Naringenin

Other Names

(2S)-5,7-Dihydroxy-2-(4-hydroxyphenyl)-2,3-dihydro-4H-chromen-4-one(2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one(2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-4-chromanone(2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one(2S)-Naringenin(R)-Naringenin(S)-2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4-benzopyrone(S)-2,3-Dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one(S)-5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-one(S)-Naringenin2,3-Dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one4',5,7-Trihydroxyflavanone4H-1-Benzopyran-4-one, 2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-, (2S)-4H-1-Benzopyran-4-one, 2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-, (S)-5,7-Dihydroxy-2-(4-hydroxy-phenyl)-chroman-4-one5,7-Dihydroxy-2-(4-hydroxyphenyl)chroman-4-oneAsahinaCCRIS 5839Flavanone, 4',5,7-trihydroxy-NaringenineNaringetolNSC 11855NSC 34875PelargidanonS-DihydrogenisteinSalipurolSalipurpol

Synopsis

Naringenin: A Comprehensive Reference

1. Identity, Chemical Characterization, and Natural Sources

Chemical Identity

Naringenin is a flavanone from the flavonoid group of polyphenols. Chemically known as 5,7-dihydroxy-2-(4-hydroxyphenyl)chroman-4-one, it is a common dietary polyphenolic constituent of citrus fruits. It is also systematically named 2,3-dihydro-5,7-dihydroxy-2-(4-hydroxyphenyl)-4H-1-benzopyran-4-one and is alternatively known as 4′,5,7-trihydroxyflavanone. Naringenin has the skeleton structure of a flavanone with three hydroxy groups at the 4′, 5, and 7 carbons.

It may be found both in the aglycone form, naringenin, or in its glycosidic form, naringin, which has the addition of the disaccharide neohesperidose attached at the 7-position. Naringenin is also produced by the cyclization of 2′,4′,6′,4-tetrahydroxychalcone (naringenin chalcone). This bioflavanone occurs naturally in an inactive form as naringin and is converted into its active form, naringenin, by bacteria belonging to the gut microbiome.

Albert Szent-Györgyi, the Hungarian scientist who won the 1937 Nobel Prize in Physiology or Medicine for his research on vitamin C, was the one who initially found and isolated naringenin in the early 1930s. The name "naringenin" likely originates from the Sanskrit word for orange, "narang."

Natural Sources

Naringenin is commonly found in citrus fruits, especially as the predominant flavanone in grapefruit. The best sources of it are grapefruit, sour orange, tart cherries, tomatoes, grapes, and Greek oregano. It is also found in smaller amounts in bergamot, beans, fenugreek, milk thistle, tea, coffee, cocoa, and red wine.

Naringenin is highly expressed in citrus plants such as grapefruit, shaddock peel, orange peel, and potato peel, and in traditional Chinese medicine plants such as Huyou peel, Phellinus igniarius, and Ilex centrochinensis. As one of the most important representatives of flavonoid compounds, it is a component of the everyday human diet, where it is responsible for the color and bitter-sour taste of food.

Common Forms and Preparations

Naringenin is commercially available in several forms. As a dietary supplement it is typically offered in oral capsule or tablet form, either as the isolated aglycone or as a standardized citrus extract. Naringenin suffers from low oral bioavailability critically limiting its clinical potential; to address this, complexation with β-cyclodextrin (an FDA-approved excipient) has been investigated. Hydroxypropoyl-β-cyclodextrin (HPβCD) specifically increased the solubility of naringenin by over 400-fold, and its transport across a Caco-2 model of the gut epithelium by 11-fold. Other emerging delivery approaches under active preclinical research include nanoparticle formulations. Naringenin's poor solubility and limited oral bioavailability hinder clinical translation, and advanced nanocarrier-based delivery systems have been engineered to facilitate blood–brain barrier penetration and sustained brain targeting, markedly improving cognitive outcomes in animal models.

2. Traditional and Historical Use

Since ancient times, citrus fruits have been utilized as natural herbal treatments in traditional medicine. However, naringenin as an isolated compound was not identified until the twentieth century, and does not appear specifically in historical herbal records in its pure form. The broader tradition involves citrus preparations.

