IngredientsFlavanones, also known as dihydroflavones, are an important class of flavonoids widely found in citrus fruits. Like all flavonoids, they possess a C6-C3-C6 structure containing two benzene rings, A and B, connected by a heterocyclic pyrene ring (C) that contains oxygen. What sets flavanones apart structurally from most other flavonoid subclasses is detailed by their ring configuration: flavanones are examples of saturated flavonoids, in contrast to anthocyanidins, flavones, flavonols, and isoflavones, which present a C2=C3 unsaturation. More precisely, 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. The aromatic A and B rings, C4-keto group, and 15-carbon flavonoid skeleton are all evident in flavanones, but a notable absence of the C2âC3 double bond and a lack of oxygenation at the C-3 position of the C-ring make them distinctively different from other groups such as flavonols.
The parent compound, flavanone itself, carries the IUPAC systematic name 2-phenylchroman-4-one (also written as 2-arylchroman-4-one), with the molecular formula Cââ HââOâ. Principal individual flavanones include flavanone, hesperetin, and naringenin, among several others. Examples of flavanones (also called dihydroflavones) are hesperetin, naringenin, and eriodictyol. The class also encompasses isosakuranetin, eriodictyol, pinocembrin, and liquiritigenin as pharmacologically studied members, together with their glycosidic derivatives hesperidin (hesperetin-7-rutinoside), naringin (naringenin-7-neohesperidoside), eriocitrin, and narirutin.
In plants, flavonoids may be found in the free form (aglycones) or linked to sugars. Flavanones usually occur as glycosides, usually rutinosides (6-O-α-L-rhamnosyl-D-glucosides) and neohesperidosides. The distinction between the rutinoside and neohesperidoside forms has practical consequences for taste and bioavailability: naringin, the glycoside of naringenin, is the most abundant flavonoid in grapefruit juice, constituting up to 10% of its dry weight with a concentration in juice of 450 Όg/mL, and is what gives grapefruit juice its distinctive smell and bitter taste.
Citrus fruit and juices represent one of the main sources of compounds with high potential for health-promoting properties. Among these, flavanones such as hesperetin, naringenin, eriodictyol, isosakuranetin, and their respective glycosides occur in quantities ranging from approximately 180 to 740 mg/L, depending on the Citrus species and cultivar. Flavonoids present in citrus fruits such as oranges, bergamots, lemons, and grapefruitâ95% from flavanonesâare emerging for their considerable nutraceutical value.
Beyond the Citrus genus, flavanones are widely distributed in higher plants, mainly in the free form in the Asteraceae, Leguminosae, and Rutaceae, including water soap, cocoa, tea, red wine, fruits, and vegetables, mainly including hesperidin and naringin. This class of flavanones (hesperetin, naringenin) has a 2,3-dihydro-2-phenylchromen-4-one structure and is very abundant in citrus fruits and tomatoes. Individual plant species outside Citrus that contain pharmacologically studied flavanones include Eysenhardtia platycarpa (used in Mexican folk medicine) and Calceolaria thyrsiflora (endemic to Chile).
In flavonoid biosynthesis, one molecule of p-coumaroyl-CoA and three molecules of malonyl-CoA are used by chalcone synthase (CHS) to generate a bicyclic chalcone such as naringenin chalcone. Chalcones are then substrates for chalcone isomerase (CHI), which carries out the B-ring closure, rendering flavanones (as naringenin from citrus fruits). All flavonoid subfamilies derive from these 15-carbon flavanones. In other words, flavanones occupy a position as biosynthetic precursors to many other flavonoid subclasses within the plant phenylpropanoid pathway.
Flavanones as isolated chemical entities were not known before modern analytical chemistry; their traditional use is inseparable from the history of citrus fruits and other flavanone-containing plants in medicine and diet across multiple cultures.
