Bioavailability of orally administered water-dispersible hesperetin and its effect on peripheral vasodilatation in human subjects: Implication of endothelial functions of plasma conjugated metabolites
ABSTRACT Hesperetin is an aglycone of citrus flavonoids and is expected to exert a vasodilatation effect in vivo. We developed water-dispersible hesperetin by the process of micronization to enhance the bioavailability of hesperetin. This study aimed to assess the effect of this process on the bioavailability of hesperetin and to estimate its efficiency on vasodilatation-related functions using endothelial cells in vitro and a human volunteer study at a single dose in vivo. We found that water-dispersible hesperetin was absorbed rapidly, with its maximum plasma concentration (C(max)) being 10.2 ± 1.2 μM, and that the time to reach C(max), which is within 1 h if 150 mg of this preparation was orally administered in humans. LC-MS analyses of the plasma at C(max) demonstrated that hesperetin accumulated in the plasma as hesperetin 7-O-β-D-glucuronide (Hp7GA), hesperetin 3'-O-β-D-glucuronide (Hp3'GA) and hesperetin sulfate exclusively. Similar to hesperetin, Hp7GA enhanced nitric oxide (NO) release by inhibiting nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) activity in a human umbilical vein endothelial cell culture system, indicating that plasma hesperetin metabolites can improve vasodilatation in the vascular system. A volunteer study using women with cold sensitivity showed that a single dose of water-dispersible hesperetin was effective on peripheral vasodilatation.These results strongly suggest that rapid accumulation with higher plasma concentration enables hesperetin to exert a potential vasodilatation effect by the endothelial action of its plasma metabolites. Water-dispersible hesperetin may be useful to improve the health effect of dietary hesperetin.
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ABSTRACT: Orally ingested hesperidin (HES) is hydrolyzed into hesperetin in the gastrointestinal tract and conjugated during absorption. Hesperetin conjugates are the main circulating metabolites in human and rat plasma. We previously reported that glucosyl hesperidin (GHES), a water-soluble HES derivative, prevents hypertension via improvement of endothelial dysfunction in spontaneously hypertensive rats (SHRs). Although these hesperetin conjugates seem to be responsible for hypotensive and endothelium-dependent vasodilatory activities of dietary GHES, little is known about the mechanisms of action of these conjugated metabolites. Therefore, the aim of the present study was to investigate the effects of hesperetin-7-O-β-d-glucuronide (HPT7G) and hesperetin-3'-O-β-d-glucuronide (HPT3'G), which are the predominant HES metabolites in rat plasma, on blood pressure and endothelial function. Intravenous administration of HPT7G (5 mg kg(-1)) decreased blood pressure in anesthetized SHRs. HPT7G enhanced endothelium-dependent vasodilation in response to acetylcholine, but had no effect on endothelium-independent vasodilation in response to sodium nitroprusside (SNP) in aortas isolated from SHRs. HPT7G decreased hydrogen peroxide-induced intracellular adhesion molecule-1 and monocyte chemoattractant protein-1 mRNA expression in rat aortic endothelial cells. In contrast, HPT3'G had little effect on these parameters. In conclusion, HPT7G exerted hypotensive, vasodilatory and anti-inflammatory activities, similar to hesperetin and these effects are associated, in part, with the activity of GHES and HES to improve hypertension and endothelial dysfunction.07/2013; 4(9). DOI:10.1039/c3fo60030k
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ABSTRACT: A proper diet is one of major factors contributing to good health and is directly related to general condition of the organism. Phenolic compounds are abundant in foods and beverages (fresh and processed fruits and vegetables, leguminous plants, cereals, herbs, spices, tea, coffee, wine, beer) and their pleiotropic biological activities result in numerous health beneficial effects. On the other hand, high reactivity and very large diversity in terms of structure and molecular weight renders polyphenols one of the most difficult groups of compounds to investigate, as evidenced by ambiguous and sometimes contradictory results of many studies. Furthermore, phenolics undergo metabolic transformations which significantly change their biological activities. Here we discuss some aspects of metabolism and absorption of phenolic compounds. On the basis of information reported in the literature as well as in summaries of clinical trials and patent applications, we also give an overview of strategies for enhancing their bioavailability.Journal of Agricultural and Food Chemistry 12/2013; DOI:10.1021/jf404439b · 2.91 Impact Factor