The dried, immature fruit of Citrus aurantium L., "Zhiqiao" in Chinese, has been used to treat cardiovascular diseases in traditional Chinese medicine for centuries. Naringenin and hesperetin and their glycosides are present in considerable amounts (about 10–15%) in this herb. Naringin (the glycosidic precursor of naringenin) is one of the most widely used active compounds in Chinese herbal medicine.

Naringin and naringenin are the main bioactive polyphenols in citrus fruits, the consumption of which is beneficial for human health and has been practiced since ancient times. The historical role of these compounds was embedded in the use of entire citrus preparations — peels, juices, and decoctions — rather than in the isolated aglycone. Naringin was first discovered in grapefruit flowers by De Vry in 1857; however, the results of his research were not published at that time. Asahina and Inubuse identified and characterized the chemical structure and molecular formula of naringin in 1928.

3. Key Constituents, Biosynthesis, and Active Compounds

Naringenin is the primary bioactive aglycone in its class. Its biosynthesis in plants proceeds from phenylalanine through the phenylpropanoid pathway: it is biosynthetically combined with malonyl-CoA to yield chalcones, which contain two phenyl rings. In the case of naringenin, the precursor is naringenin chalcone produced by the enzyme chalcone synthase.

In food and supplements, naringenin may be encountered as:

Naringenin aglycone (free form): the bioactive compound absorbed after gut metabolism.
Naringin (naringenin-7-O-neohesperidoside): the major glycosidic form found in grapefruit and citrus peels. It is composed of the flavanone naringenin bonded to a disaccharide (rhamnose and glucose). Once ingested, naringin is typically metabolized in the intestines by gut flora to form naringenin, which is more bioactive and better studied.
Naringenin chalcone: the open-chain precursor of naringenin found in some citrus peels and plant tissues.

Research confirms naringenin and 3-(4′-hydroxyphenyl)propanoic acid as the predominant metabolites which contribute to the pharmacological effects of naringin.

4. Established Mechanisms of Action

Antioxidant Activity

The ameliorative effects of naringenin are primarily attributed to its anti-inflammatory (via inhibiting recruitment of cytokines and inflammatory transcription factors) and antioxidant (via scavenging of free radicals, bolstering of the endogenous antioxidant defense system, and metal ion chelation) effects. Naringenin also inhibits a number of aspects of oxidative stress, including lipid peroxidation and superoxide anion production, as well as restoring GSH levels in UVB-induced oxidative stress. Furthermore, naringenin increases SOD in experimental stroke models, highlighting its wide-acting induction of endogenous antioxidants. Naringenin also induces nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/heme oxygenase (HO)-1 in CCl₄-induced hepatic inflammation.

Anti-Inflammatory Activity

Naringenin has been reported to exert potent anti-inflammatory activity through the inhibition of the nuclear factor kappa B (NF-κB) signaling pathway. NF-κB stimulates the expression of several important inflammatory proteins such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), cyclooxygenase-2 (COX-2), interleukin-1 (IL-1), and inducible nitric oxide synthase (iNOS). Results from in vitro studies and in vivo animal models indicate that naringenin can downregulate the expression of several inflammatory markers such as TLR4, TNF-α, IL-1β, IL-6, iNOS, and COX-2 through the attenuation of the NF-κB pathway and the activation of AMP-activated protein kinase (AMPK), which is associated with the inhibition of multiple pro-inflammatory signaling pathways.

The flavanones naringin and naringenin have various anti-inflammatory properties and act via the inhibition of regulatory enzymes, changes in arachidonic acid metabolism, modulation of gene expression, and effects on transcription factors that play essential roles in controlling mediators involved in inflammation.

