Health Benefits of There is increasingly convincing evidence from Dietary : in vitro, in vivo and epidemiological studies Flavonols and suggesting the benefits of flavonoids in fruits and Rui Hai Liu vegetables in the Department of Food Science, Cornell University, Ithaca, NY prevention of chronic diseases because of their This work was funded in part by the New York State antioxidant, anti-cancer, Apple Research and Development Program. and cardiovascular- protective effects. lavonoids are a group of phenolic . Flavonols (, compounds that have been , and ) and flavones Fidentified in fruits, vegetables and (luteolin and ) are common other plant foods, and have been linked flavonoids in the daily diet (Fig. 1, Table initially thought. Hollman et al. (1995) fed to reducing the risk of major chronic 1). nine ileostomy patients, who lack colons, diseases. More than 4,000 distinct Flavonoids are most frequently found a single dose of quercetin in onions, which flavonoids have been identified, but many in nature as glycosides, but can occur as contain mostly quercetin-3-glucoside; are still unknown and need to be aglycones, especially due to the effects of pure quercetin-3-rutinoside (), the identified before we can fully understand food processing. Many different predominant form of quercetin in tea; and the health benefits of . glycosides can be found in nature as more pure quercetin aglycone. The average More and more convincing evidence than 80 different sugars have been absorption of quercetin was 52 percent suggests that the benefits of discovered bound to flavonoids. from onions, 17 percent for quercetin-3- phytochemicals in fruits and vegetables rutinoside, and 24 percent for quercetin may be even greater than currently Bioavailability aglycone. Because the quercetin 3- understood because oxidative stress glucoside present in onions cannot be induced by free radicals is involved in the Human intake of all flavonoids is cleaved by digestive enzymes, it was etiology of a wide range of chronic estimated at a few hundred milligrams transported intact into the enterocyte by diseases. (Hollman and Katan, 1999) to 650 mg per a sodium-dependent glucose transporter. Flavonoids commonly have a generic day (Kuhnau, 1976). The total average The same group later fed nine subjects structure consisting of two aromatic rings intake of flavonols (quercetin, myricetin, quercetin as a single large dose through (A and B rings) linked by three carbons kaempferol) and flavones (luteolin, onions (quercetin glucoside), apples (both that are usually in an oxygenated apigenin) was 23 mg/day, of which glucose or non-glucose quercetin heterocycle ring, or C ring (Figure 1). quercetin contributed about 70 percent, glycosides), and pure quercetin-3- Differences in the generic structure of the kaempferol 17 percent, myricetin 6 rutinoside, and monitored plasma heterocycle C ring classify them as percent, luteolin 4 percent and apigenin 3 quercetin levels over 36 hours (Hollman flavonols, flavones, flavanols (), percent (Hertog et al, 1993). In this study, et al. 1997). Quercetin from onions was , , and tea was the major source of flavonols and absorbed most rapidly, and rutin least flavones at 48 rapidly, indicating that quercetin percent of total glucoside is likely absorbed from the OH 3' OH OH intake, followed stomach or small intestine, while 2' 4' B by onions at 29 quercetin from rutin is probably absorbed O HO O HO O 7 5' 2 percent, and from the colon after microbial cleavage of A C 6 3 apples at 7 the sugar. Peak time and peak plasma 4 5 OH O OH O percent. levels were 0.7 h and 224 ng/mL after the Generic structure Luteolin Apigenin Flavonoids are onion meal, 2.5 h and 92 ng/mL after the usually bound apples, and 9 h and 90 ng/mL after the OH OH in foods to quercetin-3-rutinoside. Bioavailability of OH OH OH sugars as beta- quercetin from apples and pure quercetin- O O O HO HO HO OH glycosides and 3-rutinoside (rutin) was 30 percent of that OH OH OH were considered from onions. Half-life of quercetin in O O O OH OH OH non-absorbable. plasma was about 24 hours, suggesting Quercetin Kaempferol Myricetin Human