Dietary Bioactive Compounds and Their Health Implications

Authors


  • Author Disclosure: The author serves on the Scientific Nutrition Research Panel for the California Raisin Marketing Board.

  • This paper is presented at the IFT Webinar: Emerging Health Benefits of Traditional Dried Fruits. Institute of Food Technologists, July 18, 2012.

Direct inquiries to author Liu (E-mail: RL23@cornell.edu).

Abstract

 There is strong scientific evidence suggesting that regular consumption of fruits and vegetables is negatively associated with risk of developing chronic diseases. The 2010 Dietary Guidelines for Americans recommend at least 9 servings of fruits and vegetables a day based on a 2000 kcal diet. However, the average person in the United States consumes 3.6 servings of fruits and vegetables per day. In order to achieve the goal of at least 9 servings, we should continue educating Americans about the health benefits of fruits and vegetables and recommend consumers to eat a wide variety of fruits and vegetables. The key is to increase the amount up to 9 to 13 servings of fruits and vegetables a day in all forms. Fresh, cooked, and processed fruits and vegetables including frozen and canned, 100% fruit juices, 100% vegetable juices, and dried fruits are all considered as servings of fruits and vegetables. A wide variety of fruits and vegetables provide a range of nutrients and different bioactive compounds including phytochemicals (phenolics, flavonoids, and carotenoids), vitamins (vitamin C, folate, and provitamin A), minerals (potassium, calcium, and magnesium), and fibers. More and more evidence suggests that the health benefits of fruits and vegetables are attributed to the additive and synergistic interactions of the phytochemicals present in whole foods by targeting multiple signal transduction pathways. Therefore, consumers should obtain nutrients and bioactive compounds from a wide variety of whole foods for optimal nutrition and health well-being, not from expensive dietary supplements.

Introduction

Cardiovascular disease (CVD) and cancer are the top 2 leading causes of death in the United States and in most industrialized countries. More and more evidence suggested that high consumption of fruits and vegetables is strongly associated with reduced risk of developing chronic diseases such as CVD, cancer, diabetes, Alzheimer's disease, cataracts, and age-related functional decline (Block and others 1992; Willet 2002; Genkinger and others 2004; Freedman and others 2008). It is estimated that more than 30% of all cancer deaths in the United States could be avoided through appropriate life style changes and dietary modification (Doll and Peto 1981; Willet 1995, 2002). This suggests that changes in dietary behavior and life style, such as increasing consumption of fruits and vegetables and exercise, are practical strategies to reducing the incidence of chronic diseases.

A wide variety of fruits and vegetables provide different nutrients and a range of bioactive compounds including vitamins (vitamin C, folate, and provitamin A), minerals (potassium, calcium, and magnesium), phytochemicals (flavonoids, phenolic acids, alkaloids, and carotenoids), and fibers (Liu 2004). The 2010 Dietary Guidelines for Americans (United States Department of Agriculture 2010) recommend that most people should eat at least 9 servings (4½ cups) of fruits and vegetables a day, 4 servings (2 cups) of fruits, and 5 servings (2.5 cups) of vegetables, based on a 2000 kcal diet. However, it was reported that the average person in the United States consumed only 3.6 servings (1.8 cups) of fruits and vegetables (0.7 cups of fruits and 1.1 cups of vegetables) per day in 2010 (Produce for Better Health Foundation 2010). This is much less than the amount recommended. In order to achieve the goal of at least 9 servings, we should continue educating Americans about the health benefits of fruits and vegetables, and recommend everyone to eat a wide variety of fruits and vegetables including all forms, fresh, frozen, canned, dried, and 100% juices; and manufacturers should make available convenient packaging to make fruits and vegetables easy to serve and to store.

This paper will review the evidence supporting a high intake of fruits and vegetables in the prevention of CVD and cancer, and their bioactive phytochemicals related to the health benefits.

Dietary phytochemicals

The word “phytochemical” is derived from appending the word “chemical” to the Greek root word phyto, meaning plant. Phytochemicals are defined as bioactive nonnutrient plant chemicals in fruits, vegetables, grains, and other plant foods that may provide desirable health benefits beyond basic nutrition to reduce the risk of major chronic diseases (Liu 2004). More than 5000 individual phytochemicals have been isolated and identified in fruits, vegetables, and grains, but a large percentage still remains unknown. These phytochemicals need to be identified before we can fully understand the health benefits of dietary phytochemicals in whole foods (Liu 2003). Dietary phytochemicals differ widely in composition from various fruits, vegetables, and whole grains, and often have complementary mechanisms to one another. Therefore, it is suggested that in order to receive the greatest health benefits, one should consume a wide variety of plant-based foods daily (Liu 2003, 2004). In addition, more and more convincing evidence suggests that the benefits of phytochemicals may be even greater than is currently understood because the oxidative stress that is induced by free radicals is involved in the etiology of a wide range of chronic diseases (Ames and Gold 1991; Liu and Hotchkiss 1995; Liu 2004).