AMPK Activation and Metabolic Signaling

Naringenin stimulates glucose uptake in L6 myotubes in a dose- and time-dependent manner. Maximum stimulation was seen with 75 μM naringenin for 2 hours (192.8 ± 24%, p<0.01), a response comparable to maximum insulin response (190.1 ± 13%, p<0.001). Naringenin did not have a significant effect on basal or insulin-stimulated Akt phosphorylation while significantly increasing AMPK phosphorylation/activation. Furthermore, silencing of AMPK, using an siRNA approach, abolished the naringenin-stimulated glucose uptake. These data show that naringenin increases glucose uptake by skeletal muscle cells in an AMPK-dependent manner.

CYP450 Modulation

Naringenin was found to inhibit the cytochrome P450 (CYP) 3A4-mediated oxidation of two dihydropyridine cardiodepressive drugs, more markedly than naringin. Interactions between naringenin and the cytochrome P450 (CYP) system have been of interest since the first demonstration that grapefruit juice reduced CYP3A activity. Naringenin was also found to inhibit the activity of CYP isoforms that activate the potent environmental carcinogen, nicotine-derived nitrosamine ketone (NNK).

Hepatic Lipid Metabolism (PPARα)

The grapefruit flavonoid naringenin dose-dependently inhibits HCV production without affecting intracellular levels of the viral RNA or protein. Naringenin blocks the assembly of intracellular infectious viral particles, upstream of viral egress. This antiviral effect is mediated in part by the activation of PPARα, leading to a decrease in VLDL production without causing hepatic lipid accumulation in Huh7.5.1 cells and primary human hepatocytes.

Nrf2 Pathway

A mechanism associated with hepatoprotection is the ability of naringenin to induce the endogenous antioxidant system by upregulating Nrf2. The administration of 50 mg/kg of naringenin to rats significantly increased Nrf2 protein levels in the cytoplasm and nucleus, elevating mRNA levels of its target genes, such as HO-1, NQO1, and GST; in addition, naringenin can prevent the decrease in Nrf2, HO-1, and SOD protein levels exerted by CCl₄ treatment in mice.

TGF-β / Smad and Antifibrotic Activity

Naringenin reversed JNK activation and Smad3 phosphorylation in the linker domain, as well as total protein and total Smad3 mRNA. These results demonstrate that naringenin blocks TGF-β–Smad3 and JNK–Smad3 pathways, thereby conferring antifibrotic effects.

5. Scientific Evidence by Area of Use

5.1 Cardiovascular Health

Emerging evidence has revealed that naringenin displays anti-inflammatory and antioxidant activities, which are thought to be required for its efficacy in treating inflammatory-associated atherosclerosis, arthritis, and metabolic syndrome. Naringenin consistently exhibited antioxidant, anti-inflammatory, and vasoprotective effects across all study types. Mechanistic studies highlighted the modulation of key signaling pathways, including PI3K/Akt, NF-κB, Nrf2, the renin-angiotensin system (RAS), and enhancement of KATP channel expression, as well as its ability to inhibit apoptosis, autophagy, and ferroptosis.

Animal/Preclinical Evidence: In animal experiments, it has been reported that naringenin can reduce blood fat, and reduce the levels of cholesterol, triglycerides, and low-density lipoprotein (LDL-C) in serum, thereby reducing the onset and development of atherosclerosis. In animal models, naringin improved endothelium-dependent vasorelaxation, reduced infarct size, and preserved myocardial function.

Human/Clinical Evidence: Compared to preclinical studies, few studies have examined the effects of naringin in humans. Although still limited, evidence on the cardiovascular effects of naringin in humans stems from dietary intervention studies and clinical trials. A randomized controlled trial reported significant improvements in cardiometabolic parameters in adults who received naringin for 90 days, showing a favorable lipid-modulating effect. Notably, one trial also documented improved arterial stiffness (reduced pulse wave velocity) with naringin-rich grapefruit juice.

Human trials reported beneficial effects on lipid profiles, arterial stiffness, and adiponectin levels. Naringin demonstrates strong potential as a dietary adjunct for cardiovascular protection, especially in the context of ischemic injury and vascular dysfunction. Further well-designed clinical trials are needed to define optimal dosing strategies and improve its bioavailability in humans.

