Nutritional summary

Function: The diversity of flavonoids is loo great to assign them specific properties. It is particularly important to emphasize that many flavonoids arc extremely toxic for humans. However, various flavonoids in edible foods are likely to promote health through antioxidant effects, actions on cellular signaling events, binding to sexhormone receptors, and modulation of detoxifying enzymes. Ftavonoid-rich fruits and vegetables (but not necessarily pharmaceutical products) are likely to decrease risk of atherosclerosis, cancer, and osteoporosis.

Food sources: Many fruits and vegetables are rich in flavonoids. Well-researched examples include soybeans (with the isoflavones genistein, daidzein, and glycitein). onions i with the flavonols quereetin, kaempferol, and luteolinl. grapefruit (with the flavanone naringenin), oranges (with the flavanone hesperitin and polymethoxylated Savones like tangeretin and nobiletin). chocolate (with anthoeyanins), and tea (with catechins and quereetin).

Requirements While there are no distinct requirements, a healthy diet should contain several servings of diverse fruits and \ egetablcs. This implicitly ensures a moderate to high intake of various flavonoids.

Deficiency: No specific functional deterioration has been linked to low or absent intake of flavonoids. However, people with low intake miss out on likely beneficial effects.

Excessive intake: While the consumption of commonly consumed flavonoid-rich foods in typical quantities is likely to be beneficial, the safety of high-dose food extracts or synthetic products is uncertain.

Structures

All flavonoids contain a bcnzopyran ring system (rings A and C) with an aromatic ring (ring B) linked to the oxygen heterocycle (Merken and Beccher, 2000), The classification of ftavonoids is based on variations in the heterocyclic ring, The oxygen heterocyclic ring in flavones such as apigcnin, luteolin (5,7,3\4'-tetrahydroxyfiavone), tricetin (5.7.3'.4',5'-pentahydroxy(lavone). and chrysin (5.7-dihydroxyflavonet. contains two double bonds and no substitution. Mcthoxyl instead of hydroxy! groups may also be attached to the basic flavone structure, as in tangeretin (5.6,7.8.4' pentamethoxyflavone nobilctin (5,6,7,X..V,4'-hexamclhoxytlavonel, and 3,5,6,7,8,3',4'-heptamethoxy flavone.

The B-ring in isoBavones (genistein. daid/ein. glycitein. biochanin A. formonetin) is linked to carbon 3 of the oxygen heterocyele. The flavonols, which include quercetin (3,5,7,3 \4'-pentahydroxyflavone), kaempferol (3.5,7.4'-tetrahydroxyflavone), and myricetin (3,5.7,3',4'.5'-hexahydroxyflavone), have an additional hydroxy group at carbon 3. In llavanoncs. such as naringenin (5,7,4'-trihydroxyfiavanone), hesperitin (5,7,3'-trihydroxy4'-methoxyflavanone), and eriodictyol (5.7.3',4' tctrahydroxy-flavanone), the heterocyclic ring is saturated. The catcchins and anthocyanidins lack the carbonyl function at carbon 4. An excellent discussion of flavonoid structures and analytical methods for flavonoid measurement in foods and other biological samples has been presented by Merken and Beechcr (Merken and Beecher. 20(10).

Flavonoids in plants arc predominantly linked in beta-configuration to sugars such as glucose, rhamnosc (6-deoxy-L-mannose), rutinose (6-O-a-L-deoxymannosyl-D-glucose). neohesperidose (6-deoxy-a-L-mannopyranosyl-^-D-glucose). galactose and xylose (Merken and Beecher. 2000). Genistein is ingested mainly as genistein-7-j3-glucoside (genistm), naringenin as naringenin-7-£f-rhamnoglucoside (nanngin), naringenm-7-ff-rutinosidc (nanrutinf, or naringetun-7-j8-glucoside (prunin), and quercetin as quercetin-3-j3-rutinoside (rutin), quercetin-4'-ii-glucoside. quercctin-3-0-glucoside (isoquercitrin), quercetin-3-/i-rhamnoside (quercitrin). or quercetin-3-0-galactoside (hyperoside). Flavonoid ^-glycosides also may carry additional small molecular modifiers, such as malonyl and acetyl groups, Aglycones are flavonoid molecules without any attached sugars or other modifiers. Sugar-linked flavonoids are called glycosides. The term glucoside only applies to flavonoids linked to glucose.

