and the presence of the sugar moiety.
Flavonoids are polyphenolic compounds that occur ubiquitously in plants having a variety of biological effects both in vitro and in vivo. They have been found to have antimicrobial, antiviral, anti-ulcerogenic, cytotoxic, anti-neoplastic, mutagenic, antioxidant, antihepatotoxic, antihypertensive, hypolipidemic, antiplatelet, and anti-inflammatory activities. Flavonoids also have biochemical effects, inhibiting a number of enzymes such as aldose reductase, xanthine oxidase, phosphodiesterase, Ca²⁺-ATPase, lipoxygenase, and cyclooxygenase.
Flavonoids inhibit the secretions of enzymes such as lysozyme and β-glucuronidase and inhibit the secretion of arachidonic acid, which reduces inflammatory reactions. Flavonoids modulate the expression and activation of cytokines such as IL-1β, TNF-α, IL-6, and IL-8; regulate the gene expression of many pro-inflammatory molecules such as NF-κB, AP-1, ICAM, VCAM, and E-selectins; and also inhibit inducible nitric oxide synthase, cyclooxygenase-2, and lipoxygenase.
Several key studies have shown that the anti-inflammatory properties of citrus flavonoids are due to their inhibition of the synthesis and biological activities of different pro-inflammatory mediators, mainly the arachidonic acid derivatives, prostaglandins E₂, F₂, and thromboxane A₂.
Hesperidin and hesperetin counteract atherosclerosis by ameliorating lipid profiles, inhibiting plaque formation, and reducing inflammation. These flavonoids possess antihypertensive properties by modulating the renin-angiotensin system (RAS), reducing oxidative stress while improving vascular function.
It is suggested that flavonoids decrease the risk of coronary heart disease by three major actions: improving coronary vasodilatation, decreasing the ability of platelets in the blood to clot, and preventing low-density lipoproteins (LDLs) from oxidizing. The anti-inflammatory properties of citrus flavonoids have also been studied.
The pleiotropic anticancer properties of naringenin include inhibition of the synthesis of growth factors and cytokines, inhibition of the cell cycle, and modification of several cellular signaling pathways. Flavonoids exert a wide variety of anticancer effects: they modulate ROS-scavenging enzyme activities, participate in arresting the cell cycle, induce apoptosis and autophagy, and suppress cancer cell proliferation and invasiveness.
Specifically among flavanones, flavanone hesperetin induced cytochrome c release as part of its pro-apoptotic action in cancer cell lines studied in vitro. Research demonstrates how flavonoid supplementation induces anti-cancer effects through various mechanisms, including regulation of angiogenesis, anti-inflammatory actions, antioxidant-induced apoptosis, and modulation of key pathways such as PI3K/Akt and MAPK.
The anti-inflammatory, antioxidant, anti-apoptotic, and neuroprotective effects of naringenin make it a promising option for treating neurodegenerative conditions. Administration of naringenin improved spatial learning and memory in a rat model of Alzheimer's disease through regulating the PI3K/AKT/GSK-3β pathway and reducing tau hyper-phosphorylation. Additionally, naringenin improved brain insulin signaling as well as peroxisome proliferator-activated receptor gamma (PPAR-γ).
With a molecular weight of 272.25 g/mol, naringenin possesses the ability to cross biological barriers, including the blood–brain barrier (BBB).
New hypotheses about possible mechanisms have been postulated, including the influence of the interaction of polyphenols and gut microbiota and also the possibility that flavonoids or their metabolites could modify gene expression or act as potential modulators of intracellular signaling cascades. This encompasses the classical view as antioxidants in the context of the oxidative stress theory, to the most recent tendencies related with the modulation of redox signaling pathways, modification of gene expression, or interactions with the intestinal microbiota.
The ability of citrus flavanones to exert beneficial effects strongly depends on their bioavailability, which can be affected by the structure of the compound, the food matrix, and host factors. The intestinal metabolism of citrus flavanones is mainly determined by their degree of conjugation to sugar moieties and the removal of these by intestinal bacteria.