Evidence Strength: Predominantly preclinical (animal and in vitro). Human trials are small, short, and limited in number. The evidence base is preliminary and insufficient to draw definitive conclusions about cardiovascular outcomes in humans.

5.2 Metabolic Syndrome, Diabetes, and Obesity

Naringenin, a flavonoid found in high concentrations in grapefruit, has been reported to have antioxidant, antiatherogenic, and anticancer effects. Effects on lipid and glucose metabolism have also been reported.

Human/Clinical Evidence: A key early-phase clinical trial (NCT03582553) tested naringenin isolated from Citrus sinensis extract. This study evaluated the safety and pharmacokinetics of naringenin in healthy adults consuming a whole orange extract. In a single ascending dose randomized crossover trial, 18 adults ingested doses of 150 mg, 300 mg, 600 mg, and 900 mg of naringenin or placebo. Each dose or placebo was followed by a washout period of at least one week. There were no relevant adverse events or changes in blood safety markers following ingestion of all naringenin doses.

Although several experimental models have suggested promising pharmacological effects of naringenin in the management of obesity and its related disorders, the effects of naringenin supplementation on cardiovascular disorders as one of the main complications of NAFLD are yet to be examined in large trials. In one double-blind, placebo-controlled, randomized clinical trial, 44 overweight/obese patients with NAFLD were equally allocated into either naringenin or placebo groups for 4 weeks. Cardiovascular risk factors including atherogenic factors, hematological indices, obesity-related parameters, blood pressure, and heart rate were assessed pre- and post-intervention. These data indicated that naringenin supplementation may be a promising treatment strategy for cardiovascular complications among NAFLD patients. However, further trials are warranted.

Most of the data reported have been obtained from in vitro or in vivo studies. Although some clinical studies have also been performed, the main focus is on naringenin bioavailability and cardioprotective action. These studies were done in compromised patients (i.e., hypercholesterolemic and overweight), with a dosage ranging between 600 and 800 μM/day, whereas the effect on healthy volunteers is still debatable.

Evidence Strength: Preclinical evidence is substantial; human clinical trial data remain sparse, with trials limited by small sample sizes and short durations. Metabolic effects in humans are considered promising but not yet established.

5.3 Hepatoprotective Activity and NAFLD

Flavonoids, a group of natural compounds, have garnered great attention in the management of NAFLD because of their profitable effects on glucose and lipid metabolism, inflammation, and oxidative stress, which are the pivotal pathophysiological pathways in NAFLD. Naringenin is a citrus-derived flavonoid with a broad spectrum of potential biological effects including anti-inflammatory and antioxidant properties, which may exert protective effects against NAFLD.

Naringenin attenuated ROS production, ROS-induced lipid peroxidation, and replenished reduced antioxidant armory, namely catalase (CAT), glutathione reductase (GR), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH). Naringenin similarly diminished expression of Cox-2 and levels of NF-κB and other inflammatory molecules induced by doxorubicin treatment. These findings are from animal (rat) models.

The results demonstrate that naringenin blocks TGF-β–Smad3 and JNK–Smad3 pathways, making it a good candidate for properly performed clinical studies in liver fibrosis.

The favorable effects of naringenin, along with its potency and efficacy compared with other antioxidants, indicate that naringenin may be a promising therapeutic approach for the management of NAFLD and associated complications. However, due to the lack of clinical trials, future robust human randomized clinical trials that address the effects of naringenin on NAFLD and other liver-related diseases are crucial. Further careful human pharmacokinetic studies are also needed to establish dosage ranges, as well as addressing preliminary safety and tolerability of naringenin, before proceeding to larger-scale endpoint trials.

Evidence Strength: Predominantly animal and cell-based. The hepatoprotective mechanisms are well-characterized preclinically. Human clinical data specific to liver outcomes are lacking.