Dietary sources

Isoflavones. The main fiavonoid compounds in soy are genistein, daidzein, and glycitin, Coumestrol is found in lima beans, peas, alfalfa sprouts, and clover sprouts. Formononetin is in green beans, clover sprouts. Biochanin A is in garbanzo, kidney, pinto and other beans, but not in soybeans (Franke et al.. 1995). These isoflavones are present as aglycones, bcta-glucosides, acetylglucosides, and malonylglucosides.

CHa Nobilin

OH O Myrieelin

(a) Apigenin Luleotin Chrysin

Enodictyol

Genistein Daidzein Glycllein

(a) Apigenin Luleotin Chrysin

Enodictyol

(e) Naringenin

Hesperelin

(d) Kaempiefoi

OH O Myrieelin

Biochantn A

Formononelin

Que reel in

(b) Tangeretin

CHa Nobilin

Figure S.4 Structures ofctimmon types of dietary flavonoids (a) flaTOnes; (b) polymethoitylated flavours. (c) loflavones. (d)flavonols. (e) flavanones; (f) catcchins: (g) anthocyarvidins

(- J-Epicaiechm

(- J-Epicaiechm

( J-Epigallocatechin 3-gallate

Pelargontdin

Cyamdin

Delphi nidi n

Pelargontdin

Cyamdin

Delphi nidi n

( J-Epigallocatechin 3-gallate

Malvidin

(9) Peonidin

Malvidin

Tiic amounts and proportions of these typos depend on species, variety, growing conditions, and processing. Median daily isoflavone consumption of postmenopausal women in (lie US is a fraction of a milligram (Framingham 1 lean Study, de Kleijn et til.. 2000). Mean daily isoflavone intake of soy-consuming individuals, such as in some East Asian countries, often is well above 30 mg.

COOH

Malonylgenislin (6' - m atony I -geni slei n 7-[i-giucosicie)

Nanngin (nanngenin 7-fJ-rtiamnoglucoside)

Que real in 4,-)l-glucoside

Figur* S.S Most flavonoids in foods are linked to sugars and other molecules

COOH

Malonylgenislin (6' - m atony I -geni slei n 7-[i-giucosicie)

Que real in 4,-)l-glucoside

Figur* S.S Most flavonoids in foods are linked to sugars and other molecules

Nanngin (nanngenin 7-fJ-rtiamnoglucoside)

Flawnes; Apigenin is consumed with parsley, chamomile tea. celery, and other fruits and vegetables. Many fruits and vegetables, including olives (Blekas et til.. 20021. contain luteolin. The peels and expressed juice of oranges and other citrus fruit contain various polymethoxylated Havones (Takanaga ei ul„ 2(HX)), including tangeretin (5,6,7,8,4'-pentamethoxyflavonc. 0.3-1.6p-g/ml), nobiletin (5.6.7,8,3\4'-hexamethoxy-llavone, 0.8 4.3 p.gfatl), and 3,5,6,7,8,3 \4'-heptamethoxytlavone (0.2-1.5 pg ml). Flavonols: Yellow onions and black tea are the main source of flavonoids. The principal llavonoi m onions is quereetin (about 0.4mg/g), 45% of it as querceiin-4'-glucoside. Berries and the peels of apples, tomatoes (especially cherry tomatoes), and other fruits and vegetables contain quercetin-3-O-rutinoside (rutin). flic quereetin content of olives can be as high as 0,6 mg/g (Blekas etal., 2002). Blackcurrants and other berries contain relatively targe amounts of myricetin (Hakkincn et ui. 1999). Kaempferol is found in gooseberries and strawberries, hut also in many other fruits and vegetables.