Citrus peel has a long-documented place in Traditional Chinese Medicine (TCM). Citrus flavonoid concentrations in different tissues of citrus from different species around the world have been compared together with citrus-related TCM ingredients, confirming that these preparations were rich in flavanones. The TCM pharmacopeia employs dried citrus peel (Chen Pi, Zhi Shi, and Zhi Ke) for digestive, circulatory, and respiratory conditions. A pharmacokinetic study of the traditional Chinese formula Zhi Zhu Wan confirmed the presence and systemic absorption of hesperetin and naringenin as active constituents after oral administration.
Eysenhardtia platycarpa is used in traditional medicine for the treatment of kidney diseases, bladder infections, and diabetes mellitus, and many compounds have been isolated from this plant, including flavanones, phenolic compounds, triterpenoid acids, chalcones, and sugars, among others. Mexico has a rich tradition of using ethnomedicine, and in recent decades the Eysenhardtia genus has attracted attention due to its medicinal properties.
Similarly, Calceolaria thyrsiflora Graham, an endemic perennial small shrub growing in the central zone of Chile, has yielded flavanones including (â)-(2S)-5,4'-dihydroxy-7-methoxyflavanone and (â)-(2S)-5,3',4'-trihydroxy-7-methoxyflavanone. Flavanone 2 showed a potent, selective, and competitive inhibition of 5-hLOX, which supports the traditional use of this plant as an anti-inflammatory in diseases of the respiratory tract.
Historically, the presence of the 'bioflavonoid fraction' was associated with improved capillary health and relief of hemorrhagic tendencies; citrus peel powders and decoctions were used for mild circulatory and respiratory conditions. Traditional medicine used citrus peel for digestion and circulation; modern use is evidence-driven, focusing on venotonic therapy and metabolic/vascular support via standardized extracts. The term vitamin P was historically applied to the bioflavonoid fraction of citrus, including flavanone glycosides, reflecting early beliefs about their role in capillary integrity. Alternative names for citrus bioflavonoid preparations include 'vitamin P' (historical) and MPFF (micronized purified flavonoid fraction when diosmin/hesperidin are specified).
For nearly 50 years between 1954 and 1991, the interest of researchers in citrus flavonoids remained negligibly low, with fewer than 3 (and often 0) articles per year published. After a first period of growth between 1996 and 2003, the year 2004 was the first in which the number of publications exceeded 100 (117), and it took only three more years to overcome the 200-publication threshold in 2007 (219 publications), and another four years to surpass the 300-publication threshold (386 in 2011). The COVID-19 health crisis led to surpassing the 1,000-publications-per-year threshold in 2020 (1,080 publications), followed by further substantial increases.
Citrus bioflavonoid extract is a botanical preparation composed of multiple flavonoidsâchiefly flavanone glycosides (hesperidin, naringin), flavanone aglycones (hesperetin, naringenin), flavonols (rutin, quercetin), and polymethoxylated flavones (nobiletin, tangeretin)âconcentrated from the peel (flavedo, albedo) and pulp of Citrus species. This extract is used clinically and nutraceutically for venous health (as micronized purified flavonoid fractions, MPFF), endothelial support, metabolic modulation, and as an antioxidant adjunct.
Commercial supplement forms include:
Oral bioavailability varies by form: unmodified glycosides often show less than 10% systemic exposure to parent aglycone equivalents, while aglycone-enriched or phytosome formulations commonly report higher values.
The antioxidant activity is the most recognized effect of flavonoids, which depends on hydrogen donation and electron stabilization in the phenolic rings. Naringenin inhibits leukocyte recruitment and production of superoxide anion, whilst increasing glutathione (GSH) and antioxidant capacity. A particularly important antioxidant pathway is Nrf2 activation: naringenin acts on macrophages, inducing Nrf2 activationâa nuclear factor that induces antioxidant and anti-inflammatory responsesâand inducing HO-1 expression. The ability of flavanones to induce the Nrf2/HO-1 axis has been highlighted as a potential therapeutic strategy for neurodegenerative diseases.