5.4 Antiviral Activity (Hepatitis C Virus)

The grapefruit flavonoid naringenin dose-dependently inhibits HCV production without affecting intracellular levels of the viral RNA or protein. Naringenin blocks the assembly of intracellular infectious viral particles, upstream of viral egress. Long-term treatment with naringenin leads to a rapid 1.4 log reduction in HCV, similar to 1000 U of interferon. The data demonstrate that naringenin is a non-toxic assembly inhibitor of HCV and that other PPARα agonists play a similar role in blocking viral production. The combination of naringenin with STAT-C agents could potentially bring a rapid reduction in HCV levels during the early treatment phase, an outcome associated with sustained virological response.

A study on whether naringenin can prevent hepatitis C virus infection is ongoing.

Evidence Strength: Currently based on cell-based models (JFH1/Huh7.5.1 cell system) and primary human hepatocytes in vitro. No completed human clinical trials have established antiviral efficacy in HCV-infected patients. This area is considered early-stage and hypothesis-generating.

5.5 Anticancer Activity

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. Naringenin has been reported to increase cell apoptosis and growth arrest of tumor cells, including those that cause cervical, bladder, prostate, and breast cancers.

The anticancer activities are pleiotropic, and naringin and naringenin can modulate different cellular signaling pathways, suppress cytokine and growth factor production, and arrest the cell cycle. Naringenin enhances gut microbiota diversity by increasing the abundance of beneficial bacterial species while reducing opportunistic pathogenic bacteria. A fecal microbiota transplantation assay demonstrated that the anti-HFD-CRC (high-fat-diet colorectal cancer) activity of naringenin depended on the gut microbiota. Furthermore, naringenin antagonized the IL-6/STAT3 pathway.

Evidence Strength: Exclusively preclinical (cell lines and rodent models). No human clinical trials have evaluated naringenin as a cancer treatment or preventive agent. The anticancer evidence is preliminary and mechanistic in nature.

5.6 Neuroprotection and Neurodegenerative Disease

Naringenin, a natural flavonoid widely present in citrus fruits, has been reported to penetrate the blood-brain barrier and exert anti-inflammatory effects in the central nervous system. In APP/PS1 mice (an Alzheimer's disease model), NRG treatment improved learning and memory ability. Furthermore, NRG significantly reduced Aβ deposition, microglial and astrocytic activation, and pro-inflammatory cytokine levels.

Phosphorylation of tau protein was suppressed, indicating that naringenin interferes with key pathogenic processes in Alzheimer's disease, including both amyloidogenesis and tauopathy. Naringenin modulates estrogen receptor and PI3K/Akt signaling, contributing to enhanced neuronal viability and reduced apoptosis. Notably, its ability to inhibit acetylcholinesterase suggests promise for restoring cholinergic neurotransmission.

In a rotenone model of Parkinson's disease, naringenin was found to have neuroprotective effects. Naringenin treatment not only restored cognitive performance in object recognition and maze tasks but also normalized oxidative markers by increasing CAT and SOD activities and decreasing MDA levels. Moreover, the compound effectively inhibited AChE activity, demonstrating its potential to preserve cholinergic neurotransmission.

This field highlights the multifaceted mechanisms and delivery strategies of naringenin in Alzheimer's disease, and underscores the need for well-designed clinical trials to confirm its efficacy and safety in humans.

Evidence Strength: Entirely preclinical (animal models and cell lines). No human clinical trials for neurodegenerative disease endpoints have been completed. Evidence is preliminary.

5.7 Anti-Inflammatory Effects (Arthritis and Inflammatory Pain)

Naringenin demonstrated therapeutic efficacy in a collagen-induced arthritis (CIA) model by reducing inflammation, modulating cytokine levels, and enhancing antioxidant capacity. The activation of autophagy through the AMPK/ULK1 signaling pathway appears to play a critical role in naringenin's anti-inflammatory effects. These findings are from animal models only and have not been confirmed in human arthritis trials.

6. Bioavailability and Pharmacokinetics

Naringenin is an aglycone; however, it is typically stored as a glycoside in plants, most commonly attached to either d-glucose or l-rhamnose. After ingestion, naringenin and its glycosides will pass through the small intestine unabsorbed and enter the large intestine, which is host to the gut microbiota. Bioavailability of naringenin depends on removal of the sugar groups by the gut microbiota to produce the aglycone naringenin, which can then be absorbed in the large intestine.

