732 MANACH ET AL fruit is practically the sole source of flavanones.in stion of nol content As with fruit peeling.dehulling of legume als can res in a loss of som don average.although sult of cellular dec on and co etween cythe of soya in the Asian counries. 00m22327374 Europeans,soya consumeony a fewmilligramsof This kin sper day.Neverth s,the i nt corporation of e in isoflavone intake.Women unde ing pet oes have low flavonoid content.The pectinolytic enzymes used dur- extract capsules(75). the main sources are apple gra and red wine(76) (63)and is also higher than that(64) apples,and pears(27) sted (42)but there are still no rence food-composition tables (as theyxs partial data and hins,and s0 ished on as much as 500- pilations(37,65).Sir e March2003.a database i n w hich the also eat small quantities of fruit and veg ables do not inge d contents mg/d(54).AGerman e aily co culture website (66).A co eive table ipa of 599 ofp-coumaric acid)(65). 图 V15. in the 90 ntile 2014 DIETARY INTAKE OF POLYPHENOLS sumed up to 100mg/d(6).The main reason for thes d as the ined t the consumption the total i976Khnu()caouaiedthadicat oid intake ake.Ifm an values are diheahonothemakesoi and davano and and 459 Although these figures were 150 to which must be de he nins and nth nidins Finally the total no more precise ning the intake nt e probab com nly rea es I g/d in people w d in the United Sta mean value was 35(0).The intake of flavanones is similar useful.A few studies have tried to correlate flavonol.flavanone
and no remaining phenolic acids were found in French fries or freeze-dried mashed potatoes (54). Industrial food processing also affects polyphenol content. As with fruit peeling, dehulling of legume seeds and decortication and bolting of cereals can result in a loss of some polyphenols. Grinding of plant tissues may lead to oxidative degradation of polyphenols as a result of cellular decompartmentation and contact between cytoplasmic polyphenol oxidase and phenolic substrates present in the vacuoles. Polyphenols are then transformed into brown pigments that are polymerized to different degrees. This unwanted process can occur, for example, during the process of making jam or compote from fruit. Production of fruit juice often involves clarification or stabilization steps specifically aimed at removing certain flavonoids responsible for discoloration and haze formation. Manufactured fruit juices thus have low flavonoid content. The pectinolytic enzymes used during such processing also hydrolyze the esters of hydroxycinnamic acid (62). Conversely, maceration operations facilitate diffusion of polyphenols in juice, as occurs during vinification of red wine. This maceration accounts for the fact that the polyphenol content of red wines is 10 times as high as that of white wines (63) and is also higher than that of grape juice (64). Because of the wide range of existing polyphenols and the considerable number of factors that can modify their concentration in foods, no reference food-composition tables (as they exist for other micronutrients such as vitamins) have yet been drawn up. Only partial data for certain polyphenols, such as flavonols and flavones, catechins, and isoflavones, have been published on the basis of direct food analysis (11, 27) or bibliographic compilations (37, 65). Since March 2003, a database in which the flavonoid contents of 225 selected foods were compiled from 97 bibliographic sources has been available on the US Department of Agriculture website (66). A comprehensive composition table for polyphenols is essential; it should allow daily polyphenol consumption to be calculated from dietary questionnaires. Polyphenol intake could then be correlated with the incidence of certain diseases or early markers for these diseases in epidemiologic studies, which would permit investigations of the protective role of these micronutrients. DIETARY INTAKE OF POLYPHENOLS Only partial information is available on the quantities of polyphenols that are consumed daily throughout the world. These data have been obtained through analysis of the main aglycones (after hydrolysis of their glycosides and esters) in the foods most widely consumed by humans. In 1976 Kuhnau (8) calculated that dietary flavonoid intake in the United States was 1 g/d and consisted of the following: 16% flavonols, flavones, and flavanones; 17% anthocyanins; 20% catechins; and 45% “biflavones.” Although these figures were obtained under poorly detailed conditions, they