Claudine Manach

Dietary Polyphenols and the Prevention of Diseases

Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of fruits, vegetables, cereals, dry legumes, chocolate, and beverages, such as tea, coffee, or wine. Experimental studies on animals or cultured human cell lines support a role of polyphenols in the prevention of cardiovascular diseases, cancers, neurodegenerative diseases, diabetes, or osteoporosis. However, it is very difficult to predict from these results the effects of polyphenol intake on disease prevention in humans. One of the reasons is that these studies have often been conducted at doses or concentrations far beyond those documented in humans. The few clinical studies on biomarkers of oxidative stress, cardiovascular disease risk factors, and tumor or bone resorption biomarkers have often led to contradictory results. Epidemiological studies have repeatedly shown an inverse association between the risk of myocardial infarction and the consumption of tea and wine or the intake level of some particular flavonoids, but no clear associations have been found between cancer risk and polyphenol consumption. More human studies are needed to provide clear evidence of their health protective effects and to better evaluate the risks possibly resulting from too high a polyphenol consumption.

Bioavailability and bioefficacy of polyphenols in humans. II. Review of 93 intervention studies

For some classes of dietary polyphenols, there are now sufficient intervention studies to indicate the type and magnitude of effects among humans in vivo, on the basis of short-term changes in biomarkers. Isoflavones (genistein and daidzein, found in soy) have significant effects on bone health among postmenopausal women, together with some weak hormonal effects. Monomeric catechins (found at especially high concentrations in tea) have effects on plasma antioxidant biomarkers and energy metabolism. Procyanidins (oligomeric catechins found at high concentrations in red wine, grapes, cocoa, cranberries, apples, and some supplements such as Pycnogenol) have pronounced effects on the vascular system, including but not limited to plasma antioxidant activity. Quercetin (the main representative of the flavonol class, found at high concentrations in onions, apples, red wine, broccoli, tea, and Ginkgo biloba) influences some carcinogenesis markers and has small effects on plasma antioxidant biomarkers in vivo, although some studies failed to find this effect. Compared with the effects of polyphenols in vitro, the effects in vivo, although significant, are more limited. The reasons for this are 1) lack of validated in vivo biomarkers, especially in the area of carcinogenesis; 2) lack of long-term studies; and 3) lack of understanding or consideration of bioavailability in the in vitro studies, which are subsequently used for the design of in vivo experiments. It is time to rethink the design of in vitro and in vivo studies, so that these issues are carefully considered. The length of human intervention studies should be increased, to more closely reflect the long-term dietary consumption of polyphenols.

Quercetin is recovered in human plasma as conjugated derivatives which retain antioxidant properties

Quercetin is one of the most abundant flavonoids in the human diet. This study aimed to determine the plasma concentrations of quercetin in 10 healthy volunteers after the consumption of a complex meal rich in plant products. Quercetin was determined in plasma (2 h before, and 3, 7 and 20 h after the meal), and in a duplicated portion of the meal by HPLC analysis with an electrochemical detection. The amount of ingested quercetin was estimated to be 87 mg. Before the meal, quercetin concentration in hydrolyzed plasmas ranged from 28 to 142 nM. A marked increase was observed 3 h after the meal in all subjects, with a mean concentration of 373 nM (S.E.M.=61). After 7 h, quercetin concentration in hydrolyzed plasmas decreased and after 20 h basal levels were found again. The antioxidant capacities of quercetin, 3′‐O‐methylquercetin, and of some of their conjugated derivatives were compared by the measurement of the conjugated dienes resulting from the Cu2+‐induced oxidation of human LDL. 3′‐O‐Methylquercetin and conjugated derivatives of quercetin significantly prolonged the lag phase, but the magnitude of their effect was about half that of the aglycone.