Naringenin was absorbed well throughout the gastrointestinal tract but mainly in the small intestine and colon (mean permeability coefficient 7.80 (SD 1.54) × 10⁻⁴ cm/s and 5.49 (SD 1.86) × 10⁻⁴ cm/s, respectively).

Naringenin (as naringin) has attracted considerable interest due to its multifaceted biological actions and potential cardioprotective role, though its clinical translation is limited by low oral bioavailability (<5%), prompting research into advanced delivery systems like liposomal encapsulation. Naringenin suffers from low oral bioavailability, critically limiting its clinical potential.

Under the metabolism mediated by human gut microbiota, naringin could be an active precursor for derived metabolites to play important physiological roles. Analysis of growth curves revealed that the gut microbe Ruminococcus gauvreauii was unaffected by naringenin, Bifidobacterium catenulatum was slightly enhanced by naringenin, and Enterococcus caccae was severely inhibited by naringenin.

Naringenin pharmacokinetics still need further investigation. Some studies investigated naringenin as a complex food supplement (i.e., whole orange juice), constituted by several polyphenols (including naringenin), making it difficult to assess the single phytochemical's contribution.

The fate and biological functions of naringenin in vivo are unknown, remaining under preliminary research, as of 2024.

7. Dosage Forms and Reported Study Dosages

The following dosages are reported from specific published studies and registered clinical trials:

NAFLD/Cardiovascular RCT (Springer Trials Protocol): Forty-four eligible overweight/obese subjects with NAFLD received naringenin capsules or identical placebo (each capsule containing 100 mg of naringenin or cellulose), twice daily for 4 weeks.
Safety and Pharmacokinetics Study (NCT03582553 — Phase I Crossover): A study evaluated safety and pharmacokinetics of naringenin in healthy adults consuming a whole orange (Citrus sinensis) extract. In a single ascending dose randomized crossover trial, 18 adults ingested 150 mg, 300 mg, 600 mg, and 900 mg doses of naringenin or placebo. Each dose or placebo was followed by a washout period of at least one week.
Clinical studies targeting cardiovascular endpoints (review summary): Studies in compromised patients (hypercholesterolemic and overweight) were done with a dosage ranging between 600 and 800 μM/day.
Animal studies (rat, for reference only): Administration of 50 mg/kg of naringenin to rats significantly increased Nrf2 protein levels. Sprague-Dawley rats were treated with naringenin at 50 mg/kg/day and subjected to myocardial ischemia-reperfusion surgery. These animal dosages are not directly translatable to human dosing.

It is vital that the safety of naringenin is evaluated when administered to humans at higher doses. The maximum recommended starting dose (MRSD) for naringenin may be estimated at approximately 135 mg, since no adverse events were reported at this dose. The first dose in the phase I trial was 150 mg, the MRSD for the practical purpose of preparing the capsule of an extract from oranges containing 30% naringenin.

According to ClinicalTrials.gov, clinical studies on naringenin and citrus fruit extracts are actively underway. Clinical studies using extracts have confirmed the safety and pharmacokinetics of naringenin. The serum naringenin concentration was confirmed after the oral administration of citrus extracts.

8. Body Systems and Health Areas of Association

Based on the available preclinical and limited clinical literature, naringenin has been studied across the following body systems:

Cardiovascular system: Lipid modulation, antiatherogenic activity, endothelial function, arterial stiffness, myocardial ischemia-reperfusion protection.
Hepatic system: Hepatoprotection against chemical and drug-induced liver injury, antifibrotic effects, NAFLD management.
Metabolic system: Glucose homeostasis, insulin sensitization, AMPK activation, adiponectin upregulation, management of hyperlipidemia.
Nervous system: Neuroprotection, Alzheimer's disease pathology modulation, Parkinson's disease models, cholinergic neurotransmission.
Immune and inflammatory system: NF-κB and MAPK pathway suppression, cytokine downregulation, arthritis models.
Oncology: Pro-apoptotic and antiproliferative activity in multiple cancer cell lines.
Antiviral (hepatic): HCV assembly inhibition via PPARα activation in cell models.
Gut microbiome: Modulation of specific bacterial species and dependence of certain effects on microbiome metabolism.