Multiple interlocking mechanisms underlie the anti-inflammatory effects of flavanones. The effects of naringenin treatment can be linked, at least in part, to the inhibition of TLR4 protein and NF-ÎșB activity, the downregulation of the expression of inflammatory mediators (iNOS, ICAM-1, MCP-1, COX-2, TNF-α, IL-6) and the inhibition of the production of inflammatory cytokines (TNF-α and IL-6). The MAPKs role in intracellular signaling during pro-inflammatory response is closely related to the NF-ÎșB signaling pathway, which exerts the pivotal role in the expression of iNOS, COX-2, IL-6, and TNF-α; it has been demonstrated that flavanones are able to downregulate NF-ÎșB, but differences in experimental models can affect outcomes.
The anti-inflammatory effects of flavonoids may also be attributed to their ability to bind cyclooxygenases (COXs), which catalyze the transition of arachidonic acid into prostaglandins and thromboxanes. COX-2 produces prostaglandins for the induction of inflammation and pain, and studies have demonstrated the ability of flavanones to bind COX-2, which can help develop potent inhibitors for the treatment of inflammation.
Naringenin inhibits UVB irradiation-induced skin inflammatory edema, cytokine production, and myeloperoxidase activity. It also modulates TRP channels such as TRPV1, TRPM3, and TRPM8, reducing pain, and activates a NO signaling pathway that induces nociceptor neuron hyperpolarization. Naringenin acts by mechanisms involving the inhibition of leukocyte recruitment, oxidative stress, NFÎșB activation, and pro-hyperalgesic cytokine production on immune cells such as macrophages.
Hesperidin and hesperetin enhance endothelial function, regulate blood pressure, and counteract oxidative stress. Flavonoids modulate several cell-signaling pathways, including PI3K/Akt, JAK/STAT, MAPK, and NF-ÎșB, to exert cardiovascular effects. They reduce inflammation and oxidative stress, inhibit platelet aggregation, and improve insulin sensitivity and lipid profiles, benefiting conditions like diabetes, hyperlipidemia, and cardiovascular disease.
Several mechanisms have been proposed for the anticancer action of naringenin and hesperidin, including the modulation of epigenetics, estrogen signaling, induction of cell death via regulation of apoptotic signaling pathways, and inhibition of tumor invasion and metastasis. In various studies, flavonoids have been found capable of demonstrating anticancer effects by acting as antioxidants; modulating ROS-scavenging enzyme activity; upregulating apoptosis, autophagy, and cell cycle arrest; and downregulating inflammation, proliferation processes, and metastasis formation.
In vitro studies showed that flavanones such as hesperidin, neohesperidin, and hesperetin exerted antiosteoclastic and anti-inflammatory effects, inhibiting the expression of osteoclastic markers and reducing the levels of reactive oxygen species, proinflammatory cytokines, and matrix metalloproteinase levels; such studies also favored the osteogenic potential of preosteoblastic cells and induced the overexpression of osteogenic markers.
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 their removal by intestinal bacteria.
These flavanones naturally occur in their glycosidic form, in which the respective aglycones naringenin and hesperetin are bound to a sugar moiety that is either a neohesperidose or a rutinose. These sugar moieties prevent efficient absorption in the small intestine and therefore reduce the bioavailability and bioactivity of flavanones.
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 ÎČ-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 is highly dependent on conversion by the gut microbiome. Gut microbes in the large intestine cleave the attached rutinose moiety, forming hesperetin and enhancing bioavailability. After intestinal absorption, flavanones undergo hepatic phase II metabolism, forming glucuronide and sulfate conjugates. The metabolites hesperetin 7-O-glucuronide, hesperetin 3'-O-glucuronide, hesperetin 3-O-sulfate, naringenin 4'-O-glucuronide, and naringenin 7'-O-glucuronide have been quantified with their corresponding standards in pharmacokinetic studies.
Flavanones seem to be more bioavailable than other closely related flavonoids such as flavonols or flavan-3-ols. Studies confirmed that the glycosylated forms of flavanones (naringin and hesperidin) exhibited significantly lower bioavailability than their aglycone counterparts.
Epidemiological evidence: An association between reduced risk of death due to CVD and dietary intake of flavanones, anthocyanidins, and certain flavonoid-rich foods such as apples, red wine, grapefruit, and chocolate has been found. In addition to epidemiological evidence and clinical studies demonstrating that fruits in the Citrus genus significantly reduce the incidence of cardiovascular disease risk, pre-clinical investigations highlight cellular and subcellular targets responsible for these beneficial effects.
