Hesperidin

    Written by:
    Giulia Guerrini

    Fact-checked

    by:

    Nick Milazzo
    Last Updated: October 5, 2023

    Hesperidin, found abundantly in orange peels and various citrus fruits, exhibits promising potential in reducing risk factors associated with cardiovascular disease, such as triglycerides and total cholesterol. Additionally, it appears to some have anti-inflammatory properties. While other potential benefits of hesperidin exist, further clinical studies are required to fully understand its range of effects.

    What is hesperidin?

    Hesperidin is a flavanone glycoside (a type of flavonoid) that was isolated from the spongy inner peel of oranges, which is known as the mesocarp.[5]

    Hesperidin (Hsd) is prominently found in citrus fruits like oranges, lemons, clementines, mandarins, and grapefruits. The name hesperidin is derived from the word “hesperidium”, a word for a berry with a pulpy, segmented interior and a leathery rind containing aromatic oils.[6][7] Its aglycone (i.e., missing a glycosyl group) form is called hesperetin (Hst).[8]

    What are the other forms of hesperidin?

    What are hesperidin’s main benefits?

    Trials of the anti-inflammatory properties of hesperidin have yielded mixed results. One meta-analysis found that hesperidin, whether consumed through citrus juice or oral supplements, reduced the pro-inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-4 (IL-4) in a non-dose-dependent manner. However, a second meta-analysis did not replicate these findings for CRP and IL-6, although it did find a significant decreased in levels of the inflammatory marker vascular cell adhesion molecule-1 (VCAM-1). These conflicting outcomes could be attributed to variability in study quality, methodology, and participant characteristics, necessitating further research to validate the anti-inflammatory properties of hesperidin.[9][1]

    Additionally, one meta-analysis indicated that hesperidin supplementation led to significant reduction of several cardiovascular disease (CVD) risk factors. These benefits included decreased triglyceride (TG) levels, total cholesterol (TC), low-density lipoprotein (LDL) levels, tumor necrosis factor (TNF-α), and systolic blood pressure (SBP). Notably, these effects were predominantly observed with hesperidin doses exceeding 500 mg per day and were considerably influenced by factors such as the duration of hesperidin treatment (typically more effective when exceeding 6 weeks) and participants’ BMI, age, and overall health status.[10]

    Hesperidin also appears to promote blood flow, as demonstrated in one randomized controlled trial (RCT) involving participants with metabolic syndrome who took 500 mg of hesperidin daily for 3 weeks. Hesperidin improved blood flow by 2.5%, as assessed by flow-mediated dilation (FMD).[11] Another study noted an improvement in microcirculation (blood flow in the small vessels) 6 hours after supplementation on a full stomach with either hesperidin capsules or standardized orange juice given for 4 weeks to healthy but overweight men.[12] Despite these results being promising, it is still unclear whether these effects are long-lasting and whether they have an impact on blood pressure.

    Furthermore, one RCT evaluated the impact of a synthetic form of hesperidin, hesperidin methyl chalcone (HMC), on muscle damage and pain associated with delayed onset muscle soreness (DOMS) induced by an intense anaerobic exercise protocol. HMC supplementation improved muscle recovery, performance, and postural balance. The group taking HMC also showed increased physical performance (measured by the number of repetitions to failure) and improved muscle soreness during passive quadriceps palpation, although not during activities like walking up and down the stairs.[2]

    What are some other potential benefits of hesperidin?

    What are hesperidin’s main drawbacks?

    Studies have not yet reported any side effects associated with hesperidin supplementation. However, it’s important to note that the absence of side effects in research does not definitively rule them out, and further investigation is warranted. One study found that a 500 mg dose of hesperidin methyl chalcone (HMC) did not affect renal and hepatic function markers.[2]

    One meta-analysis found that hesperidin supplementation was linked to an increase in body weight, which could potentially be concerning for people with obesity or overweight. However, this effect has not been consistently observed in other studies, and it may be influenced by many factors beyond hesperidin supplementation.[10]

    Does hesperidin interact with any medications?

    How does hesperidin work?

    The precise mechanism of action of hesperidin is still unknown. However, a number of studies (mostly animal studies), have highlighted potential pathways through which hesperidin may exert its effects.

