Flavonoids are a class of secondary plant phenolics with significant antioxidant and chelating properties. In the human diet, they are most concentrated in fruits, vegetables, wines, teas and cocoa. Their cardioprotective effects stem from the ability to inhibit lipid peroxidation, chelate redox-active metals, and attenuate other processes involving reactive oxygen species. Flavonoids occur in foods primarily as glycosides and polymers that are degraded to variable extents in the digestive tract. Although metabolism of these compounds remains elusive, enteric absorption occurs sufficiently to reduce plasma indices of oxidant status. The propensity of a flavonoid to inhibit free-radical mediated events is governed by its chemical structure. Since these compounds are based on the flavan nucleus, the number, positions, and types of substitutions influence radical scavenging and chelating activity. The diversity and multiple mechanisms of flavonoid action, together with the numerous methods of initiation, detection and measurement of oxidative processes in vitro and in vivo offer plausible explanations for existing discrepancies in structure-activity relationships. Despite some inconsistent lines of evidence, several structure-activity relationships are well established in vitro. Multiple hydroxyl groups confer upon the molecule substantial antioxidant, chelating and prooxidant activity. Methoxy groups introduce unfavorable steric effects and increase lipophilicity and membrane partitioning. A double bond and carbonyl function in the heterocycle or polymerization of the nuclear structure increases activity by affording a more stable flavonoid radical through conjugation and electron delocalization. Further investigation of the metabolism of these phytochemicals is justified to extend structure-activity relationships (SAR) to preventive and therapeutic nutritional strategies.

Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships.

The main dietary sources of polyphenols are reviewed, and the daily intake is calculated for a given diet containing some common fruits, vegetables and beverages. Phenolic acids account for about one third of the total intake and flavonoids account for the remaining two thirds. The most abundant flavonoids in the diet are flavanols (catechins plus proanthocyanidins), anthocyanins and their oxidation products. The main polyphenol dietary sources are fruit and beverages (fruit juice, wine, tea, coffee, chocolate and beer) and, to a lesser extent vegetables, dry legumes and cereals. The total intake is approximately 1 g/d. Large uncertainties remain due to the lack of comprehensive data on the content of some of the main polyphenol classes in food. Bioavailability studies in humans are discussed. The maximum concentration in plasma rarely exceeds 1 microM after the consumption of 10-100 mg of a single phenolic compound. However, the total plasma phenol concentration is probably higher due to the presence of metabolites formed in the body's tissues or by the colonic microflora. These metabolites are still largely unknown and not accounted for. Both chemical and biochemical factors that affect the absorption and metabolism of polyphenols are reviewed, with particular emphasis on flavonoid glycosides. A better understanding of these factors is essential to explain the large variations in bioavailability observed among polyphenols and among individuals.

Dietary Intake and Bioavailability of Polyphenols

Flavonoids, a group of natural substances with variable phenolic structures, are found in fruits, vegetables, grains, bark, roots, stems, flowers, tea and wine. These natural products are well known for their beneficial effects on health and efforts are being made to isolate the ingredients so called flavonoids. Flavonoids are now considered as an indispensable component in a variety of nutraceutical, pharmaceutical, medicinal and cosmetic applications. This is attributed to their anti-oxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties coupled with their capacity to modulate key cellular enzyme function. Research on flavonoids received an added impulse with the discovery of the low cardiovascular mortality rate and also prevention of CHD. Information on the working mechanisms of flavonoids is still not understood properly. However, it has widely been known for centuries that derivatives of plant origin possess a broad spectrum of biological activity. Current trends of research and development activities on flavonoids relate to isolation, identification, characterisation and functions of flavonoids and finally their applications on health benefits. Molecular docking and knowledge of bioinformatics are also being used to predict potential applications and manufacturing by industry. In the present review, attempts have been made to discuss the current trends of research and development on flavonoids, working mechanisms of flavonoids, flavonoid functions and applications, prediction of flavonoids as potential drugs in preventing chronic diseases and future research directions.

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Flavonoids: an overview

Flavonoids: a review of probable mechanisms of action and potential applications

Brazilian plant extracts belonging to 16 species of 5 different families (71 extracts) were tested against the stable DPPH (2,2-diphenyl-1-picryl-hydrazyl-hydrate) free-radical. The ability to scavenge DPPH radical was measured in these experiments by the discoloration of the solution. Ginkgo biloba and rutin, commonly used as antioxidants for medical purposes, were used as standards. Based on our results, we can say that as a general rule the ethanol extracts of plants belonging to the Verbenaceae family showed lower EC50 values than the other plant extracts. Among the partitions, the more polar ones (ethyl acetate and n-butanol) are those that generally have higher antioxidant activity (AA). Copyright © 2001 John Wiley & Sons, Ltd.

