Hesperidin found in oranges and lemons
November 22 2015 by
Ray Sahelian, M.D.

Hesperidin is an abundant flavonoid found in citrus fruits. It is the predominant flavonoid in lemons and oranges. The peel and membranous parts of these fruits have the highest hesperidin concentrations. Therefore, orange juice containing pulp is richer in the flavonoids and hesperidin than that without pulp. Sweet oranges (Citrus sinensis) and tangelos are the richest dietary sources of hesperidin. Hesperidin is classified as a Citrus bioflavonoid. Hesperidin, in combination with a flavone glycoside called diosmin, is used in Europe for the treatment of venous insufficiency and hemorrhoids. Hesperidin, Rutin and other flavonoids thought to reduce capillary permeability and to have anti-inflammatory action were collectively known as vitamin P. These substances, however, are not vitamins and are no longer referred to, except in older literature, as vitamin P.

Hesperidin is an abundant and inexpensive by-product of citrus cultivation. A deficiency of hesperidin in the diet has been linked with abnormal capillary leakiness as well as pain in the extremities causing aches, weakness and night leg cramps. No signs of toxicity have been observed with normal intake or related compounds. Both hesperidin and its aglycone Hesperitin have been reported to possess a wide range of pharmacological properties.

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Supplement Facts:
Vitamin C -  (Ascorbic acid)
Citrus bioflavonoids
     (eriocitrin, hesperidin, flavonols, flavones, flavonoids, naringenin, and quercetin)
Mixed carotenoids
     (alpha carotene, astaxanthin, beta carotene, cryptoxanthin,
Lutein, Lycopene, Zeaxanthin)
Bilberry extract (Vaccinium myrtillus)
Eyebright extract (Euphrasia officianales)
Jujube extract (Zizyphus jujube)
Ginkgo biloba (Ginkgo biloba)
Suma extract (Pfaffia paniculata)
Mucuna pruriens extract (Cowhage)
Cinnamon (Cinnamomum zeylanicum)
Lycium berry extract (Lycium Barbarum) - also known as Goji Berry
Sarsaparila (Sarsaparilla Smilax)
Alpha lipoic acid also known as thiotic acid

Hesperidin has antioxidant and anti-inflammatory properties. Hesperidin can also act as a vasodilator, which may be useful in Hypertension.

Crit Rev Food Sci Nutr. 2015. Health-promoting Effects of the Citrus Flavanone Hesperidin. Hesperidin, a member of the flavanone group of flavonoids, can be isolated in large amounts from the rinds of some citrus species. Considering the wide range of pharmacological activities and widespread application of hesperidin, this paper reviews preclinical and clinical trials of hesperidin and its related compounds, including their occurrence, pharmacokinetics, and some marketed products available. Preclinical studies and clinical trials demonstrated therapeutical effects of hesperidin and its aglycone hesperetin in various diseases, such as neurological disorders, psychiatric disorders and cardiovascular diseases and others, due to its anti-inflammatory, antioxidant, lipid-lowering and insulin-sensitizing properties.

Kidney disease and cancer
Exp Mol Pathol. 2015. Chemopreventive efficacy of hesperidin against chemically induced nephrotoxicity and renal carcinogenesis via amelioration of oxidative stress and modulation of multiple molecular pathways.

Hesperidin Diosmin combination
Hesperidin, together with a flavone glycoside called diosmin, is used in Europe for the treatment of venous insufficiency and hemorrhoids. Diosmin is a flavonoid that can be isolated from various plant sources or derived from the flavonoid hesperidin.

Synergistic interaction between hesperidin, a natural flavonoid, and diazepam.
Eur J Pharmacol. 2005.
It has been recently reported the presence in Valeriana of the flavone 6-methylapigenin and the flavanone glycoside hesperidin. The apigenin derivative is a ligand for the benzodiazepine binding site in the gamma-aminobutyric acid receptor type A (GABA(A)) and has anxiolytic properties. Hesperidin has sedative and sleep-enhancing properties but is not a ligand for the benzodiazepine binding site. 6-Methylapigenin is able to potentiate the sleep-enhancing effect of hesperidin. In this work we demonstrate that this property is shared with various GABA(A) receptor ligands, among them the agonist diazepam, which was used to study the potentiation as measured in the hole board test. Isobolar analysis of the results showed the interaction being synergistic. We discarded pharmacokinetic effects or a direct action of hesperidin on the benzodiazepine binding site. A possible use of hesperidin properties to decrease the effective therapeutic doses of benzodiazepines is suggested.