Hesperidin and naringin are exposed to α-rhamnosidases secreted by the gut microbiota, which remove the rhamnose moiety followed by the removal of glucose by β-glucosidases. Although the majority is converted in the colon, some breakdown can already take place in the distal part of the small intestine. Upon release, the aglycones hesperetin and naringenin are absorbed through the intestinal epithelium by means of passive diffusion and proton-coupled active transport, or are further metabolized into phenolic acids and simple phenolics by C-ring cleavage, demethylation, and dehydroxylation by bacterial enzymes.
In the small intestine, hesperidin is poorly absorbed, and it is highly dependent on the conversion by the gut microbiome. Gut microbes in the large intestine cleave the attached rutinose moiety, forming hesperetin, enhancing bioavailability.
Flavanones seem to be more bioavailable than other close flavonoids such as flavonols or flavan-3-ols.
A human pharmacokinetic study comparing eriocitrin and hesperidin found that no significant biomarker changes were observed, but plasma and urinary concentrations of all metabolites, including hesperetin metabolites, were higher after lemon extract intake. Total plasma metabolites showed significantly lower mean Tmax (6.0 ± 0.4 vs. 8.0 ± 0.5 h) and higher Cmax and AUC values after lemon extract intake.
From prospective cohort studies, higher intakes of flavanones are associated with a lower incidence of mortality by cardiovascular disease (CVD). This relation is supported by results from a number of animal studies demonstrating a slowdown in atherosclerosis development and vascular protective effects in dietary interventions with flavanones.
At the clinical level, the role of citrus flavanone hesperidin consumption on cardiovascular disease risk factors has been examined in many clinical trials, but conflicting results have been found. This evidence has been systematically evaluated through meta-analyses of randomized controlled trials.
RCTs have investigated the effectiveness of hesperidin consumption on various CVD risk factors. However, very small sample sizes, different supplementation dosages, and diverse underlying health states hampered the outcomes and made them inconsistent.
The outcomes of one meta-analysis suggest that hesperidin administration could benefit patients with CVD by reducing LDL, TC, and TG. Further high-quality studies are needed to firmly establish the clinical efficacy of hesperidin.
Clinical trials also support the potential benefits of hesperidin and hesperetin supplementation in improving blood pressure, endothelial function, and inflammatory markers.
The intake of hesperidin-rich sources, mostly found in orange juice, can decrease cardiometabolic risk, potentially linked to the gut microbial phase-II hesperetin derivatives.
Evidence strength: Moderate for lipid reduction (supported by multiple RCTs and meta-analyses), but overall results are mixed and heterogeneous. Evidence for blood pressure effects is preliminary. The body of clinical data, while growing, is limited by small sample sizes and lack of standardization.
Supplementation with hesperidin has various benefits, such as anti-inflammatory, anticancer, and antioxidant characteristics. Flavonoids have been found to have anti-inflammatory activity in both proliferative and exudative phases of inflammation.
There are a large number of remedies in traditional medicine focused on relieving pain and inflammation. Flavanones have been a potential source in the search for leading compounds and biologically active components, and they have been the focus of much research and development in recent years.
Evidence strength: Strong at the mechanistic (in vitro and animal) level, but direct human clinical evidence for inflammatory disease endpoints is limited. Anti-inflammatory activity is primarily supported by preclinical research and biomarker studies in RCTs, not by large-scale clinical outcomes trials.
Naringin and naringenin are the main bioactive polyphenols in citrus fruits, the consumption of which is beneficial for human health. Numerous studies have reported these substances' antioxidant and antiandrogenic properties, as well as their ability to protect from inflammation and cancer, in various in vitro and in vivo experimental models in animals and humans.
The inactivation of carcinogens following treatment with pure naringenin, naringenin-loaded nanoparticles, and naringenin combined with anti-cancer agents was demonstrated by data in vitro and in vivo studies.
