Michael N. Clifford

Dietary phenolics: chemistry, bioavailability and effects on health

There is much epidemiological evidence that diets rich in fruit and vegetables can reduce the incidence of non-communicable diseases such as cardiovascular diseases, diabetes, cancer and stroke. These protective effects are attributed, in part, to phenolic secondary metabolites. This review summarizes the chemistry, biosynthesis and occurrence of the compounds involved, namely the C6-C3-C6 flavonoids-anthocyanins, dihydrochalcones, flavan-3-ols, flavanones, flavones, flavonols and isoflavones. It also includes tannins, phenolic acids, hydroxycinnamates and stilbenes and the transformation of plant phenols associated with food processing (for example, production of black tea, roasted coffee and matured wines), these latter often being the major dietary sources. Events that occur following ingestion are discussed, in particular, the deglycosylation, glucuronidation, sulfation and methylation steps that occur at various points during passage through the wall of the small intestine into the circulatory system and subsequent transport to the liver in the portal vein.We also summarise the fate of compounds that are not absorbed in the small intestine, but which pass into the large intestine where they are degraded by the colonic microflora to phenolic acids, which can be absorbed into the circulatory system and subjected to phase II metabolism prior to excretion. Initially, the protective effect of dietary phenolics was thought to be due to their antioxidant properties which resulted in a lowering of the levels of free radicals within the body.However, there is now emerging evidence that themetabolites of dietary phenolics,which appear in the circulatory systemin nmol/L to low mmol/L concentrations, exertmodulatory effects in cells through selective actions on different components of the intracellular signalling cascades vital for cellular functions such as growth, proliferation and apoptosis. In addition, the intracellular concentrations required to affect cell signalling pathways are considerably lower than those required to impact on antioxidant capacity. The mechanisms underlying these processes are discussed.

Chlorogenic acids and other cinnamates – nature, occurrence and dietary burden†

This review defines the range of forms in which cinnamates (p-coumarates, caffeates, ferulates and sinapates) occur in foods and beverages subdividing them into (i) the classic chlorogenic acids and close allies, (ii) other esters, amides and glycosides, and (iii) transformation products formed during processing. Cinnamate derivatives which would not release cinnamic acid by hydrolysis are excluded. The quantitative data are reviewed concisely and attention is drawn to certain shortcomings, in particular a complete absence of data for certain commodities (breakfast cereals, baked goods, tomato products and nuts) and minimal data for pulses, legumes and processed or cooked foods. In addition, more data are required for the edible portion of modern varieties. By extrapolating from such data as are available the important source(s) (i) of individual cinnamates (regardless of the conjugate type) and (ii) of each major class of conjugate, have been identified as follows: (i) Cinnamates: caffeic acid: coffee beverage, blueberries, apples, ciders; p-coumaric acid: spinach, sugar beet fibre, cereal brans; ferulic acid: coffee beverage, citrus juices, sugar beet fibre, cereal brans; sinapic acid: broccoli, kale, other leafy brassicas, citrus juices. (ii) Conjugates: caffeoylquinic acids: coffee beverage, blueberries, apples, ciders; p-coumaroylquinic acids: sweet cherries; feruloylquinic acids: coffee beverage; tartaric conjugates: spinach, lettuce, grapes and wines; malic conjugates: lettuce, spinach, possibly legumes; rosmarinic acid: culinary herbs, mixed herbs, possibly stuffings; cell wall conjugates: spinach, sugar beet fibre, cereal brans. It seems likely that the UK population will fall into several categories depending on (i) their consumption of coffee, (ii) their consumption of bran, and (iii) their consumption of citrus. Those who drink several cups of coffee per day augmented by bran and citrus might easily ingest 500-800mg cinnamates (or even 1 g for the greatest coffee ingest consumption) whereas those who eschew all these and take little fresh fruit or vegetables might struggle to consume 25 mg.

Chlorogenic acids and other cinnamates – nature, occurrence, dietary burden, absorption and metabolism

This paper summarises the occurrence in foods and beverages of the cinnamic acids, their associated conjugates and transformation products. Quantitative data are lacking for some commodities known to contain them, but it is clear that for many people coffee will be the major source. The daily dietary intake of total cinnamates may vary substantially from almost zero to perhaps close to 1 g. The data relating to their absorption and metabolism are presented along with a consideration of their possible in vivo effects. Data for true bioavailability are incomplete: in particular it is not clear whether availability differs markedly with the form of the conjugate, and whether as a consequence some dietary sources may be superior to others.

Anthocyanins - nature, occurrence and dietary burden

This paper reviews the literature on the occurrence of anthocyanins in foods and their transformation during processing, including the formation of adducts and derived tannins. Data describing the safety of anthocyanins and possible dietary effects are examined. Attention is drawn to some misquotations in the literature and to some serious gaps in our knowledge, in particular, the lack of pharmacokinetic data in humans essential to an understanding of associated biological effects.

Ellagitannins - nature, occurrence and dietary burden.

The occurrence of ellagitannins in common foodstuffs is limited to a few fruit and nut species. Dietary intake of ellagitannins is largely explained by the consumption of strawberries, raspberries and blackberries. No reliable figures are available for the ellagitannin burden, but it will probably not exceed 5 mg day−1. Their bioavailability is not well defined. A fraction of the ellagitannins ingested is hydrolysed in the gut and the resulting ellagic acid absorbed and metabolised, but whether intact ellagitannins are absorbed is not clear. There are apparently conflicting claims for beneficial and toxic effects caused by ellagitannins, ellagic acid or ellagitannin-containing extracts in various animal species including rodents and ruminants. It seems unlikely that normal consumption can cause toxic effects in man, but any attempt to increase the intake significantly in pursuit of the suggested benefits should be resisted until the metabolism and pharmacokinetics are better understood. © 2000 Society of Chemical Industry

Bioavailability of dietary flavonoids and phenolic compounds.