Polyphenols and prevention of cardiovascular diseases

Purpose of review Polyphenols are the most abundant dietary antioxidants and research on their role in the prevention of degenerative diseases has developed quickly over these last few years. This paper reviews the recent studies on the prevention of cardiovascular diseases by polyphenols, focusing on human studies. Recent findings A large number of recent intervention studies have shown that several biomarkers of cardiovascular risk are influenced by the consumption of polyphenol-rich foods. Effects on biomarkers of oxidative stress, lipemia and inflammation appear so far unconclusive. More consistent effects have been observed on endothelial function and haemostasis and support a reduction of risk by polyphenols in agreement with the few epidemiological studies already published. All clinical studies have used foods or beverages containing a mixture of different polyphenols and the exact nature of the most active compounds remains largely unknown. Absorption, metabolism and elimination vary widely between polyphenols. These data on bioavailability should be taken into account to improve the experimental design and the interpretation of the observed effects. Summary Future intervention studies should include a detailed assessment of the bioavailability of polyphenols. Beyond clinical trials carried out with polyphenol-rich foods, more studies with pure polyphenols will also be needed to establish their role in the prevention of cardiovascular diseases. Abbreviations FMD: flow-mediated dilation; HDL: high-density lipoprotein; LDL: low-density lipoprotein.

Absorption and metabolism of polyphenols in the gut and impact on health.

Polyphenols are the most abundant antioxidants in the human diet. They show a considerable structural diversity, which largely influences their bioavailability. Phenolic acids like caffeic acid are easily absorbed through the gut barrier, whereas large molecular weight polyphenols such as proanthocyanidins are very poorly absorbed. Once absorbed, polyphenols are conjugated to glucuronide, sulphate and methyl groups in the gut mucosa and inner tissues. Non-conjugated polyphenols are virtually absent in plasma. Such reactions facilitate their excretion and limit their potential toxicity. The polyphenols reaching the colon are extensively metabolised by the microflora into a wide array of low molecular weight phenolic acids. The biological properties of both conjugated derivatives and microbial metabolites have rarely been examined. Their study will be essential to better assess the health effects of dietary polyphenols. Alternatively, some health effects of polyphenols may not require their absorption through the gut barrier. Their role as iron chelators in the gut lumen is briefly discussed.

Bioavailability of rutin and quercetin in rats

Quercetin is a powerful antioxidant which is widely distributed in edible plants, mainly as glycosides such as rutin. It has been reported to be absorbed in mammals, but its metabolism needs further investigation to evaluate its possible physiological effects. We compared the evolution of the absorption of quercetin and rutin in rats fed with supplemented diets. Rutin was absorbed more slowly than quercetin because it must be hydrolysed by the cecal microflora, whereas quercetin was absorbed from the small intestine. Conjugated derivatives of quercetin, and its methylated forms isorhamnetin and tamarixetin, were recovered in plasma from rats receiving the two kinds of experimental diets after the first meal, but after 10 days, no traces of tamarixetin were detected anymore. The rate of elimination of quercetin metabolites seems very low, and high plasma concentrations are easily maintained with a regular supply of quercetin or rutin in the diet.

Bioavailability in humans of the flavanones hesperidin and narirutin after the ingestion of two doses of orange juice

Objective: Flavanones are polyphenols specific of citrus fruits, where they are present in high amounts. Although citrus fruits and juices are widely consumed in the world, little information has been published on flavanone bioavailability in humans. The aim of the present study was to determine the nature of the circulating metabolites, the plasma kinetics and the urinary excretion patterns of the flavanones, hesperidin and narirutin.Design: After an overnight fast, five healthy volunteers ingested 0.5 or 1 l of a commercial orange juice providing 444 mg/l hesperidin and 96.4 mg/l narirutin, together with a polyphenol-free breakfast. Blood was sampled at 10 different timepoints over a 24 h period. Urine was collected for 48 h, in five fractions.Results: Flavanones metabolites appeared in plasma 3 h after the juice ingestion, reached a peak between 5 and 7 h, then returned to baseline at 24 h. The peak plasma concentration of hesperetin was 0.46±0.07 µmol/l and 1.28±0.13 µmol/l after the 0.5 and 1 l intake, respectively. It was lower for naringenin: 0.20±0.04 µmol/l after the 1 l dose. The circulating forms of hesperetin were glucuronides (87%) and sulphoglucuronides (13%). For both flavanones, the urinary excretion was nearly complete 24 h after the orange juice ingestion. The relative urinary excretion was similar for hesperetin and naringenin and did not depend on the dose: values ranged from 4.1±1.2 to 7.9±1.7% of the intake.Conclusion: In case of a moderate or high consumption of orange juice, flavanones may represent an important part of the pool of total polyphenols present in plasma.

