Hesperetin Extract
Also known as: Hesperetin, Hesperidin, citrus bioflavonoid, flavanone, (S)-2,3-dihydro-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)-4H-1-benzopyran-4-one, (2S)-5-hydroxy-2-(3-hydroxy-4-methoxyphenyl)-7-[(2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-[[(2R,3R,4R,5R,6S)-3,4,5-trihydroxy-6-methyloxan-2-yl]oxymethyl]oxan-2-yl]oxy-2,3-dihydrochromen-4-one
Overview
Hesperetin is a flavanone, a type of citrus bioflavonoid, primarily found in citrus fruits like oranges, lemons, and grapefruits. It exists naturally as its glycoside precursor, hesperidin, which is then hydrolyzed in the gut to the more bioavailable aglycone form, hesperetin. This compound is recognized for its potent antioxidant and anti-inflammatory properties. Research indicates its potential benefits in cardiovascular health, neuroprotection, and radioprotection. While preclinical data is robust, and growing clinical evidence supports some applications, large-scale human trials are still limited. Hesperetin's higher bioavailability compared to hesperidin makes it a focus for supplementation aimed at leveraging its therapeutic effects.
Benefits
Hesperetin, primarily consumed as its glycoside hesperidin, offers several evidence-based benefits. A meta-analysis of randomized controlled trials demonstrated that hesperidin supplementation significantly reduces serum triglycerides, total cholesterol, and LDL cholesterol in humans, indicating a benefit for cardiovascular health. Preclinical systematic reviews consistently show neuroprotective effects, reducing neuroinflammation and memory impairment in animal models of neurodegeneration (e.g., Alzheimer's, Parkinson's). Animal studies also suggest radioprotective properties, with hesperidin reducing radiation-induced DNA damage (e.g., 33% decrease in micronuclei in human lymphocytes) and accelerating wound healing. Beyond these primary effects, hesperetin exhibits strong anti-inflammatory actions by reducing pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and potent antioxidant activity by scavenging free radicals and upregulating endogenous antioxidant defenses. While beneficial for populations at risk of cardiovascular disease due to its lipid-lowering effects, clinical translation of neuroprotective and radioprotective benefits, largely observed in animal models, is still pending. Effects on blood glucose control in humans have not been found to be significant.
How it works
Hesperetin exerts its effects through multiple biological pathways. As an antioxidant, it directly scavenges reactive oxygen species (ROS) and upregulates the Nrf2/ARE pathway, enhancing the body's endogenous antioxidant defenses. Its anti-inflammatory action involves inhibiting the NF-κB pathway, which subsequently reduces the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6. In terms of lipid metabolism, hesperetin modulates hepatic lipid synthesis and clearance, contributing to its observed lipid-lowering effects. For neuroprotection, it reduces neuroinflammation, oxidative stress, and apoptosis in neuronal cells. Hesperidin, the glycoside form, has low bioavailability and must be hydrolyzed in the gut to hesperetin (the aglycone) for better absorption and systemic effects, with peak plasma levels typically occurring within hours of ingestion.
Side effects
Hesperetin is generally well tolerated in both clinical and preclinical studies. Common side effects are rarely reported, with mild gastrointestinal discomfort being the most frequent, though still uncommon. Uncommon side effects (1-5%) are not well documented, but mild allergic reactions are theoretically possible, especially in individuals with citrus allergies. Rare side effects (<1%) are very infrequent, and no significant adverse events have been consistently reported in clinical trials. While no major drug interactions have been definitively established, there is a theoretical potential for additive effects with anticoagulants or antiplatelet drugs due to hesperetin's anti-inflammatory properties. Contraindications are not established, but caution is advised for individuals with known citrus allergies. Safety in special populations such as pregnant or lactating women and children has not been established due to limited research.
Dosage
The minimum effective dose for hesperetin is not well established, as most human studies have utilized its glycoside form, hesperidin. Optimal dosage ranges typically involve 500–1000 mg of hesperidin daily. Due to hesperetin's higher bioavailability as an aglycone compared to hesperidin, a lower dose of pure hesperetin might be effective, though specific guidelines are less defined. Doses up to 1000 mg of hesperidin daily have appeared safe in clinical trials, but a maximum safe dose for hesperetin itself has not been formally established. Hesperetin can be taken with or without food, though absorption may be enhanced when consumed with meals. For optimal absorption, the aglycone form (hesperetin) is preferred over hesperidin, which requires hydrolysis in the gut. No specific cofactors are identified as necessary for its absorption or efficacy.
FAQs
Is Hesperetin safe to take daily?
Yes, hesperetin, primarily consumed as hesperidin, is generally considered safe for daily use. Clinical trials have shown good tolerability, with rare reports of mild gastrointestinal discomfort.
How long does it take to see benefits from Hesperetin?
For cardiovascular benefits like lipid-lowering, effects may be observed after several weeks of consistent supplementation. Neuroprotective and radioprotective effects are primarily supported by preclinical data.
Can Hesperetin replace my prescribed medications?
No, hesperetin is not a substitute for prescribed medications. Always consult your healthcare provider before making changes to your medication regimen or starting new supplements.
Does Hesperetin affect blood sugar levels?
Current research, including meta-analyses, indicates that hesperetin (via hesperidin) has minimal to no significant effect on blood glucose control in humans.
What is the difference between hesperetin and hesperidin?
Hesperidin is the glycoside form, meaning it has a sugar molecule attached, and is less bioavailable. Hesperetin is the aglycone form, without the sugar, and is more readily absorbed by the body after hesperidin is hydrolyzed in the gut.
Research Sources
- https://pmc.ncbi.nlm.nih.gov/articles/PMC10369082/ – This meta-analysis of randomized controlled trials investigated the effects of hesperidin supplementation on lipid profiles in humans. It found a significant reduction in serum triglycerides, total cholesterol, and LDL cholesterol, supporting hesperidin's role in cardiovascular health. The study utilized robust methodology, including a random effects model, but noted heterogeneity in dosing and study duration as limitations.
- https://pmc.ncbi.nlm.nih.gov/articles/PMC7402130/ – This systematic review focused on the neuroprotective effects of hesperetin in preclinical animal models of neurodegeneration. It consistently demonstrated that hesperetin reduced neuroinflammation and memory impairment. While providing strong preclinical evidence, the review highlighted the need for human clinical data to translate these findings.
- https://www.mdpi.com/1648-9144/55/7/370 – This systematic review explored the radioprotective properties of hesperetin in preclinical animal and cell models. Key findings included a reduction in radiation-induced DNA damage (e.g., 33% decrease in micronuclei) and accelerated wound healing. The review concluded that hesperetin shows promise as a radioprotective agent, though human clinical trials are currently lacking.
- https://www.mdpi.com/2072-6643/14/13/2647 – This source discusses the bioavailability of hesperidin and hesperetin, noting that hesperidin has low bioavailability due to its glycoside form and requires hydrolysis in the gut to hesperetin. Hesperetin, as the aglycone, exhibits higher bioavailability with peak plasma levels occurring within hours of ingestion. It also touches upon the lack of significant effect on blood glucose control in humans.
- https://journals.sagepub.com/doi/full/10.1177/1934578X211042540 – This research highlights the anti-inflammatory and antioxidant mechanisms of hesperetin. It explains that hesperetin scavenges free radicals, upregulates the Nrf2/ARE pathway, and inhibits NF-κB, thereby reducing pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6. This detailed mechanism of action underpins many of its observed health benefits.