This paper reviews recent human studies on the bioavailability of dietary flavonoids and related compounds, including chlorogenic acids and ellagitannins, in which the identification of metabolites, catabolites and parent compounds in plasma, urine and ileal fluid was based on mass spectrometric methodology. Compounds absorbed in the small intestine appear in the circulatory system predominantly as glucuronide, sulfate and methylated metabolites which seemingly are treated by the body as xenobiotics as they are rapidly removed from the bloodstream. As a consequence, while analysis of plasma provides valuable information on the identity and pharmacokinetic profiles of circulating metabolites after acute supplementation, it does not provide accurate quantitative assessments of uptake from the gastrointestinal tract. Urinary excretion, of which there are great variations with different classes of flavonoids, provides a more realistic figure but, as this does not include the possibility of metabolites being sequestered in body tissues, this too is an under estimate of absorption, but to what degree remains to be determined. Even when absorption occurs in the small intestine, feeding studies with ileostomists reveal that substantial amounts of the parent compounds and some of their metabolites appear in ileal fluid indicating that in volunteers with a functioning colon these compounds will pass to the large intestine where they are subjected to the action of the colonic microflora. A diversity of colonic-derived catabolites is absorbed into the bloodstream and passes through the body prior to excretion in urine. There is growing evidence that these compounds, which were little investigated until recently, are produced in quantity in the colon and form a key part of the bioavailability equation of dietary flavonoids and related phenolic compounds.

Flavanones, chalcones and dihydrochalcones - nature, occurrence and dietary burden.

This paper reviews the occurrence in foods of flavanones, chalcones and dihydrochalcones. The major dietary sources of flavanones and dihydrochalcones are citrus fruits and apples respectively. These compounds may make a greater contribution to the total daily intake of flavonoids than the more extensively studied flavonols. There are no data for plasma or tissue levels, but both endogenous and gut flora metabolites of both classes of compound are found in urine. For these reasons, these compounds deserve greater attention in epidemiological studies.

Dietary polyphenols decrease glucose uptake by human intestinal Caco-2 cells

The effect of different classes of dietary polyphenols on intestinal glucose uptake was investigated using polarised Caco‐2 intestinal cells. Glucose uptake into cells under sodium‐dependent conditions was inhibited by flavonoid glycosides and non‐glycosylated polyphenols whereas aglycones and phenolic acids were without effect. Under sodium‐free conditions, aglycones and non‐glycosylated polyphenols inhibited glucose uptake whereas glycosides and phenolic acids were ineffective. These data suggest that aglycones inhibit facilitated glucose uptake whereas glycosides inhibit the active transport of glucose. The non‐glycosylated dietary polyphenols appear to exert their effects via steric hindrance, and (−)‐epigallochatechingallate, (−)‐epichatechingallate and (−)‐epigallochatechin are effective against both transporters.

Dietary hydroxybenzoic acid derivatives - nature, occurrence and dietary burden.

Quantitative data for hydroxybenzoic acids (naturally occurring and permitted additives) and their conjugates in foods and beverages are summarised. Tea, rosaceous fruits, red wines and potatoes are important sources for which more comprehensive compositional data are required. Their absorption, metabolism, toxicological evaluation and possible biological significance are discussed. There are insufficient data to properly define the dietary burdens, but it would seem that ellagic acid and gallic acid from natural sources may dominate in many cases, although the intake of added benzoic acid may be of a similar magnitude. It is pointed out that an additional, previously overlooked and possibly significant burden, particularly of benzoic acid itself, might arise as a result of the gut flora metabolism of larger-mass dietary phenols. © 2000 Society of Chemical Industry

Human studies on the absorption, distribution, metabolism, and excretion of tea polyphenols

Recent research on the bioavailability of flavan-3-ols after ingestion of green tea by humans is reviewed. Glucuronide, sulfate, and methyl metabolites of (epi)catechin and (epi)gallocatechin glucuronide reach peak nanomolar per liter plasma concentrations 1.6-2.3 h after intake, indicating absorption in the small intestine. The concentrations then decline, and only trace amounts remain 8 h after ingestion. Urinary excretion of metabolites over a 24-h period after green tea consumption corresponded to 28.5% of the ingested (epi)catechin and 11.4% of (epi)gallocatechin, suggesting higher absorption than that of most other flavonoids. The fate of (-)-epicatechin-3-O-gallate, the main flavan-3-ol in green tea, is unclear because it appears unmetabolized in low concentrations in plasma but is not excreted in urine. Possible enterohepatic recirculation of flavan-3-ols is discussed along with the impact of dose and other food components on flavan-3-ol bioavailability. Approximately two-thirds of the ingested flavan-3-ols pass from the small to the large intestine where the action of the microbiota results in their conversion to C-6-C-5 phenylvalerolactones and phenylvaleric acids, which undergo side-chain shortening to produce C-6-C-1 phenolic and aromatic acids that enter the bloodstream and are excreted in urine in amounts equivalent to 36% of flavan-3-ol intake. Some of these colon-derived catabolites may have a role in vivo in the potential protective effects of tea consumption. Although black tea, which contains theaflavins and thearubigins, is widely consumed in the Western world, there is surprisingly little research on the absorption and metabolism of these compounds after ingestion and their potential impact on health.