These effects are especially notable in the prevention and progression of breast, colon, liver, and lung cancers. Research highlights findings that supplementation with citrus fruits may induce angiogenic effects, anti-inflammatory actions, and antioxidant-induced apoptosis and may modulate pathways such as PI3K/Akt, MAPK, and TGF-β2/Smad2/3Akt/PTEN that are involved in anti-cancer responses.
Despite the remarkable preclinical activities of flavonoids, their clinical applications have been limited and this is due, in part, to problems in drug delivery and poor bioavailability, and these problems are being addressed.
Evidence strength: Evidence is currently preclinical (in vitro and animal models). There are no established human clinical trials demonstrating that flavanone supplementation prevents or treats cancer in humans. Epidemiological data linking higher citrus consumption to lower cancer risk are observational and do not establish causality.
Flavanones, a key subclass of flavonoids, exhibit a wide range of biological activities, including antioxidant, anti-inflammatory, and neuroprotective properties.
Overall, findings indicate that naringenin combats oxidative stress, neuroinflammation, and neuroapoptosis to overcome cognitive dysfunction, thereby demonstrating therapeutic potential. Due to the potential dopamine-enhancing, potent antioxidant, as well as anti-inflammatory effects of naringenin, it could be used as a beneficial agent in the treatment of Parkinson's disease.
The glycosides of two flavonoids, naringin and naringenin, are found in various citrus fruits, bergamots, tomatoes, and other fruits. These phytochemicals are associated with multiple biological functions, including neuroprotective, antioxidant, anticancer, antiviral, antibacterial, anti-inflammatory, antiadipogenic, and cardioprotective effects.
Research explores the potential role of flavanones in modulating gut microbiota and their consequent effects on cognitive function, with a focus on underlying mechanisms and therapeutic implications.
Evidence strength: Primarily preclinical (animal and cell-based). Human clinical data on cognitive outcomes from flavanone supplementation are very limited, and the gut–brain axis evidence in humans is nascent.
In many studies, naringin and naringenin have been proved to have multiple effects such as anti-tumor, anti-inflammatory and antiviral, antioxidant, hypoglycemic, cholesterol-lowering, gastrointestinal protection, prevention and treatment of bone injury, neuroprotection, antidepressant, and cardio-cerebral protection effects.
Regarding blood glucose specifically, a systematic review and meta-analysis found that hesperidin supplementation had no significant effect on blood glucose control in RCTs. One meta-analysis including 10 RCTs showed that hesperidin supplementation might not improve lipid profile and blood pressure. However, other meta-analyses have reached different conclusions, reflecting the inconsistency in the literature.
Evidence strength: Mixed and inconsistent across clinical trials. Animal evidence is robust, but human RCT results are heterogeneous and require further investigation with larger, standardized trials.
The effects of hesperidin, hesperetin-7-O-glucoside, hesperetin, naringin, prunin, naringenin, rutin, isoquercitrin, and quercetin on gut microbiota structural and metabolic differences in healthy subjects were studied by means of in vitro simulated fermentation technology. Results showed that hesperetin-7-O-glucoside, prunin, and isoquercitrin were found to have more effect on the structure of human gut microbiota, and they could significantly enhance Bifidobacterium.
To investigate the impact of oral administration of hesperidin on gut microbiota composition, 100–200 mg of hesperidin was administered orally to Lewis rats for four weeks. The administration of hesperidin resulted in a higher Lactobacillus proportion.
Studies have not always shown a beneficial effect of tested flavanones on the intestinal microbiota, indicating that an increased concentration of flavanones may inhibit the growth of beneficial bacteria in the gut. Research showed that naringenin partially or completely reduced the growth of certain bacteria in a dose-dependent manner. A similar but less pronounced effect was observed for hesperetin. The study confirmed that the glycosylated forms of flavanones (naringin and hesperidin) exhibited significantly lower bioavailability.
Evidence strength: Preliminary. Most microbiota data comes from in vitro fermentation models and animal studies; robust human clinical data are lacking.