continue to serve as reference data. Certain studies have subsequently provided more precise individual data concerning the intake of various classes of polyphenols. Flavonols have been more extensively studied. Consumption of these substances has been estimated at 20–25 mg/d in the United States, Denmark, and Holland (67– 69). In Italy, consumption ranged from 5 to 125 mg/d, and the mean value was 35 mg/d (70). The intake of flavanones is similar to or possibly higher than that of flavonols, with a mean consumption of 28.3 mg hesperetin/d in Finland (71). Because citrus fruit is practically the sole source of flavanones, ingestion of these substances is probably greater in regions where these fruits are produced, such as southern Europe. Anthocyanin consumption was studied only in Finland, where high amounts of berries are eaten, and was found to be 82 mg/d on average, although some intakes exceeded 200 mg/d (72). Consumption of soya in the Asian countries is 10–35 g/d, which is equivalent to a mean intake of 25–40 mg isoflavones/d, with a maximum intake of 100 mg/d (23, 73, 74). Americans and Europeans, who eat little soya, consume only a few milligrams of isoflavones per day. Nevertheless, the incorporation of growing quantities of soya extracts into manufactured food products could result in an increase in isoflavone intake. Women undergoing phytoestrogen replacement therapy for menopause consume between 30 and 70 mg isoflavones/d in the form of soya extract capsules (75). In Spain the total consumption of catechins and proanthocyanidin dimers and trimers has been estimated at 18–31 mg/d, and the main sources are apples, pears, grapes, and red wine (76). Consumption of monomer flavonols in Holland is significantly higher (50 mg/d), and the principal sources are tea, chocolate, apples, and pears (27). Ingestion of more highly polymerized proanthocyanidins could be as high as several hundred milligrams per day as previously suggested (42), but there are still no reliable data. Consumption of hydroxycinnamic acids may vary highly according to coffee consumption. Some persons who drink several cups per day may ingest as much as 500–800 mg hydroxycinnamic acids/d, whereas subjects who do not drink coffee and who also eat small quantities of fruit and vegetables do not ingest 25 mg/d (54). A German study estimated daily consumption of hydroxycinnamic acids and hydroxybenzoic acids at 211 and 11 mg/d, respectively. Caffeic acid intake alone was 206 mg/d, and the principal sources were coffee (which provides 92% of caffeic acid) and fruit and fruit juices combined (source of 59% of p-coumaric acid) (65). Various authors have noted a high variability in polyphenol intake. Intake of phenolic acids ranged from 6 to 987 mg/d in Germany (65). The mean consumption of flavonols and flavones in the Dutch population was 23 mg/d; values at the 10th and 90th percentiles were 4 and 46 mg/d, respectively; and some subjects consumed up to 100 mg/d (69). The main reason for these variations is individual food preferences. When polyphenol content is expressed as the amount provided by a food serving, as in Table 1, the consumption of one particular food, such as berries for anthocyanins or coffee for hydroxycinnamic acids, clearly appears to be capable of markedly changing the total polyphenol intake. If mean values are required, the addition of the intakes of flavonols, flavanones, flavanols (monomers, dimers, and trimers), and isoflavones gives a total daily consumption of 100– 150 mg in Western populations, to which must be added the considerably variable intake of hydroxycinnamic acids, anthocyanins, and proanthocyanidins. Finally, the total polyphenol intake probably commonly reaches 1 g/d in people who eat several servings of fruit and vegetables per day. Note that it is really difficult to follow a diet totally free of polyphenols. Because polyphenol intake is difficult to evaluate by using dietary questionnaires, biomarkers for polyphenol exposure would be very useful. A few studies have tried to correlate flavonol, flavanone, and isoflavone intakes with plasma concentrations or urinary excretion of metabolites (77–82), but we are not yet able to 732 MANACH ET AL by guest on February 15, 2012 www.ajcn.org Downloaded from