    Hesperidin may improve lipid metabolism via several potential mechanisms: In rat models, a possible pathway involves inhibiting cholesterol synthesis by downregulating the expression of retinol-binding protein (RBP), heart fatty acid binding protein (H-FAB), and cutaneous fatty acid-binding protein (C-FAB). Animal studies suggest that hesperidin may also inhibit the enzymes 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and acyl coenzyme A: cholesterol acyltransferase (ACAT), which play a role in cholesterol biosynthesis.[10]

    Furthermore, clinical studies on G-hesperidin (see FAQ “What are the other forms of hesperidin?”) suggest that it enhances very low density lipoprotein (VLDL) catabolism, leading to reduced TG and LDL levels. G-hesperidin also appeared to work by activating the lipoprotein lipase (LPL), an enzyme responsible for hydrolyzing TG. In vitro studies further suggested that G-hesperidin may suppress excessive liver LDL secretion by decreasing the release of apolipoprotein B (a key LDL component).[10]

    Regarding its anti-inflammatory effect, both in vitro and in vivo studies suggest that hesperidin may reduce inflammation by suppressing the expression of inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), along with inflammatory markers (e.g., TNF-α, IL-6), thereby reducing prostaglandin levels.[10]

    Additionally, one hypothesis explaining hesperidin’s blood pressure-lowering effect is that it increases nitric oxide (NO) production, which induces vasodilation by relaxing blood vessels smooth muscles, leading to a reduction in blood pressure. Another potential mechanism involves hesperidin reducing levels of the vasoconstrictor angiotensin-2 through inhibition of the angiotensin-converting enzyme.[10] It’s worth noting that these mechanisms remain hypothetical, and require clinical confirmation.

    Hesperidin and hesperetin also appear to moderately increase blood flow either by stimulating the production of intracellular hydrogen peroxide, which activates the Src family kinase, a group of enzymes that regulate the production of nitric oxide in blood vessels, or through estrogen signaling, which is also involved in the production of nitric oxide.[11][13]

    What affects hesperidin’s bioavailability?

    What are other names for Hesperidin?

    Note that Hesperidin is also known as:

    • hesperitin-7-O-rutinoside
    • Hesperitin glycoside
    • glucosyl hesperidin
    • Vitamin P
    • hesperitin
    • G-hesperidin
    • 3' 5 7-trihydroxy-4'-methoxyflavanone

    Hesperidin should not be confused with:

    • Hesperitin (its aglycone)
    • Eriodictyol (another flavonoid known as Vitamin P)

    Dosage information

    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.[1]

    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. HMC concentration typically peaks 1–2 hours after oral administration.[2]

    When it comes to food products, the amount of hesperidin contained in orange juice or other citrus peels (e.g., tangerine peel) may vary depending on multiple factors. As a result, establishing a recommended quantity of specific foods containing hesperidin to achieve effects similar to those obtained with oral supplements is challenging. For instance, one study analyzing the composition of citrus juices found hesperidin concentrations ranging from 20–60 mg/100 ml in orange juice, 8–46 mg/100 ml in tangerine juice, 4–41 mg/100 ml in lemon juice, and 2–17 mg/100 ml in grapefruit juice.[3] Sun-dried tangerine peels, used in traditional Chinese medicine, appear to confer such a substantial dose of hesperidin that additional supplementation may not be required. These peels may be made more palatable by blending them into a shake.[4]

    Frequently asked questions

    What is hesperidin?

    Hesperidin is a flavanone glycoside (a type of flavonoid) that was isolated from the spongy inner peel of oranges, which is known as the mesocarp.[5]

    Hesperidin (Hsd) is prominently found in citrus fruits like oranges, lemons, clementines, mandarins, and grapefruits. The name hesperidin is derived from the word “hesperidium”, a word for a berry with a pulpy, segmented interior and a leathery rind containing aromatic oils.[6][7] Its aglycone (i.e., missing a glycosyl group) form is called hesperetin (Hst).[8]

    What are the other forms of hesperidin?

    Glucosyl-hesperidin (G-Hesperidin) is a synthetically modified form of hesperidin with three (instead of two) glycoside groups. This modification greatly enhances its water solubility and bioavailability compared to regular hesperidin.[14] Once ingested, G-hesperidin is converted to hesperidin, which is then converted into hesperetin in the colon.

    Another synthetic variant of hesperidin is hesperidin-7,3'-O-dimethylether (HDME). This variant is more lipid-soluble and has higher phosphodiesterase inhibitory potential than hesperetin.[15]

    What are hesperidin’s main benefits?