Dietary phytochemicals can be classified into broad categories as phenolics, alkaloids, nitrogen-containing compounds, organosulfur compounds, phytosterols, and carotenoids (Liu 2004). Of these phytochemical groups, the phenolics are the most studied.

Phenolics

Phenolics are defined as compounds possessing 1 or more aromatic rings with 1 or more hydroxyl groups in the structures. They are generally categorized as phenolic acids, flavonoids, stilbenes, coumarins, and tannins (Liu 2004).

Phenolics are the products of secondary metabolism in plants. They provide essential functions in the reproduction and growth of the plants, act as defense mechanisms against pathogens, parasites, predators, and UV irradiation, and also contribute to the color of plants. In addition to their roles in plants, phenolic compounds in our diet may provide additional health benefits associated with reduced risk of developing chronic diseases. Among the 25 most common fruits consumed in the United States, wild blueberry and blackberry are known to have the highest total phenolic contents, followed by pomegranate, cranberry, blueberry, plum, raspberry, strawberry, red grape, and apple (Figure 1; Sun and others 2002; Wolfe and others 2008). The remaining fruits, in order of total phenolic content, were pear, pineapple, peach, grapefruit, nectarine, mango, kiwifruit, orange, banana, lemon, avocado, cantaloupe, honeydew, and watermelon. Apples were the largest contributors, 33%, of fruit phenolics to the American diet (Wolfe and others 2008). Among the 27 vegetables commonly consumed in the United States, spinach had the highest total phenolic content, followed by red pepper, beets and broccoli, Brussels sprouts, eggplant and asparagus, and green pepper. The remaining vegetables, in order of total phenolic content, were yellow onion, cauliflower, cabbage, radish, chili pepper, mushroom, sweet potato, carrot, sweet corn, potato, squash, white onion, green pea, tomato, green bean, celery, lettuce, romaine lettuce, and cucumber (Figure 1; Chu and others 2002; Song and others 2010). Dried fruits are also good sources of dietary phenolics (Yeung and others 2003; Wu and others 2004; Zhao and Hall 2008). Raisins are high in total phenolics and have high antioxidant activity as measured by oxygen radical absorbance capacity (ORAC) and peroxyl radical scavenging capacity (PSC; Table 1). Golden raisins had higher phenolic content and antioxidant activity than the sun-dried raisin (Yeung and others 2003).

Table 1. Total phenolic content and antioxidant activity of raisins
 Sun-dried raisinsGolden raisins
Total phenolics  
(mg of gallic acid equivalents/100 g)192.4 ± 14.8568.6 ± 26.4
ORAC  
(Trolox equivalents/g)42.6 ± 5.1116.4 ± 9.8
PSC  
(mg of Vitamin C equivalent/100 g)130 ± 8.6336.5 ± 21.2
Figure 1.

Total phenolic content of common fruits and vegetables (Adapted from Yeung and others 2003; Wolfe and others 2008; Song and others 2010).

Phenolic acids account for approximately 1/3 of the phenolics in our diet and that the remaining 2/3 are from flavonoids (Liu 2004).

Phenolic acids

Phenolic acids, one of the major sources of dietary phenolics, can be subdivided into 2 major groups, hydroxybenzoic acid and hydroxycinnamic acid derivatives (Liu 2004). Hydroxybenzoic acid derivatives include p-hydroxybenzoic, gallic, protocatechuic, vanillic, and syringic acids. These phenolic acids are commonly present in the bound form in foods and are typically components of a complex structure like lignins and hydrolyzable tannins. They are also attached to fiber, sugar, and proteins, and found in sugar derivatives and organic acids in plant foods.

Hydroxycinnamic acid derivatives include p-coumaric, caffeic, ferulic, and sinapic acids. They are mainly present in the bound form, linked to cell wall structural components such as cellulose, lignin, and proteins through ester bonds (Liu 2004). Ferulic acids occur primarily in the seeds and leaves of plants, mainly covalently conjugated to mono- and disaccharides, plant cell wall polysaccharides, glycoproteins, polyamines, lignin, insoluble carbohydrate biopolymers, and fibers (Liu 2007). Wheat bran is a good source of ferulic acids, which are esterified to hemicellulose of the cell walls. Bound ferulic acids are the predominant form in grains, and free, soluble-conjugated, and bound ferulic acids in grains are present in the ratio of 0.1:1:100 (Adom and Liu 2002). Food processing, such as thermal processing, pasteurization, fermentation, and freezing, releases free and soluble-conjugated ferulic acids from bound phenolic acids (Dewanto and others 2002).