POLYPHENOLS:FOOD SOURCES AND BIOAVAILABILITY 733 me that the long-term intake of the various polyphenols BIOAVAILABILITY OF POLYPHENOLS It is important to realize that the polyphenols that are the most s questio tivityor because they are poorly absorbed from the intestine because ofa smaller exchange areaand a lower density of trans port systems.as ageneral geosidcsTmisthsbendleatyhonnnar ercetin of the bioavailability of glycos ab tial if their nd e 01 health effects are to be under 00d quantity of rutin( 3B-ruti form o than after ing on of ap the colonic microffora ore they can be ab orption oc rs in the small intest and the that i leSecsgndprodiurcS5wernoussimplearomatrcacid cetin ab orption has been partly cidated.Hollman et al su This is methylation, could then be inside the cells that restricts their potential agluc the aglycones are gen nt in the brush border (9).Both enz are r nvolyed bu on for the various d de nols are olic R.ol s certainly absorbec ey are m inchydrolasc,atlfS st in hydrolys 粉 tigated.Polyph nd the vatives are e 81 namofdcgt vlati the ypre the are subiected to the nila on of This enterohepatic recvcling may lead to a onger presence of B-gluc polyphenols within the body. cone sent in fermented Intestinal absorption and metabolisn du wn to be bette Much about the intestinal mechanisms of the gastrointestinal matr x effect may exp absorption pure but ane carriers that ld be involved in ministered orally to healthy that has he d f rable transpor mechanism involved in cin- 294 54 52 and 4.95 h/mL for daid n foods all fla e found in e ingestion than aft stomach showed that c level is pos ble for cones in a soy drink dnot ch inge the bic bilit中yo in humans.but note that in of
propose a reliable measurement in urine or plasma samples that could reflect the long-term intake of the various polyphenols. BIOAVAILABILITY OF POLYPHENOLS It is important to realize that the polyphenols that are the most common in the human diet are not necessarily the most active within the body, either because they have a lower intrinsic activity or because they are poorly absorbed from the intestine, highly metabolized, or rapidly eliminated. In addition, the metabolites that are found in blood and target organs and that result from digestive or hepatic activity may differ from the native substances in terms of biological activity. Extensive knowledge of the bioavailability of polyphenols is thus essential if their health effects are to be understood. Metabolism of polyphenols occurs via a common pathway (83). The aglycones can be absorbed from the small intestine. However, most polyphenols are present in food in the form of esters, glycosides, or polymers that cannot be absorbed in their native form. These substances must be hydrolyzed by intestinal enzymes or by the colonic microflora before they can be absorbed. When the flora is involved, the efficiency of absorption is often reduced because the flora also degrades the aglycones that it releases and produces various simple aromatic acids in the process. During the course of absorption, polyphenols are conjugated in the small intestine and later in the liver. This process mainly includes methylation, sulfation, and glucuronidation. This is a metabolic detoxication process common to many xenobiotics that restricts their potential toxic effects and facilitates their biliary and urinary elimination by increasing their hydrophilicity. The conjugation mechanisms are highly efficient, and aglycones are generally either absent in blood or present in low concentrations after consumption of nutritional doses. Circulating polyphenols are conjugated derivatives that are extensively bound to albumin. Polyphenols are able to penetrate tissues, particularly those in which they are metabolized, but their ability to accumulate within specific target tissues needs to be further investigated. Polyphenols and their derivatives are eliminated chiefly in urine and bile. Polyphenols are secreted via the biliary route into the duodenum, where they are subjected to the action of bacterial enzymes, especially -glucuronidase, in the distal segments of the intestine, after which they may be reabsorbed. This enterohepatic recycling may lead to a longer presence of polyphenols within the body. Intestinal absorption and metabolism Much about the intestinal mechanisms of the gastrointestinal absorption of polyphenols remains unknown. Most polyphenols are probably too hydrophilic to penetrate the gut wall by passive diffusion, but the membrane carriers that could be involved in polyphenol absorption have not been identified. To date, the unique active transport mechanism that has been described is a Na-dependent saturable transport