Dietary intake of 337 polyphenols in French adults

BACKGROUND Epidemiologic studies have suggested an association between polyphenol intake and health. These studies have been limited to ≤40 flavonoid and lignan aglycones. OBJECTIVE We estimated intakes of all known individual polyphenols in the French cohort SUpplémentation en VItamines et Minéraux AntioXydants (SU.VI.MAX) by using the recently developed database Phenol-Explorer, which contains content values for 502 polyphenols in 452 foods. DESIGN A total of 4942 men and women, who were aged 45-60 y and who had completed at least six 24-h dietary records, participated in this study. Foods documented in 24-h dietary records and the Phenol-Explorer database were matched, and intakes of all individual polyphenols were calculated. RESULTS A total of 337 polyphenols were consumed by SU.VI.MAX subjects, including 258 polyphenols consumed by at least one-half of the population and 98 polyphenols consumed in an amount >1 mg/d. Mean total polyphenol intake was estimated at 1193 ± 510 mg/d (or 820 ± 335 mg/d when expressed as aglycone equivalents), with hydroxycinnamic acid esters and proanthocyanidins being the most largely consumed polyphenols. These values may have been underestimated because of insufficient data or lack of accurate data on the content in foods for proanthocyanidins and thearubigins. Nonalcoholic beverages and fruit were the most important contributors to polyphenol intakes. CONCLUSIONS The current study provides intake data for all individual polyphenols known to be present in the diet of a cohort. This information will be essential to characterize the health effects of individual phenolic compounds that differ widely in their bioavailability and physiologic properties. The SU.VI.MAX study was registered at clinicaltrials.gov as NCT00272428.

The food metabolome: a window over dietary exposure

The food metabolome is defined as the part of the human metabolome directly derived from the digestion and biotransformation of foods and their constituents. With >25,000 compounds known in various foods, the food metabolome is extremely complex, with a composition varying widely according to the diet. By its very nature it represents a considerable and still largely unexploited source of novel dietary biomarkers that could be used to measure dietary exposures with a high level of detail and precision. Most dietary biomarkers currently have been identified on the basis of our knowledge of food compositions by using hypothesis-driven approaches. However, the rapid development of metabolomics resulting from the development of highly sensitive modern analytic instruments, the availability of metabolite databases, and progress in (bio)informatics has made agnostic approaches more attractive as shown by the recent identification of novel biomarkers of intakes for fruit, vegetables, beverages, meats, or complex diets. Moreover, examples also show how the scrutiny of the food metabolome can lead to the discovery of bioactive molecules and dietary factors associated with diseases. However, researchers still face hurdles, which slow progress and need to be resolved to bring this emerging field of research to maturity. These limits were discussed during the First International Workshop on the Food Metabolome held in Glasgow. Key recommendations made during the workshop included more coordination of efforts; development of new databases, software tools, and chemical libraries for the food metabolome; and shared repositories of metabolomic data. Once achieved, major progress can be expected toward a better understanding of the complex interactions between diet and human health.

Bioavailability, metabolism and physiological impact of 4-oxo-flavonoids

4-oxo-flavonoids are dietary compounds widely distributed in the plant kingdom. Interest in these substances has arisen because of possible effects on human health. Indeed, in spite of extensive metabolism by the intestinal flora, 4-oxo-flavonoids seem to be sufficiently absorbed to have physiological effects. This review discusses the possibilities of a positive role in cardiovascular disease and cancer prevention, particularly by their antioxidant properties and their ability to modulate the activity of many enzymes, and summarizes the data concerning an eventual carcinogenicity of 4-oxo-flavonoids.