Clinical trial evidence â hesperidin (meta-analyses): A 2024 updated meta-analysis of RCTs (PubMed, PMID 39279783) examined hesperidin's effect on cardiovascular disease risk factors. The analysis included 12 trials with 589 participants and found evident effects of hesperidin on LDL cholesterol (WMD: â0.22 mmol/L; 95% CI: â0.33, â0.11 mmol/L), total cholesterol (WMD: â0.20 mmol/L; 95% CI: â0.31, â0.08 mmol/L), fasting blood glucose (WMD: â0.15 mg/dL; 95% CI: â0.29, â0.02 mg/dL), QUICKI (WMD 0.06, 95% CI 0.01â0.10), ICAM-1 (WMD: â13.60 ng/mL), VCAM-1 (WMD: â15.60 ng/mL), and C-reactive protein (WMD: â0.56 mg/L), whereas no effects were found for other CVD risk factors. The findings demonstrate that hesperidin might be advantageous in improving numerous CVD risk factors in humans, such as blood lipid concentrations, blood glucose control, and management of inflammatory indicators.
Limitations: Very small sample sizes, different supplementation dosages, and diverse underlying health states have hampered outcomes and made them inconsistent. A definitive conclusion cannot be drawn from human clinical trials alone at this time.
Clinical trial evidence â naringenin and grapefruit flavanones (mixed results): A plant extract preparation was able to decrease triglycerides, total and LDL cholesterol levels; however, in a randomized placebo-controlled trial including 194 moderately hypercholesterolemic patients, a daily dose of 1300 ÎŒM pure hesperidin or 862 ÎŒM pure naringin over 4 weeks did not affect total or LDL cholesterol levels. A randomized controlled crossover trial of grapefruit juice consumption in postmenopausal women for 6 months found that flavanones protected from arterial stiffness.
Combination product trial: A single-center, randomized, double-blind controlled trial assessed a food supplement based on a combination of grapefruit, bitter orange, and olive extracts administered for eight weeks (n=51) versus placebo (n=45). In the active product group, there were statistically significant within-group differences at eight weeks compared with baseline in FMD, systolic and diastolic blood pressure, total cholesterol, LDL-C, LDL-oxidase, oxidized/reduced glutathione ratio, protein carbonyl, and IL-6.
Overall strength of cardiovascular evidence: Moderate for hesperidin on lipid profiles and inflammatory markers based on meta-analysis; mixed and preliminary for naringenin and combination products. Studies are generally small and of short duration.
Flavanones, a group of polyphenolic compounds, have been the focus of intense research and development due to their wide range of biological activities, including anti-inflammatory effects. The bulk of mechanistic evidence for anti-inflammatory and analgesic action is currently derived from in vitro and animal studies. Naringenin presents therapeutic effects in several models of inflammatory pain and inhibits the pain-like behavior induced by inflammatory stimuli such as phenyl-p-benzoquinone, acetic acid, formalin, complete Freund's adjuvant, capsaicin, carrageenan, superoxide anion, and LPS. Naringenin treatment is described as a promising analgesic, anti-inflammatory, and antioxidant compound, requiring further investigation in preclinical models and clinical settings.
Human clinical data specifically for anti-inflammatory outcomes of isolated flavanones are limited. Reductions in circulating inflammatory markers (CRP, ICAM-1, VCAM-1) in the hesperidin meta-analyses (cited above) provide indirect clinical evidence. Direct human trials targeting pain or inflammatory disease endpoints with flavanone isolates remain sparse and are largely preliminary.
Due to their antioxidative, anti-inflammatory, and anti-carcinogenic activities, flavonoids have been revealed to benefit skeletal muscle, liver, pancreas, adipocytes, and neural cells. Animal and cell culture studies consistently show naringenin can improve insulin sensitivity and reduce adipogenesis. Flavonoids reduce inflammation and oxidative stress, inhibit platelet aggregation, and improve insulin sensitivity and lipid profiles, benefiting conditions like diabetes and hyperlipidemia.