    Trials of the anti-inflammatory properties of hesperidin have yielded mixed results. One meta-analysis found that hesperidin, whether consumed through citrus juice or oral supplements, reduced the pro-inflammatory markers C-reactive protein (CRP), interleukin-6 (IL-6), and interleukin-4 (IL-4) in a non-dose-dependent manner. However, a second meta-analysis did not replicate these findings for CRP and IL-6, although it did find a significant decreased in levels of the inflammatory marker vascular cell adhesion molecule-1 (VCAM-1). These conflicting outcomes could be attributed to variability in study quality, methodology, and participant characteristics, necessitating further research to validate the anti-inflammatory properties of hesperidin.[9][1]

    Additionally, one meta-analysis indicated that hesperidin supplementation led to significant reduction of several cardiovascular disease (CVD) risk factors. These benefits included decreased triglyceride (TG) levels, total cholesterol (TC), low-density lipoprotein (LDL) levels, tumor necrosis factor (TNF-α), and systolic blood pressure (SBP). Notably, these effects were predominantly observed with hesperidin doses exceeding 500 mg per day and were considerably influenced by factors such as the duration of hesperidin treatment (typically more effective when exceeding 6 weeks) and participants’ BMI, age, and overall health status.[10]

    Hesperidin also appears to promote blood flow, as demonstrated in one randomized controlled trial (RCT) involving participants with metabolic syndrome who took 500 mg of hesperidin daily for 3 weeks. Hesperidin improved blood flow by 2.5%, as assessed by flow-mediated dilation (FMD).[11] Another study noted an improvement in microcirculation (blood flow in the small vessels) 6 hours after supplementation on a full stomach with either hesperidin capsules or standardized orange juice given for 4 weeks to healthy but overweight men.[12] Despite these results being promising, it is still unclear whether these effects are long-lasting and whether they have an impact on blood pressure.

    Furthermore, one RCT evaluated the impact of a synthetic form of hesperidin, hesperidin methyl chalcone (HMC), on muscle damage and pain associated with delayed onset muscle soreness (DOMS) induced by an intense anaerobic exercise protocol. HMC supplementation improved muscle recovery, performance, and postural balance. The group taking HMC also showed increased physical performance (measured by the number of repetitions to failure) and improved muscle soreness during passive quadriceps palpation, although not during activities like walking up and down the stairs.[2]

    What are some other potential benefits of hesperidin?

    Certain animal and in vitro studies have identified potential additional benefits of hesperidin, but these findings await confirmation through clinical research.

    One study on rats found that rikkunshito (RKT), a traditional Japanese medicine containing hesperidin and other compounds, effectively countered chemotherapy-induced anorexia by increasing appetite. It is hypothesized that RKT inhibits the decrease in the expression of the growth hormone secretagogue receptor (GHS-R1a) receptor caused by cisplatin (a compound commonly used in chemotherapy) by acting as a 5-HT2B/2C serotonin receptor antagonist, therefore increasing the signal transduction of ghrelin (an appetite-stimulating hormone which binds to the GHS-R1a receptor).[16]

    Low doses of hesperidin (25 mg/kg in rats) demonstrated notable protection against prolonged toxicity when administered alongside nicotine in rat studies.[17][18]

    Another animal study found that a 5-week regimen of hesperidin reduced colonic tumor formation by 60%, induced by an injection of a carcinogenic toxin.[19]

    In mice, hesperidin also displayed anti-asthmatic and antiallergic properties by reducing the airways’ responsiveness to an antigen. The antiallergic effect was associated with reduced infiltration of immune cells (leukocytes and macrophages) into lung tissue.[20]

    Finally, hesperidin exhibited various neuroprotective effects in animal studies at standard oral doses. These effects appear to rely on suppressing errant nitric oxide signaling, thereby activating an antioxidant and anti-inflammatory defense.[21]

    What are hesperidin’s main drawbacks?

    Studies have not yet reported any side effects associated with hesperidin supplementation. However, it’s important to note that the absence of side effects in research does not definitively rule them out, and further investigation is warranted. One study found that a 500 mg dose of hesperidin methyl chalcone (HMC) did not affect renal and hepatic function markers.[2]

    One meta-analysis found that hesperidin supplementation was linked to an increase in body weight, which could potentially be concerning for people with obesity or overweight. However, this effect has not been consistently observed in other studies, and it may be influenced by many factors beyond hesperidin supplementation.[10]

    Does hesperidin interact with any medications?