that accumulation of the compound is absorption was possible. In a recent study, six subjects Figure 1. The generic structure of flavonoids, and structures of common greater than was were fed a meal containing fried onions flavonols and flavones. NEW YORK FRUIT QUARTERLY • VOLUME 10 NUMBER 3 • 2002 21 and fresh cherry tomatoes (Boyle et al. TABLE 1 2000). Plasma quercetin levels increased Major food sources of flavonols and flavones from 16.5 ± 2.7 ng/mL to 104.9 ± 10.42 ng/ mL four hours after ingestion and Flavonoids Major Food Sources remained elevated at eight hours. After 24 Flavonols Quercetin Onion, apple, broccoli, cranberry, grape, red wine* hours, plasma quercetin levels were still Kaempferol Kale, broccoli, parsley, leek, apple, berries, tea higher than the baseline. Therefore, the Myricetin Parsley, cranberry, grape, red wine, berries, spinach sugar moiety is important for Flavones Luteolin Celery, green pepper, spinach, green bean absorption and bioavailability, and Apigenin Celery, parsley, apple, grape, leek, onion conjugation with glucose enhances bioavailability. * Listed in order of content in foods (Arai et al, 2000; Hertog et al, 1993; Hollman and Arts, 2000).

Effects of Processing and Storage glycosides in the range of 7-46 percent showed an inverse association between (Dupont et al, 2000). Kaempferol the intake of flavonoids and incidence of The effect of processing on flavonoids conjugates, including kaempferol 3-O- all sites of cancer combined (Knekt et al, depends on the type of food, class of glucoside, kaempferol 3-O-glucuronide, 1997). After a 24-year follow-up, the risk flavonoids being evaluated, and and kaempferol 3-O-(6-O-malonyl) of lung cancer was reduced to 50 percent processing and storage conditions. glucoside have been found in endive in the highest quartile of flavonol intake. Flavonoids are usually present in foods as varieties. Analysis of kaempferol levels in Consumption of quercetin in onions and conjugates in glycosylated or esterified nine berries before and after they were apples was found to be inversely forms. Different processing techniques used for jam preparation indicated that associated with lung cancer risk in Hawaii may affect flavonoid release from the fresh and jam samples did not change (Le Marchand et al. 2000). The effect of bound. The effects of heat treatments on much, indicating the effect of jam onions was particularly strong against quercetin and kaempferol levels in onions, processing was little (Amakura et al, squamous cell carcinoma. Boyle et al. green beans, and peas have been studied 2000). However, the effect of processing (2000) showed that increased plasma (Ewald et al. 1999). Pre-processing of on the bioavailability of flavonoids has not levels of quercetin following a meal of onions (peeling, trimming, and chopping) been investigated. onions was accompanied by increased prior to blanching caused the greatest loss resistance to strand breakage by (39 percent) in flavonoids. Subsequent Health Benefits lymphocyte DNA and decreased levels of cooking, frying or warm-holding for up some oxidative metabolites in the urine. to 2 h of the blanched vegetables, resulted More and more convincing evidence Carcinogenesis is a multi-step process in insignificant losses, with kaempferol from in vitro, in vivo and epidemiological and oxidative damage is linked to showing a higher loss compared to studies suggests the benefits of flavonoids formation of tumors through several quercetin. in fruits and vegetables in the prevention mechanisms. Oxidative stresses induced In studying the effects of domestic of chronic diseases is because of their by free radicals cause DNA damage, and processing and storage on quercetin, antioxidant, anti-cancer, and when left unrepaired can lead to base myricetin, and kaempferol in five berries, cardiovascular-protective effects. mutation, single and double strand Hakkinen et al. (2000) reported that Cancer: Evidence suggests that breaks, DNA cross-linking and cooking strawberries with sugar to make dietary antioxidants can reduce cancer chromosomal breakage and jam resulted in minor losses (quercetin 15 