Hesperidin, a citrus bioflavonoid, decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney.
BMC Pharmacol. 2005.
Exposure to CCl4 induces acute and chronic renal injuries. The present study was designed to establish the protective effect of hesperidin, a citrus bioflavonoid, on CCl4-induced oxidative stress and resultant dysfunction of rat liver and kidney. Animals were pretreated with Hesperidin (100 and 200 mg/kg orally) for one week and then challenged with CCl4 (2 ml/kg/s.c.) in olive oil. Rats were sacrificed by carotid bleeding under ether anesthesia. Liver enzymes, urea and creatinine were estimated in serum. Oxidative stress in liver and kidney tissue was estimated using Thiobarbituric acid reactive substances (TBARS), glutathione (GSH) content, superoxide dismutase(SOD), and Catalase (CAT) CCl4 caused a marked rise in serum levels of ALT and AST. TBARS levels were significantly increased whereas GSH, SOD and CAT levels decreased in the liver and kidney homogenates of CCl4 treated rats. Hesperidin (200 mg/kg) successfully attenuated these effects of CCl4: In conclusion, our study demonstrated a protective effect of Hesperidin in CCl4 induced oxidative stress in rat liver and kidney. This protective effect of Hesperidin can be correlated to its direct antioxidant effect.

Protective activity of hesperidin and lipoic acid against sodium arsenite acute toxicity in mice.
Toxicol Pathol. 2004.
The objective of the present work was to evaluate the toxic effects of sodium arsenite, As(III), in mice and the protective effect of 2 antioxidants, hesperidin and lipoic acid, against the observed As(III)-induced toxicity. In each study, mice were assigned to 1 of 4 groups: control, antioxidant, antioxidant + arsenite, and arsenite. Animals were first injected with the vehicle or 25 mg antioxidant/kg BW. After 30 minutes they received an injection of 10 mg arsenite/kg BW or 0.9% NaCl. Two hours after the first injection, the liver, kidney, and testis were collected for histological evaluation. Liver samples were also taken for quantification of arsenic. In mice exposed only to As(III), various histopathological effects were observed in the liver, kidneys, and testes. In mice pretreated with either hesperidin or lipoic acid, a reduction of histopathologic effects on the liver and kidneys was observed. No protective effects were observed in the testes for either of the 2 studied antioxidants. In conclusion, hesperidin and lipoic acid provided protective effects against As(III)-induced acute toxicity in the liver and kidneys of mice. These compounds may potentially play an important role in the protection of populations chronically exposed to arsenic.

The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice.
J Nutr. 2004 Oct.
Dietary antioxidant compounds such as bioflavonoids may offer some protection against the early stage of diabetes mellitus and the development of complications. We investigated the effect of citrus bioflavonoids on blood glucose level, hepatic glucose-regulating enzymes activities, hepatic glycogen concentration, and plasma insulin levels, and assessed the relations between plasma leptin and body weight, blood glucose, and plasma insulin. The current results suggest that hesperidin and naringin both play important roles in preventing the progression of hyperglycemia, partly by increasing hepatic glycolysis and glycogen concentration and/or by lowering hepatic gluconeogenesis.

[Effect of hesperidin and rutin on oxidative modification of high density lipoprotein in vitro]
Zhong Xi Yi Jie He Xue Bao. 2004.
To study the effect of hesperidin and rutin on oxidative modification of high density lipoprotein (HDL) in vitro. METHODS: HDL was isolated from healthy human plasma by sequential ultracentrifugation, and was oxidized by copper ions.The inhibitory effects of hesperidin and rutin on HDL oxidative modification were valued by the formation of malondialdehyde (MDA). RESULTS: Hesperidin and rutin significantly inhibited copper-induced oxidation of HDL in a dose-dependent manner. CONCLUSION: Both hesperidin and rutin can prevent HDL from copper-induced oxidative modification in vitro. This result suggests that they might have antiatherogenic effect.

Chemistry and pharmacology of the Citrus bioflavonoid hesperidin.
Phytother Res. 2001.
Hesperidin, a bioflavonoid, is an abundant and inexpensive by-product of Citrus cultivation. A deficiency of this substance in the diet has been linked with abnormal capillary leakiness as well as pain in the extremities causing aches, weakness and night leg cramps. No signs of toxicity have been observed with the normal intake of hesperidin or related compounds. Both hesperidin and its aglycone hesperetin have been reported to possess a wide range of pharmacological properties. This paper reviews various aspects of hesperidin and its related compounds, including their occurrence, physical and chemical properties, analysis, pharmacokinetics, safety and toxicity and the marketed products available. A special emphasis has been laid on the pharmacological properties and medicinal uses of these compounds.

Flavanone absorption after naringin, hesperidin, and citrus administration.
Clin Pharmacol Ther. 1996.
Disposition of citrus flavonoids was evaluated after single oral doses of pure compounds (500 mg naringin and 500 mg hesperidin) and after multiple doses of combined grapefruit juice and orange juice and of once-daily grapefruit. Cumulative urinary recovery indicated low bioavailability ( < 25%) of naringin and hesperidin. The aglycones naringenin and hesperitin were detected in urine and plasma by positive chemical ionization-collisionally activated dissociation tandem mass spectrometry (PCI-CAD MS/MS). After juice administration, PCI-CAD MS/MS detected naringenin, hesperitin, and four related flavanones, tentatively identified as monomethoxy and dimethoxy derivatives. These methoxyflavanones appear to be absorbed from juice. Absorbed citrus flavanones may undergo glucuronidation before urinary excretion.