In clinical trials, the hesperidin meta-analysis found statistically significant reductions in fasting blood glucose and improvements in insulin sensitivity index. Although some clinical studies have been performed, the main focus is on naringenin bioavailability and cardioprotective action; studies were done in compromised patients (i.e., hypercholesterolemic and overweight), with a dosage ranging between 600 and 800 ÎŒM/day, whereas the effect on healthy volunteers is still debatable.
Strength of evidence: Preliminary to moderate for glycemic markers in metabolically compromised individuals; mechanistic evidence is largely preclinical.
Among flavonoids, flavanones are the most prominent in citrus, and naringenin and hesperidin are emerging compounds with anticancer potential, especially for breast cancer. Several mechanisms have been proposed, including the modulation of epigenetics, estrogen signaling, induction of cell death via regulation of apoptotic signaling pathways, and inhibition of tumor invasion and metastasis.
In a case-control study, associations were made between serum concentrations of flavanones (naringenin and hesperidin) and the risk of breast cancer in 792 female patients, although establishing causation from such observational data is not possible. Hesperidin is considered a potential anticancer, antioxidant, anti-depressive, and immunomodulatory agent.
Strength of evidence: Largely in vitro and animal (preclinical). Human data consist primarily of observational epidemiological associations and a small number of mechanistic biomarker studies. No completed phase II or III RCTs for cancer endpoints with isolated flavanones have been identified in the published literature as of this writing.
The ability of flavanones to induce the Nrf2/HO-1 antioxidant defense axis is highlighted as a potential therapeutic strategy for neurodegenerative diseases. Chronic inflammation and oxidative stress are involved in the pathogenesis of obesity, cancer, and neurodegenerative diseases, and flavonoids are emerging as potential therapeutic molecules for these diseases due to their anti-inflammatory and antioxidative properties. Animal studies in rodent models of Alzheimer's-like pathology, Parkinson's disease, and neuroinflammation have demonstrated benefits of naringenin, hesperetin, and eriodictyol, primarily through suppression of neuroinflammatory signaling and protection against oxidative damage.
Strength of evidence: Predominantly preclinical (in vitro and in vivo). No robust human RCT evidence exists for neuroprotective endpoints with isolated flavanones.
In vivo, flavanones (hesperidin, neohesperidin, hesperetin) favored the regeneration of bone defects and minimized inflammation in arthritis- and periodontitis-induced models; they exerted a significant anticatabolic effect in ovariectomy models, reducing trabecular bone loss and increasing bone mineral density. Although research should advance to the clinical field, these flavanones may have therapeutic potential for controlling the progression of metabolic, autoimmune, or inflammatory bone diseases.
Strength of evidence: Largely preclinical. Clinical data in humans for bone-specific endpoints are not yet available.
Citrus flavanones, with hesperidin and naringin as the most abundant representatives, have various beneficial effects including anti-oxidative and anti-inflammatory activities; evidence also indicates that they may impact the intestinal microbiome and are metabolized by the microbiota as well, thereby affecting their bioavailability. This body of evidence may contribute to understanding of gastrointestinal health in various diseases. The interaction with the gut microbiota is bidirectional: flavanones are transformed by gut bacteria, and they in turn can modulate the microbial community composition, though this relationship is complex. Some study results have not shown a clearly beneficial effect of tested flavanones on intestinal microbiota, indicating that increased concentrations of flavanones may inhibit the growth of beneficial bacteria in the gut in a dose-dependent manner.
Several pharmacological studies have highlighted the antimicrobial potential of flavanones, among other health benefits including diuretic, antidiabetic, antiglycation, antioxidant, anti-inflammatory, and cytotoxic properties. Biological tests revealed that one flavanone from Calceolaria thyrsiflora exhibited a moderate inhibitory activity against the methicillin-resistant strain S. aureus MRSA 97-77 (MIC value of 50 ”g/mL). Antiviral activities against Sindbis virus (for hesperetin and naringenin) and influenza virus (for certain flavanone glycosides from Citrus junos) have been reported in laboratory and cell culture studies.