risk. Block et al. (1992) established this in rearrangement. This potentially cancer- percent, kaempferol 18 percent), while a an epidemiological review of inducing oxidative damage might be 40 percent quercetin loss occurred during approximately 200 studies that examined prevented or limited by dietary cooking of bilberries with water and sugar the relationship between fruit and antioxidants found in fruits and to make soup. Cold-pressing was better vegetable intake and cancers of the lung, vegetables. Studies to date have than steam-extraction in extracting colon, breast, cervix, esophagus, oral demonstrated that flavonoids in common flavonols from black currants. When cavity, stomach, bladder, pancreas and fruits and vegetables can have stored at -20˚C for nine months, quercetin ovary. In 128 of 156 dietary studies, the complementary and overlapping content decreased (40 percent) in consumption of fruits and vegetables was mechanisms of actions, including bilberries and lingonberries, but not in found to have a significant protective modulation of detoxification enzymes, black currants or red raspberries. Under effect. In persons whose intake of fruits scavenging oxidative agents, stimulation similar conditions, myricetin and and vegetables was low compared to of the immune system, regulation of gene kaempferol were more susceptible to those with high intake, the risk of cancer expression in cell proliferation and losses (Hakkinen et al. 2000). Exposure of was twice as much. Significant protection apoptosis, hormone metabolism, and lettuce leaf to light after shredding was found in 24 of 25 studies for lung antibacterial and antiviral effects. produced significant losses of flavonoid cancer. Fruits were significantly protective Cardiovascular disease: Dietary moieties in green oak leaf (94 percent), in cancers of the esophagus, oral cavity, flavonoid intake was significantly green batavia (25 percent), iceberg (36 and larynx. In 26 of 30 studies, there was inversely associated with mortality from percent), lollo biondo (24 percent), red oak a protective effect of fruit and vegetable coronary heart disease, and an inverse leaf (43 percent) and lollo rosso (6 percent) intake in respect to cancers of the pancreas relation (weaker but significant) with samples (DuPout et al, 2000). Storage of and stomach and in 23 of 38 studies for incidence of myocardial infarction lettuce and endive heads in the dark at 1˚C colorectal and bladder cancers. A (Hertog et al, 1993b). In a study in and 98 percent humidity for seven days prospective study involving 9,959 men Finland, the intake of apples and onions, also caused losses of total flavonol and women at ages 15-99 in Finland both high in quercetin, was inversely 22 NEW YORK STATE HORTICULTURAL SOCIETY correlated with total and coronary Boyle, S. P., V. L. mortality (Knekt et al. 1996). In a recent Dobson, S. J. Duthie, Japanese study, the total intake of J. A. M. Kyle and A. flavonoids (quercetin, myricetin, R. Collins (2000). kaempferol, luteolin and ficetin) was Absorption and DNA inversely correlated with the plasma total protective effects of flavonoid glycosides cholesterol and low density lipoprotein from an onion meal. (LDL) cholesterol concentrations (Arai et European Journal of al. 2000). As a single , Nutrition 39: 213-223. quercetin intake was inversely related to DuPont, M. S., total cholesterol and LDL plasma levels. Mondin, Z., Mechanisms for the prevention of Williamson, G., Price, artheriosclerosis by antioxidants have K. R. (2000). Effect of been proposed. For example, oxidized variety, processing, low-density lipoprotein (LDL) and storage on the cholesterol is known as the atherogenic flavonoid glycoside factor that contributes to heart disease. content and Oxidized LDL is typically taken up by composition of macrophage scavenger receptors, thus lettuce and endive. J. Agric. Food Chem., 48, promoting cholesterol ester accumulation 3957-3964. and foam cell formation, which promotes Ewald, C., S. atherosclerotic disease. Dietary Fjelkner-Modig, K. antioxidants that are incorporated in LDL Johansson, I. Sjoholm Services are are