Average daily quereetin intake in the Netherlands is I6mg<day I Hertog el at., 1993), A much lower intake (3.3 mg) was found in Finland (Knekt et at.. 2002). The Finnish survey also estimated mean daily intakes of kaempferol (O.ftmg) and myricetin (0.12 mg). Development of a flavonoid database has been undertaken to facilitate meaningful assessment of intakes in the US (Pillow et ul.. 1999), flavamnes: The principal flavonoids in grapefruit are naringin (naringenm-7-mtinoside, 0.35mg ml) and naringeiiin-7-rhainnoglueoside (0.1-0.5 mg ml). The bitter llavor is an approximate indicator of the naringenin content in different grapefruit varieties. Oranges contain mainly hcsperitin-7-rutinosidc (0.21 mg ml) and a smaller amount ofnaringin (0.04mg/ml). Beer provides small amounts of hops-derived 8-prenylnaringenin (Rong et al.. 20011, xanthohumol (3'-preny 1-6'-O-methy Ichalconaringenin). and desmethvl-xanthohumol, 3'-gerany Ichalconaringenin (Stevens et al., 2000). Tomato peels eontain naringenin chalcone. Owing to widespread use of llavanone-containing foods and beverages, intakes are significant. A survey in Finland (Knckt et al.. 2002) assessed mean daily consumption of naringenin (5.1 mg) and hesperttin (15.1 mg). Catechins: Green lea is a particularly rich source of (+)-eatechin, ( — )-cpicatechiu. ( )-epigallocatechin, and the 3-O-gaIlate derivatives of (— )-cpieateehm and ( - )-cpi-gallocatechin. Black and other teas, red wine, apple cider, and beer are less concentrated sources of catechins.

Anthotyanidins: This class of colorful compounds, many of which are toxic, has many representatives in herbs and flowers. Many berries and other fruits and vegetables get their vibrant colors from anthocyanidins. The depth of the coloring tends to indicate the tolal ftavonoid content of different fruit cultivars (Liu etal.. 2002). Relatively common derivatives are eyanidin (in cocoa, chocolate, and fruits), pelargonidin (the red dye in strawberries), delphinidin (gives pomegranates their violet hue), malvidin (red to violet color), petunidin (violet), and peonidin (reddish-brown to purple). Anthocyanidins usually have one, two or three sugars attached (and arc then called anthocyanins) and may be acylated, The poor solubility and strong coloring of anthocyanins guarantees fairly permanent stains on fabrics t for example when blueberry juice spills on a shirt).

Absorption

Ftavonoid absorption ranges from virtually nonexistent for some to extensive for others. There is good reason to believe that the limited bioavailability, particularly of carbohydrate-linked llavonoids, affords some protection from the potent toxicity of many plant glycosides. Howev er, some absorption docs occur. Some glycosides can be cleaved by lactase (EC3.2.1.108) at the brush border of the proximal small intestine (Day etui.. 2000; Kohlmeier et al.. 2000; Setchell et al.. 2002) and by bacterial 0-glucosidases (FX'3.2.1.21) in the terminal ileum and colon (Setchell et al.. 1984). Hydrolysis improves bioavailability, if the aglycone is better absorbed than the glycoside.