Strength of evidence: Primarily in vitro. No clinical data in humans for antimicrobial endpoints.
The following dosages are reported as they appear in the cited sources and should not be interpreted as recommended therapeutic doses.
A preclinical toxicity study of an oral naringeninâhesperidin 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) were assayed for 28 days; results 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. The findings indicated the formulation did not exhibit relevant toxic effects. Hesperidin therapy at supplemental doses is generally regarded as safe (GRAS) in humans based on the available toxicological record.
The drugâgrapefruit juice interaction is caused by inhibition of intestinal CYP3A4, by one or more of the components in grapefruit juice. Many active components in grapefruit juice have been evaluated for potentially causing this interaction, including flavonoids such as naringenin, naringin, quercetin, and kaempferol, and nonflavonoids such as 6,7-dihydroxybergamottin, bergaptol, and 6,7-epoxybergamottin. Naringin exerts no effect on the activity of the CYP450 system in vitro, but in vivo, its metabolite, naringenin, is a potent inhibitor of both CYP3A4 and CYP1A2.
Naringin has no effect on the activity of the human CYP system in vitro, but its metabolite naringenin is a potent inhibitor of both CYP3A4 and CYP1A2 isoforms in vitro. However, in vivo, oral naringenin only weakly inhibits CYP3A4 and CYP1A2. For the CYP1A2 system, this is not surprising as most CYP1A2 is in the liver and not in the intestine, and only low levels of naringenin reach the plasma.
Grapefruit juice is known to be a weak inhibitor of CYP3A4 and is therefore expected to increase the exposure of medicines metabolized by CYP3A4. However, the variability between different grapefruit juice products means its effects on medicines can be unpredictable. Grapefruit juice exerts the majority of its inhibitory effect on CYP3A4 in the intestine, but has minimal effect on hepatic CYP3A4.
Flavonoids such as naringin and hesperidin have been implicated in the mechanism of OATP (organic anion transporting polypeptide) inhibition. The net effect is reduced bioavailability of the drug, with a decrease in its systemic and tissue concentrations and thus a decrease in its efficacy. In contrast to the effect of grapefruit juice on CYP3A4, the inhibition of OATPs shows a clear volume (dose)-response association, which is competitive in nature, with inhibition lasting about four hours.
Bergamottin and naringenin have been shown to inhibit simvastatin metabolism and increase serum concentrations of simvastatin and its active metabolite. The probable mechanism is inhibition of CYP3A4-mediated first-pass metabolism of simvastatin in the small intestine. Bergamottin and naringenin have been proposed as markers in food-drug interaction studies in order to adjust posology, and the dose of simvastatin should accordingly be reduced. Adverse drug reactions including inhibition of CYP3A4 by grapefruit active ingredients led to marked increases in blood terfenadine concentrations, subsequently causing prolonged QT intervals and cardiac arrhythmias.
Research examining naringin, naringenin, hesperetin, and hesperidin for their effects on the growth of human intestinal bacteria found that results did not show a clearly beneficial effect of the tested flavanones on intestinal microbiota, indicating that an increased number of polyphenolic compounds such as flavanones may inhibit the growth of beneficial bacteria in the gut. Naringenin partially or completely reduced the growth of certain bacteria in a dose-dependent manner. The clinical significance of this finding in the context of normal dietary or supplemental flavanone intake remains uncertain.
The growing body of scientific evidence indicates that flavonoids play a beneficial role in disease prevention; however, further clinical and epidemiological trials are greatly needed. Although some mechanisms of action remain unclear and bioavailability problems remain to be solved, the current evidence supports the use of a nutraceutical approach with citrus fruits to prevent and cure several aspects of cardiovascular disease. Across all areas of study, key limitations include small sample sizes in RCTs, short intervention durations, use of whole citrus products rather than isolated compounds in many trials, significant inter-individual variability in flavanone absorption (owing to differences in gut microbiota), and lack of standardized dosing protocols.
Health conditions that Flavanones may help support.
Body systems that Flavanones may help support.
Go back