themselves oxidized when these LDL and B. Akesson FREE are exposed to prooxidative conditions (1999). Effect of to Growers! before any extensive oxidation can occur processing on major in the sterol or polyunsaturated fatty flavonoids in acids (Sanchez-Moreno et al., 2000). In processed onions, addition, phytochemicals have been green beans, and shown to have roles in reduction of peas. Food Chemistry platelet aggregation, modulation of 64(2): 231-235. cholesterol synthesis and absorption, and reduction of blood pressure. Hakkinen, S. H., S. O. Karenlampi, H. M. (1997). Relative bioavailability of the Mykkanen and A. R. Torronen (2000). antioxidant flavonoid quercetin from various Summary Influence of domestic processing and storage foods in man. FEBS Letters 418(1-2): 152-156. In summary, dietary modifications on flavonol contents in berries. Journal of Knekt, P., R. Jarvinen, A. Reunanen and by increasing the consumption of fruits, Agricultural and Food Chemistry 48(7): 2960- J. Maatela (1996). Flavonoid intake and vegetables, and whole grains is a practical 2965. coronary mortality in Finland: a cohort study. Hertog, M. G. L., P. C. H. Hollman, M. B. British Medical Journal 312(7027): 478-481. strategy for consumers to optimize their Katan and D. Kromhout (1993). Intake of Knekt, P., R. Jarvinen, R. Seppanen, M. health and reduce the risk of chronic potentially anticarcinogenic flavonoids and Heliovaara, L. Teppo, E. Pukkala, and A. diseases. It is recommended that their determinants in adults in The Aromaa (1997). Dietary flavonoids and the consumers follow the USDA/USDHHS Netherlands. Nutrition and Cancer 20(1): 21-29. risk of lung cancer and other malignant Dietary Guidelines to meet their nutrient Hertog, M. G. L., E. J. M. Feskens, P. C. neoplasms. American Journal of requirements for health improvement H. Hollman, M. B. Katan and D. Kromhout Epidemiology 146, 223-230. and disease prevention. Antioxidants are (1993b). Dietary antioxidant flavonoids and Kuhnau, J. (1976). The flavonoids. A class best acquired through whole food risk of coronary heart disease: The Zutphen of semi-essential food components: their role consumption. Elderly Study. Lancet, 342: 1007-1011. in human nutrition. World Review of References Hollman, P. C. H. and I. C. W. Arts (2000). Nutrition and Dietetics 24, 117-191. Amakura, Y., Umino, Y., Tsuji, S., Tonogai, Flavonols, flavones and flavanols - Journal of Le Marchand, L., S. P. Murphy, J. H. Y. (2000). Influence of jam processing on the the Science of Food And Agriculture 80(7): 1081- Hankin, L. R. Wilkens and L. N. Kolonel radical scavenging activity and phenolic 1093. (2000). Intake of flavonoids and lung cancer. content in berries. J. Agric. Food Chem, 48: 6290- Hollman, P. C. H. and M. B. Katan (1999). Journal of the National Cancer Institute 92(2): 6297. Dietary flavonoids: intake, health effects and 154-160. Arai, Y., S. Watanabe, M. Kimira, K. bioavailability. Food and Chemical Toxicology Sanchez-Moreno, C., Jimenez-Escrig, A Shimoi, R. Mochizuki and N. Kinae (2000). 37(9-10): 937-942. and Saura-Calixto, F. (2000) Study of Low- Dietary intakes of flavonols, flavones and Hollman, P. C. H., J. H. M. de Vries, S. D. Density Lipoprotein Oxidizability Indexes to by Japanese women and the van Leeuwen, M. J. B. Mengelers and M. B. Measure the Antioxidant Activity of Dietary inverse correlation between quercetin intake Katan (1995). Absorption of dietary quercetin . Nutrition Research. 20(7):941-953. and plasma LDL chloesterol concentration. glycosides and quercetin in healthy ileostomy Journal of Nutrition 131(9): 2243-2250.. volunteers. American Journal of Clinical Rui Hai Liu is an assistant professor of food Block G, Patterson B, Subar A. Fruit, Nutrition 62(6): 1276-1282. science in Ithaca who studies the antioxidant vegetables, and cancer prevention: a review Hollman, P. C. H., J. M. P. van Trijp, M. and anticancer activities of the of the epidemiological evidence. Nutr Cancer; N. C. P. Buysman, M. S. Gaag, M. J. B. phytochemicals in fruit and vegetables. 18(1):1-29 1992. Mengelers, J. H. M. de Vries and M. B. Katan 24 NEW YORK STATE HORTICULTURAL SOCIETY