Screening of Brazilian plant extracts for antioxidant activity by the use of DPPH free radical method

Scavenging effects of tea catechins and their derivatives on 1,1-diphenyl-2-picrylhydrazyl radical

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2898%2901304-0

Intestinal absorption of luteolin and luteolin 7‐O‐β‐glucoside in rats and humans

The role of neutrophil and its chlorinated oxidant were investigated in Helicobacter pylori-induced gastric mucosal injury in vitro. Luminol-dependent chemiluminescence (ChL) was used to detect neutrophil-derived oxidants. ChL activity was significantly elevated when neutrophils were incubated in H. pylori, indicating that H. pylori actually elicits oxidative burst of neutrophils. To assess whether H. pylori-activated neutrophils exert the cytotoxicity for gastric mucosal cells, rabbit gastric mucosal cell was monolayered in culture wells and labeled with a fluorescence dye, 2',7'-bis(2-carboxyethyl)-5(6)carboxy-fluorescein, which is retained in the intracellular space as long as the cell membrane is intact. Labeled cells were coincubated with neutrophils and H. pylori. We inferred from the cytotoxicity index (specific %cytotoxicity), which was calculated from fluorometrical measurements of supernatant and lysate, that the mucosal cells were significantly damaged by H. pylori-activated neutrophils. This injury was largely attenuated by eliminating urea from the incubation mixture or by acetohydroxamic acid, a potent urease inhibitor. Additionally, the scavengers of neutrophil-derived oxidants, including taurine, methionine, and catalase, also attenuated this injury. Cultured mucosal cells that were exposed to the solution containing monochloramine (an oxidant yielded by reaction of hypochlorous acid and ammonia) were highly damaged compared with cells exposed to hypochlorous acid or hydrogen peroxide at physiological concentrations. These data suggest that H. pylori-activated neutrophils promote gastric mucosal cell injury and that monochloramine plays a unique and important role in this process.

Helicobacter pylori-associated ammonia production enhances neutrophil-dependent gastric mucosal cell injury.

After oral administration of [4-3H]EGCg to rats, the radioactivity in blood, major tissues, urine, and feces was measured over time. The radioactivity in blood and most tissues remained low for 4 h postdose, began to increase after 8 h, peaked at 24 h, and then decreased. Major urinary excretion of radioactivity occurred in the 8−24 h period, and the cumulative radioactivity excreted by 72 h was 32.1% of the dose. The radioactivity in the feces was 35.2% of the dose within 72 h postdose. In the case of rats pretreated with antibiotics (antibiotic-pretreated rats), the radioactivity levels of the blood and urine were definitely lower than those in rats not pretreated with antibiotics (normal rats). The radioactivity recovered in the antibiotic-pretreated rat urine was estimated to be only 1/100 of that in the normal rat urine. These results clearly demonstrated that the radioactivity detected in the blood and urine of normal rats mostly originated from degradation products of EGCg produced by intestinal ba...

Metabolic Fate of (−)-[4-3H]Epigallocatechin Gallate in Rats after Oral Administration

After oral administration of (-)-epicatechin to rats, three kinds of metabolites (M-1, M-2, and M-3) were detected in the urine. After isolation of the compounds by preparative high-performance liquid chromatography, structural analysis was carried out by mass spectrometry and NMR. As a result, two compounds, M-1 and M-2, were identified as (-)-epicatechin and 3'-O-methyl-(-)-epicatechin, respectively. M-3 was suggested to be a monomethylated (-)-epicatechin, but definitive elucidation was not possible because of its small quantity. Methylation of (-)-epicatechin with rat liver homogenates and subsequent structural analysis showed that M-3 was 4'-O-methyl-(-)-epicatechin. Identification of conjugated forms of the urinary metabolites also was attempted. Two conjugates in the urine were purified and analyzed by mass spectrometry and NMR. These conjugates were shown to be (-)-epicatechin-5-O-beta-glucuronide and 3'-O-methyl-(-)-epicatechin-5-O-beta-glucuronide, respectively. Metabolism and excretion of (-)-epicatechin were examined. (-)-Epicatechin and its methylated derivatives in the free forms were detected in plasma and urine, but not in bile. Significant differences in the excretion ratio of the conjugated forms of (-)-epicatechin and 3'-O-methyl-(-)-epicatechin were observed between urine and bile. Time-course analysis of (-)-epicatechin metabolites showed that the most predominant metabolites in plasma and urine were the conjugates of (-)-epicatechin and 3'-O-methyl-(-)-epicatechin, respectively, and the cumulative amount of the urinary metabolites excreted during the 24-h period was about 8% of the administered (-)-epicatechin.

Masayuki Suzuki

Papers

Scavenging effects of tea catechins and their derivatives on 1,1-diphenyl-2-picrylhydrazyl radical

Intestinal absorption of luteolin and luteolin 7‐O‐β‐glucoside in rats and humans

Helicobacter pylori-associated ammonia production enhances neutrophil-dependent gastric mucosal cell injury.

Metabolic Fate of (−)-[4-3H]Epigallocatechin Gallate in Rats after Oral Administration

Identification of (−)-Epicatechin Metabolites and Their Metabolic Fate in the Rat