The sodium/glucose cotransponer I (SGLT1. SLC5A1) is a port of entry for q u e rcet in~4'-gl ucoside and its aglycone (Walgren t'f al.. 2000), but the efficiency and selectivity of this pathway for other flavonoids remains to be investigated (Wolffram et at.. 2002). The multidrug resistance protein 2 (MRP2. ABCC2) actively pumps conjugated llavonoids such as ge n i stei n-7-g I ucoside back into the intestinal lumen (Walle et al.. 1999). P-glycoprotein (Pgp. VIDR1, ABCB1) and MDR3 (ABCB4] at the luminal membrane show similar activity, the former with particularly high affinity for llavones (Comte et al.. 2001). In addition. MRP1 (ABCC1). and the organic anion transporter OATP8 (SLC21A8) at the basolateral membrane import some llavonoid conjugates across the basolateral membrane from the pericellular space.

Intestinal (JDP-glucuronosy(transferase (EC2.4.I.17) UGTIA1 conjugates most flavonoids. Sulfation by aryl sulfotransfera.se (phenol sulfotransferase, SULT; EC2.8.2.1)

Flai/onoid glycoside

Flai/onoid glycoside

Na* Ravonoid conjugale

Flavo notd conjugate

Brush border membrane

Basóla toral membrane

Fijjur« 5.6 Mechanisms thai: affect intestinal absorpoon of ftavonoids

Ravonoid glycoside

Bacterial P-glucos-idasas

Aglycone

Na* Ravonoid conjugale

Flavo notd conjugate

Brush border membrane

Capillary endothelium

Fijjur« 5.6 Mechanisms thai: affect intestinal absorpoon of ftavonoids is not as extensive, but of equal importance, since the sulfate conjugates may be the most activ e form of many flavonoids.

The mechanisms for export of llavonoids across the basolateral membrane towards pericapillary space remain uncertain, but may involve active transport \ia MRP3 (ABCC3), MRP5 (ABCC5), and/orMRP6 (ABCC6). Effective fractional absorption therefore depends on the net transpon rates across each side of the enterocyte as well as on losses due to intestinal catabohsm. Extensive en tero hepatic circulation is likely to occur with isollavones (Sfakianos et a I.. 1997) and presumably other flavonoids. Isoflavones: Absorption is maximal within 4 f>hours in health) subjects, and complete within IK hours: urinary excretion is maximal v\ ¡thin i> 8hours, nearly complete v\ ithin 12 hours (Lu and Anderson. I99X; Fanti et a!.. 1999). Fractional intestinal absorption may be (Xu eta¡., 1994) as low as 9% forgcnistinigenistein 7-O-0-glucoside) and 21% fordaidzin (daidzein 7-0-/£S-glucoside) or even less (Hutchins eta!.. 1995), but possibly higher with ingestion of aglycones. Others have found that glucósido and aglycone of gcnistcin are similarly well absorbed, presumably after hydrolysis of the glucoside [King et al„ 1996). Recent evidence strongly indicates that net absorption of uncleaved isofiavone glucosides is minimal (Setchelt et a!.. 2002).

The aglycones are converted to 7-0-j9-glucuronide, to a smaller extent to the sulfate conjugate. The mechanism of export is unknown,

Flavones: A very small, kit biologically significant traction of ingested apigenin is absorbed, as indicated by the fact that 0.f>% of an oral dose can be recovered from urine (Nielsen et a /.. 1999). The bioavailability ofehrysin seems to be similarly low (Watle ei ul., 2001). Flavones bind to the reverse transporter P-glycoprotein (Pgp. MDRI, ABCBI) with higher affinity than isoflavones, flavanones, and glycosylated derivatives (Comte et al., 2001). It should be noted that polymethoxylated flavottes in orange juice are potent inhibitors of this transporter and may therefore increase net absorption of other flavonoids (Takanaga et al.. 2000),

Flavonols: Quercetin rutinoside is very poorly absorbed. The bioavailability of the agiycon is slightly greater, and quercetin glucosides from onions are absorbed best (Hoiman eta!., 1995).

Flavanones: Cytosolic /i-glucosidase (EC3.21.2.1) in enterocytes and heputocytes can cleave naringenin-7-glucoside. but not naringenin-7-rhamnoglucoside (Day et al.. 199N).

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