The micronized purified flavonoid fraction (MPFF), a pharmaceutical preparation containing diosmin (90%) and hesperidin (10%), has been evaluated in RCTs for chronic venous insufficiency (CVI) and hemorrhoids. Hesperidin is most often used for cardiovascular health, and the Examine Database covers high cholesterol, metabolic health, and 7 other conditions and goals. The combination preparation (traded as Daflon 500 mg in Europe) has demonstrated efficacy in reducing hemorrhoid symptoms and improving venous tone in several controlled trials, though this evidence pertains to the combination product rather than hesperidin as an isolated ingredient.
Flavonoids are evaluated to have drug-like nature since they possess different therapeutic activities, and can act as cardioprotective, antiviral, antidiabetic, anti-inflammatory, antibacterial, anticancer, and also work against Alzheimer's disease and others.
Most studies tend to use 500 mg or more of supplemental hesperidin, and use the standard form of hesperidin if taking it as a daily preventative. For the prevention of muscle soreness associated with delayed onset muscle soreness (DOMS), a daily dosage of 500 mg of hesperidin methyl chalcone (HMC) for 3 days prior to intensive anaerobic exercise has shown positive outcomes.
Orange juice contains between 200 and 600 mg hesperidin per liter and 15–85 mg narirutin per liter; one glass of orange juice may contain between 40 and 140 mg flavanone glycosides.
In preclinical animal toxicology work, a naringenin–hesperidin molar mixture showed no mortality or significant changes in body weight, food consumption, or tissue/organ mass in rats. Three daily oral doses (50, 300, and 2000 mg/kg of the mixture) were assayed for 28 days.
To investigate the impact of oral administration of hesperidin on gut microbiota composition, 100–200 mg of hesperidin was administered orally to Lewis rats for four weeks.
The MPFF pharmaceutical formulation (Daflon 500 mg) is used clinically in Europe for venous conditions at a dose of 500 mg twice daily, representing a standardized, medically supervised application of hesperidin in combination with diosmin.
Hesperidin is relatively safe and well tolerated, but there is a general lack of clinical research examining potential side effects and drug interactions. Research suggests that hesperidin is generally well tolerated; however, thorough safety analyses still need to be done, and clinical evidence is lacking.
A preclinical study showed no structural abnormalities in histological analysis and no significant changes in liver biochemical markers (total bilirubin, AST, and ALT) compared to the control group, suggesting the potential safety of naringenin/hesperidin combination as a drug candidate.
Hesperidin may interfere with the way the body processes certain drugs, herbs, or supplements using the liver's cytochrome P450 enzyme system. As a result, the levels of these agents may change in the blood and may cause increased or decreased effects or potentially serious adverse reactions. This is a particularly important interaction because grapefruit and its constituents (including naringenin) are well-documented inhibitors of CYP3A4, the most abundant drug-metabolizing enzyme in the human gut wall and liver.
The low hesperidin solubility hampers its bioavailability. Despite their broad benefits and wide distribution, flavonoids have poor bioavailability, which can significantly influence their nutritional value.
Hesperidin is likely safe during pregnancy. While likely also safe during lactation, caution is advised due to a lack of evidence.
Individuals with low blood pressure should be careful as hesperidin can further lower blood pressure, potentially leading to symptoms like dizziness or fainting.
Despite promising findings, further research is needed to determine optimal dosages, strategies to enhance bioavailability, and long-term safety profiles. Randomized controlled clinical trials to corroborate the suggested vasculo-protective effects of orange juice presumably mediated by flavanones are scarce, and available data do not allow firm conclusions about their efficacy.
Preclinical studies with individual flavonoids demonstrate that these compounds exhibit anti-inflammatory and anticancer activities and they enhance the immune system. Their effectiveness in both chemoprevention and chemotherapy is associated with their targeting of multiple genes and pathways including nuclear receptors, the aryl hydrocarbon receptor (AhR), kinases, receptor tyrosine kinases, and G protein-coupled receptors.
Health conditions that Flavonones may help support.
Body systems that Flavonones may help support.
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