mechanism involved in cinnamic and ferulic acid absorption in the rat jejunum (84). In foods, all flavonoids except flavanols are found in glycosylated forms, and glycosylation influences absorption. The fate of glycosides in the stomach is not clear. Experiments using surgically treated rats in which absorption was restricted to the stomach showed that absorption at the gastric level is possible for some flavonoids, such as quercetin and daidzein, but not for their glycosides (85, 86). Most of the glycosides probably resist acid hydrolysis in the stomach and thus arrive intact in the duodenum (87). Only aglycones and some glucosides can be absorbed in the small intestine, whereas polyphenols linked to a rhamnose moiety must reach the colon and be hydrolyzed by rhamnosidases of the microflora before absorption (88, 89). The same probably applies to polyphenols linked to arabinose or xylose, although this question has not been specifically studied. Because absorption occurs less readily in the colon than in the small intestine because of a smaller exchange area and a lower density of transport systems, as a general rule, glycosides with rhamnose are absorbed less rapidly and less efficiently than are aglycones and glucosides. This has been clearly shown in humans for quercetin glycosides: maximum absorption occurs 0.5–0.7 h after ingestion of quercetin 4'-glucoside and 6–9 h after ingestion of the same quantity of rutin (quercetin-3-rutinoside). The bioavailability of rutin is only 15–20% of that of quercetin 4'-glucoside (90, 91). Similarly, absorption of quercetin is more rapid and efficient after ingestion of onions, which are rich in glucosides, than after ingestion of apples containing both glucosides and various other glycosides (92). In the case of quercetin glucosides, absorption occurs in the small intestine, and the efficiency of absorption is higher than that for the aglycone itself (93, 94). The underlying mechanism by which glucosylation facilitates quercetin absorption has been partly elucidated. Hollman et al suggested that glucosides could be transported into enterocytes by the sodium-dependent glucose transporter SGLT1 (93). They could then be hydrolyzed inside the cells by a cytosolic -glucosidase (95). Another pathway involves the lactase phloridzine hydrolase, a glucosidase of the brush border membrane of the small intestine that catalyzes extracellular hydrolysis of some glucosides, which is followed by diffusion of the aglycone across the brush border (96). Both enzymes are probably involved, but their relative contribution for the various glucosides remains to be clarified. Quercetin 3-glucoside, which is not a substrate for cytosolic-glucosidase, is certainly absorbed after hydrolysis by lactase phloridzine hydrolase, at least in rats, whereas hydrolysis of quercetin 4'-glucoside seems to involve both pathways (97, 98). In humans, whatever the mechanism of deglucosylation, the kinetics of plasma concentrations are similar after ingestion of quercetin 3-glucoside or quercetin 4'-glucoside (99). Isoflavone glycosides present in soya products can also be deglycosylated by-glucosidases from the human small intestine (95, 96). However, the effect of glucosylation on absorption is less clear for isoflavones than for quercetin. Aglycones present in fermented soya products were shown to be better absorbed than were the glucosides ingested from soybeans (100). However, a dose or matrix effect may explain the difference in absorption observed in this first study. Setchell et al (101) showed that when pure daidzein, genistein, or their corresponding 7-glucosides were administered orally to healthy volunteers, a tendency toward greater bioavailability was observed with the glucosides, as measured from the area under the curve of the plasma concentrations: 2.94, 4.54, 4.52, and 4.95 g · h/mL for daidzein, genistein, daidzin, and genistin, respectively. However, in another human study, peak plasma concentrations were markedly higher after aglycone ingestion than after glucoside ingestion, and this effect was observed with low or high single doses and after long-term intakes (102). In addition, hydrolysis of isoflavone glycosides into aglycones in a soy drink did not change the bioavailability of the isoflavones in humans (103). No data are available for other polyphenols in humans, but note that in rats, no enhancement of POLYPHENOLS: FOOD SOURCES AND BIOAVAILABILITY 733 by guest on February 15, 2012 www.ajcn.org Downloaded from