Structurally related (−)-epicatechin metabolites in humans: Assessment using de novo chemically synthesized authentic standards

Ottaviani, Javier I.; Momma, Tony Y.; Kuhnle, Gunter; Keen, Carl L.; Schroeter, Hagen

doi:10.1016/j.freeradbiomed.2011.12.010

Cited by 133 publications

(150 citation statements)

References 38 publications

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“…This is in line with the notion of altered metabolism, accumulation, and excretion of certain metabolites and uremic solutes in ESRD (48). Recent data suggest that the elimination of CF is dependent on the urinary excretion of their corresponding metabolites (49). We now show that metabolites are dialyzable, which opens new insights into pharmacokinetics.…”

Section: Flavanol Intake In Patients With Esrdsupporting

confidence: 88%

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis

Rassaf

Rammos

Hendgen‐Cotta

et al. 2016

Clinical Journal of the American Society of Nephrology

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Background and objectives Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow-mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)-rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol-rich bioactive food ingredients on acute and chronic HD-induced vascular dysfunction in ESRD.Design, setting, participants, & measurements We conducted a randomized, double-blind, placebo-controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross-over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD-mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics.Results CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.260.6% to 4.860.9% versus placebo, 3.260.7% to 3.360.8%; P,0.001), with no effects on BP or heart rate. A 30-day ingestion of CF led to an increase in baseline FMD by 18% (3.460.9% to 3.960.8% versus placebo, 3.560.7% to 3.560.7%; P,0.001), with reduced diastolic BP (73612 to 69611 mmHg versus placebo, 70611 to 73613 mmHg; P=0.03) and increased heart rate (70612 to 74613 bpm versus placebo, 75615 to 74613 bpm; P=0.01). No effects were observed for placebo. Acute ingestion of CF during HD alleviated HD-induced vascular dysfunction (3.460.9% to 2.760.6% versus placebo, 3.560.7% to 2.060.6%; P,0.001). This effect was sustained throughout the study (acute on chronic, 3.960.9% to 3.060.7% versus placebo, 3.560.7% to 2.260.6; P=0.01).Conclusions Dietary CF ingestion mitigates acute HD-induced and chronic endothelial dysfunction in patients with ESRD and thus, improves vascular function in this high-risk population. Larger clinical trials are warranted to test whether this translates into an improved cardiovascular prognosis in patients with ESRD.

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Section: Flavanol Intake In Patients With Esrdsupporting

confidence: 88%

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis

Rassaf

Rammos

Hendgen‐Cotta

et al. 2016

Clinical Journal of the American Society of Nephrology

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“…Despite reported differences in analytical procedures between laboratories [47], the consensus is that (−)-epicatechin-3 -O-glucuronide, (−)-epicatechin-3 -O-sulfate, and a 3 -Omethyl-(−)-epicatechin-5/7-sulfate are the predominant epicatechin metabolites in humans after oral consumption [47,49]. The apparent half-life of most epicatechin conjugates is 2-4 h…”

Section: Absorption Into the Bloodstreammentioning

confidence: 99%

“…It undergoes sulfation, methylation and glucuronidation with typical T max for conjugates of ~2 h [46,47]. After both oral ingestion and direct jejunal perfusion, the EC-3 -O-glucuronide conjugate is the most abundant metabolite found in plasma [48] (Fig.…”

Section: Absorption Into the Bloodstreammentioning

confidence: 99%

“…When hesperidin is consumed orally, hesperetin (conjugates of sulfate and glucuronide) appear in the plasma with a T max of 4-6 h. When hesperetin-7-Oglucoside is consumed orally, the same conjugates appear in the plasma but with a much higher C max and a much shorter T max of ~ 30 min indicating absorption in the small intestine (Fig. 4).Despite reported differences in analytical procedures between laboratories [47], the consensus is that (−)-epicatechin-3 -O-glucuronide, (−)-epicatechin-3 -O-sulfate, and a 3 -Omethyl-(−)-epicatechin-5/7-sulfate are the predominant epicatechin metabolites in humans after oral consumption [47,49]. The apparent half-life of most epicatechin conjugates is 2-4 h…”

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confidence: 99%

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Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols

Williamson

Clifford

2017

Biochemical Pharmacology

257

172

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Please cite this article as: G. Williamson, M.N. Clifford, Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols, Biochemical Pharmacology (2017), doi: http://dx.doi.org/10.1016/ j. bcp.2017.03.012 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1Role of the small intestine, colon and microbiota in determining the metabolic fate of in the small intestine, or reaches the colon and is subject to extensive catabolism by colonic microbiota. Untransformed substrates may be absorbed, appearing in plasma primarily as methylated, sulfated and glucuronidated derivatives, with in some cases the unchanged substrate. Many of the catabolites are well absorbed from the colon and appear in the plasma either similarly conjugated, or as glycine conjugates, or in some cases unchanged.Although many (poly)phenol catabolites have been identified in human plasma and / or urine, the pathways from substrate to final catabolite, and the species of bacteria and enzymes involved, are still scarcely reported. While it is clear that the composition of the human gut microbiota can be modulated in vivo by supplementation with some (poly)phenol-rich commodities, such modulation is definitely not an inevitable consequence of supplementation, it depends on the treatment, length of time and on the individual metabotype, and it is not clear whether the modulation is sustained when supplementation ceases. Some catabolites have been recorded in plasma of volunteers at concentrations similar to those shown to be effective in in vitro studies suggesting that some benefit may be achieved in vivo by diets yielding such catabolites. and are also present at high levels in supplements [4], and form essential components of many Chinese medicines [5]. A study within the European Prospective Investigation intoCancer and Nutrition (EPIC) using the Phenol Explorer database reported that the cohort studied consumed 427 different polyphenols including 94 that were consumed at a rate of >1 g/day. The estimated total polyphenol consumption ranged from 584 mg/day by Greek women to 1786 mg/day for men in Aarhus-Denmark. The corresponding data for Greek men and for Aarhus women were 744 mg/day and 1626 mg/ day, respectively, with all data adjusted for age and weighted by season and weekday of dietary recall [6]. This study defined the major contributors to be the phenolic acids (predominantly the caffeoylquinic acids (27-53%), also called chlorogenic acids) and flavonoids (predominantly flavanols (16-29%), proanthocyanidins (5-9%) and theaflavins (14-25%)) [6]. Hydroxybenzoic acids (3.3-7.4%), alkyl-phenols (1.6...

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“…EC and other flavan-3-ols are extensively metabolized in the small intestine and in the liver in humans and rodents following oral consumption (4,37), which has generated questions as to whether the parent compound or bioactive metabolites are responsible for its beneficial effects. We and others have hypothesized an alternative mechanism of protection involving activation of the nuclear transcription factor erythroid 2p45-related factor-2 (Nrf2).…”

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confidence: 99%

Efficacy of prophylactic flavan-3-ol in permanent focal ischemia in 12-mo-old mice

Leonardo

Mendes

Ahmad

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Structurally related (−)-epicatechin metabolites in humans: Assessment using de novo chemically synthesized authentic standards

Cited by 133 publications

References 38 publications

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis

Vasculoprotective Effects of Dietary Cocoa Flavanols in Patients on Hemodialysis

Role of the small intestine, colon and microbiota in determining the metabolic fate of polyphenols

Efficacy of prophylactic flavan-3-ol in permanent focal ischemia in 12-mo-old mice

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