    There are currently no human studies which have identified interactions between hesperidin and medications. However, some animal studies suggest potential drug-supplement interactions, warranting caution.

    Both hesperidin and hesperetin, albeit to different degrees, show inhibitory activity towards cytochrome P450 enzymes, notably CYP2C8 and CYP3A4, which play a role in the metabolism of various substances and medications. One study in rats indicated that orally administered hesperidin at 5-15 mg/kg (but not at 1 mg/kg) reduced the metabolism of the antiarrhythmic drug diltiazem, therefore increasing its overall and maximum plasma concentration. This suggests hesperidin’s potential to inhibit CYP3A4 or P-glycoprotein, which are responsible for expelling substances like toxins or drugs (such as diltiazem) and drug metabolites from cells.[22]

    In another animal study, rats receiving orange juice or a hesperidin supplement for eight weeks exhibited increased exposure and peak concentration of the cholesterol-lowering drug pravastatin. This effect might be attributed to the inhibition of a transporter protein that facilitates pravastatin efflux into the intestine following absorption.[23]

    How does hesperidin work?

    The precise mechanism of action of hesperidin is still unknown. However, a number of studies (mostly animal studies), have highlighted potential pathways through which hesperidin may exert its effects.

    Hesperidin may improve lipid metabolism via several potential mechanisms: In rat models, a possible pathway involves inhibiting cholesterol synthesis by downregulating the expression of retinol-binding protein (RBP), heart fatty acid binding protein (H-FAB), and cutaneous fatty acid-binding protein (C-FAB). Animal studies suggest that hesperidin may also inhibit the enzymes 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and acyl coenzyme A: cholesterol acyltransferase (ACAT), which play a role in cholesterol biosynthesis.[10]

    Furthermore, clinical studies on G-hesperidin (see FAQ “What are the other forms of hesperidin?”) suggest that it enhances very low density lipoprotein (VLDL) catabolism, leading to reduced TG and LDL levels. G-hesperidin also appeared to work by activating the lipoprotein lipase (LPL), an enzyme responsible for hydrolyzing TG. In vitro studies further suggested that G-hesperidin may suppress excessive liver LDL secretion by decreasing the release of apolipoprotein B (a key LDL component).[10]

    Regarding its anti-inflammatory effect, both in vitro and in vivo studies suggest that hesperidin may reduce inflammation by suppressing the expression of inflammatory enzymes such as inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), along with inflammatory markers (e.g., TNF-α, IL-6), thereby reducing prostaglandin levels.[10]

    Additionally, one hypothesis explaining hesperidin’s blood pressure-lowering effect is that it increases nitric oxide (NO) production, which induces vasodilation by relaxing blood vessels smooth muscles, leading to a reduction in blood pressure. Another potential mechanism involves hesperidin reducing levels of the vasoconstrictor angiotensin-2 through inhibition of the angiotensin-converting enzyme.[10] It’s worth noting that these mechanisms remain hypothetical, and require clinical confirmation.

    Hesperidin and hesperetin also appear to moderately increase blood flow either by stimulating the production of intracellular hydrogen peroxide, which activates the Src family kinase, a group of enzymes that regulate the production of nitric oxide in blood vessels, or through estrogen signaling, which is also involved in the production of nitric oxide.[11][13]

    What affects hesperidin’s bioavailability?

    Hesperidin is a molecule resistant to the stomach and to the enzymes of the small intestine, and it therefore remains intact until it reaches the colon. In the colon, hesperidin is metabolized by the intestinal microbiota into its aglycone form, hesperetin; a portion of this hesperetin is converted into secondary bioavailable metabolites, which then enter the bloodstream. This emphasizes the potential impact of an individual's microbiota on the bioavailability of hesperidin. However, factors beyond the gut microbiota also play a role. Hesperidin’s source (e.g., sweet orange, tangerines, oral supplements), its form (e.g., juice, capsule, soluble compound), and the processing and storage methods to which it has been subjected also affect its absorption in the lower gastrointestinal tract.[24] The combined effects of these variables likely contributes to the variablility in the outcomes observed in studies of hesperidin.

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