Comparative study of the vasorelaxant activity, superoxide-scavenging ability and cyclic nucleotide phosphodiesterase-inhibitory effects of hesperetin and hesperidin.
Naunyn Schmiedebergs Arch Pharmacol. 2004;
This study investigated the vasorelaxant activity, superoxide radicals (O2(*-))-scavenging capacity and cyclic nucleotide phosphodiesterase (PDE)-inhibitory effects of hesperidin and hesperetin, two flavonoids mainly isolated from citrus fruits. Hesperetin concentration-dependently relaxed the isometric contractions induced by noradrenaline (NA, 1 microM) or by a high extracellular KCl concentration (60 mM) in intact rat isolated thoracic aorta rings. However, hesperetin (10 microM-0.3 mM) did not affect the contractile response induced by okadaic acid (OA, 1 microM). Mechanical removal of endothelium and/or pretreatment of aorta rings with glibenclamide (GB, 10 microM), tetraethylammonium or nifedipine did not significantly modify the vasorelaxant effects of this flavonoid. Hesperetin (10 microM-0.1 mM) did not affect the basal uptake of (45)Ca(2+) but decreased the influx of (45)Ca(2+) induced by NA and KCl in endothelium-containing and endothelium-denuded rat aorta. Hesperetin did not scavenge O2(*-) generated by the phenazine methosulfate (PMS)-reduced beta-nicotinamide adenine dinucleotide (NADH) system. Hesperetin (0.1 mM) significantly reversed the inhibitory effects of NA and high KCl (60 mM) on cyclic nucleotide (cAMP and cGMP) production in cultured rat aortic myocytes. Hesperetin preferentially inhibited calmodulin (CaM)-activated PDE1 and PDE4 isolated from bovine aorta with IC(50) values of about 74 microM and 70 microM respectively. In contrast, the 7-rhamnoglucoside of hesperetin, hesperidin (10 microM-0.1 mM), was inactive in practically all experiments, although it inhibited basal and cGMP-activated PDE2 isolated from platelets. These results suggest that the vasorelaxant effects of hesperetin are basically due to the inhibition of PDE1 and PDE4 activities.

A citrus flavonoid hesperidin suppresses infection-induced endotoxin shock in mice.
nobiletin Biol Pharm Bull. 2004.
Administration of a citrus flavonoid hesperidin to mice before LPS challenge significantly reduced tumor necrosis factor (TNF)-alpha production in a dose-dependent manner. Treatment of hesperidin 3 h before intraperitoneal (i.p.) infection with 10(8) CFU Salmonella typhimurium aroA resulted in rescue from lethal shock as similar to LPS-nonresponder mice. Not only bacterial numbers in livers and spleens but also plasma LPS levels significantly decreased by pretreatment with Hesperidin. In addition, hesperidin markedly suppressed plasma levels of TNF-alpha and high mobility group box chromosomal protein 1 (HMGB-1), decreased the number of apoptotic cells in livers and normalized the activated states of blood coagulation factors such as prothrombin time and platelet numbers caused by infection. Pretreatment of LPS with hesperidin suppressed the chromogenic Limulus reaction.

Hesperidin, a citrus flavonoid, inhibits bone loss and decreases serum and hepatic lipids in ovariectomized mice.
J Nutr. 2003.
The purpose of this study was to examine whether hesperidin inhibits bone loss in ovariectomized mice (OVX), an animal model of postmenopausal osteoporosis. Forty 8-wk-old female ddY mice were assigned to five groups: a sham-operated group fed the control diet (AIN-93G), an OVX group fed the control diet, an OVX+HesA group fed the control diet containing 0.5 g/100 g hesperidin, and an OVX+HesB group fed the control diet containing 0.7 g/100 g alpha-glucosylhesperidin and an OVX+17beta-estradiol (E(2)) group fed the control diet and administered 0.03 micro g E(2)/d with a mini-osmotic pump. After 4 wk, the mice were killed and blood, femoral, uterine and liver were sampled immediately. Hesperidin administration did not affect the uterine weight.These results suggest a possible role for citrus bioflavonoids in the prevention of lifestyle-related diseases because of their beneficial effects on bone and lipids.

Effects of long-term administration of hesperidin and glucosyl hesperidin to spontaneously hypertensive rats.
J Nutr Sci Vitaminol (Tokyo). 2002.
Hesperidin is a flavonoid contained in citrus fruit peel. We investigated the effects of long-term administration of hesperidin and its newly developed water soluble analogue, glucosyl hesperidin, to spontaneously hypertensive rats and normotensive Wistar-Kyoto rats (WKY).  These results suggest that Hesperidin and glucosyl hesperidin have anti-hypertensive effects on hypertensive animals.

Q. Can a flavonoid supplement be taken the same day as ahcc mushroom extract, serrapeptase enzyme, coq10 or saw palmetto?
     A. As long as the dosages are not excessive, this should be okay.