Investigated areas include metabolic disorders such as diabetes, obesity, hyperlipidemia, hypertension, cardiac toxicity, hypertrophy, steatosis, liver disease, and arteriosclerosis, as well as neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.

9. Safety Considerations and Drug Interactions

General Safety

The fate and biological functions of naringenin in vivo are unknown, remaining under preliminary research, as of 2024. High consumption of dietary naringenin is generally regarded as safe, mainly due to its low bioavailability. Safety profiles in rodents indicate low toxicity at therapeutic doses, reinforcing its viability as a candidate compound. Oral administration of naringin (1250 mg/kg/day) for six consecutive months showed no adverse effects in Sprague-Dawley rats. In the human phase I ascending dose trial, there were no relevant adverse events or changes in blood safety markers following ingestion of all naringenin doses (150 mg, 300 mg, 600 mg, and 900 mg).

CYP450 Enzyme Interactions

Taking dietary supplements or consuming grapefruit excessively may impair the action of anticoagulants and increase the toxicity of various prescription drugs. Similar to furanocoumarins present in citrus fruits, naringenin may evoke CYP3A4 suppression in the liver and intestines, possibly resulting in adverse interactions with common medications.

It is important to note that research has clarified the relative roles of naringenin versus furanocoumarins in grapefruit interactions: a 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. It was previously thought that flavonoids such as naringin or naringenin were the main biologically active components in grapefruit juice, but research has shown that a naringenin solution had virtually no effect on the disposition of certain hormones.

However, at pharmacological (supplemental) doses above normal dietary intake, naringenin's own CYP effects may become relevant: naringenin was found to inhibit CYP3A4-mediated oxidation of two dihydropyridine cardiodepressive drugs, more markedly than naringin. Naringenin also inhibited quinine 3-hydroxylation mediated by CYP3A4, although other components of grapefruit juice are more active.

Specific Drug Interactions

A well-known interaction is with statin drugs, which are used to reduce cholesterol. Because naringenin can prevent statins from being metabolized, blood levels of these medications may rise, increasing the possibility of adverse effects such as muscle damage. Similarly, naringenin may interfere with immunosuppressants, anticoagulants, blood pressure medicines, and sedatives, among other drugs.

The probable mechanism of statin interaction involves the inhibition of CYP3A4-mediated first-pass metabolism in the small intestine. Bergamottin and naringenin could therefore be applied as markers in food-drug interaction studies in order to adjust posology, and the dose of simvastatin should accordingly be reduced.

CYP3A4 is particularly essential, because it is involved in the bioinactivation of about 50% of all drugs. CYP3A4 is located in epithelial cells (enterocytes) lining the small intestines and colon, and in the parenchymal cells of the liver. Drugs that are substrates of this enzyme — including certain calcium channel blockers, immunosuppressants (cyclosporine), some antifungals, and benzodiazepines — may be subject to altered pharmacokinetics when naringenin is co-administered at supplemental doses.

Limitations of the Current Evidence Base

Naringenin's ability to improve endothelial function has been well-established preclinically. Indeed, the currently available data are very promising, but further research on pharmacokinetic and pharmacodynamic aspects is encouraged to improve both available production and delivery methods and to achieve feasible naringenin-based clinical formulations. Naringenin pharmacokinetics still need further investigation. As of 2024, the fate and biological functions of naringenin in vivo remain under preliminary research.

References

Health Conditions

Health conditions that Naringenin may help support.

Arterial HealthScientific
Naringenin is a citrus flavanone (from grapefruit and oranges) with documented arterial benefits including endothelial eNOS activation, inhibition of LDL oxidation, ACE inhibition, and anti-inflammatory effects. Multiple in vitro and animal studies confirm anti-atherosclerotic properties, and limited clinical data show lipid improvements and endothelial protection.

Body Systems

Body systems that Naringenin may help support.

No body systems available.