Caffeic, ferulic, p-coumaric, protocatechuic, and vanillic acids are present in almost all plants. Chlorogenic acids and curcumin are major derivatives of hydroxycinnamic acids present in plants. Chlorogenic acids are the esters of caffeic acids and are the substrates for enzymatic oxidation leading to browning, particularly in apples and potatoes. Curcumin consists of 2 ferulic acids linked by methylene in a diketone structure and is the major yellow pigment of spice turmeric (Liu 2004).

In raisins, the most abundant phenolic acids are caftaric acid, coutaric acid, gallic acid, and clorogenic acid (Karadeniz and others 2000; Parker and others 2007; Zhao and Hall 2008).

Flavonoids

Flavonoids are one of largest groups of phenolic compounds in fruits, vegetables, and other plant foods. Epidemiological studies have consistently shown that high intake of flavonoids is negatively associated with reduced risk of major chronic diseases (Liu 2004). It is estimated that more than 4000 flavonoids have been identified in the literature. They commonly have a generic structure consisting of 2 aromatic rings (A and B rings) linked by 3 carbons that are usually in an oxygenated heterocycle ring, or C ring. Differences in the generic structure of the heterocycle C ring classify them as flavonols, flavones, flavanols (catechins), flavanones, anthocyanidins, and isoflavonoids. Flavonols (quercetin, kaempferol, myricetin, and galangin), flavones (luteolin, apigenin, and chrysin), flavanols [catechin, epicatechin, epigallocatechin (EGC), epicatechin gallate (ECG), and EGC gallate (EGCG)], flavanones (naringenin, hesperitin, and eriodictyol), anthocyanidins (cyanidin, malvidin, peonidin, pelargonidin, and delphinidin), and isoflavonoids (genistein, daidzein, glycitein, and formononetin) are common dietary flavonoids in our diet. In nature, flavonoids are frequently present as conjugates in glycosylated or esterified forms, but can occur as aglycones, especially as a result of the effects of food processing. There are many different glycosides of flavonoids in nature, because more than 80 different sugars have been identified bound to flavonoids (Hollman and Arts 2000). Red and blue colors in some fruits, vegetables, and whole grains are from anthocyanidins. Oranges and orange juices are good sources for hesperetin and naringenin. The major flavonoids in apples are quercetin, epicatechin, and cyanidin. In raisins, the most abundant flavonoids are quercetin glycoside, quercetin, kaempferol glycoside, kaempferol, catechin, epicatechin, and rutin (Karadeniz and others 2000; Parker and others 2007; Zhao and Hall 2008).

Human intake of all dietary flavonoids is estimated at a few hundred milligrams (Hollman and Katan 1999) to 650 mg/d. Hertog and others (1993) reported the total average intake of flavonols (quercetin, myricetin, and kaempferol) and flavones (luteolin and apigenin) was estimated as 23 mg/d, of which quercetin contributed about 70%, kaempferol 17%, myricetin 6%, luteolin 4%, and apigenin 3%.

Dietary phytochemicals in the prevention of CVD

Hertog and others (1993, 1995) reported that dietary flavonoid intake was significantly inversely associated with mortality from coronary heart disease (CHD), and had an inverse relationship with the incidence of myocardial infarction. In another study, the total intake of flavonoids (quercetin, myricetin, kaempferol, luteolin, and ficetin) was inversely correlated with the plasma total cholesterol and low-density lipoprotein (LDL) cholesterol concentrations (Arai and others 2000). As a single phytochemical, quercetin intake was inversely related to total cholesterol and LDL plasma levels. The relative risk of CVD in the Women's Health Study subjects was 0.68 for CVD when comparing the highest with the lowest quintiles of fruit and vegetable intake, and the relative risk for myocardial infarction was 0.47. It was estimated that there was a 20% to 30% reduction in risk of CVD associated with high fruit and vegetable intake (Liu and others 2000). Joshipura and others (2001) reported that total intake of both fruits and vegetables was each associated with decreased risk for CHD. An inverse association between total consumption of fruits and vegetables and CHD was observed in a dose-dependent manner above intake of more than 4 servings per day. In a study involving subjects from the National Health and Nutrition Examination Survey Epidemiologic Follow-up Study, participants with consumption of fruits and vegetables at least 3 times per day had a 27% lower CVD mortality when compared to only once per day. Fruit and vegetable intake was inversely associated with incidence of stroke, stroke mortality, CHD mortality, CVD mortality, and all-cause mortality (Bazzano and others 2002).

Trichopoulos and others (2003) reported that people with a higher degree of adherence to the Mediterranean diet, which consists of an increased consumption of fruits and vegetables, were associated with a 25% reduction in total mortality and a 33% reduction of death due to CHD. Genginker and others (2004) found that participants with the highest quintile of fruit and vegetable intake had a lower risk of all-cause mortality (relative risk of 0.63, 95% CI: 0.51 to 0.78) and CVD mortality (relative risk of 0.76, 95% CI: 0.54 to 1.06) than those in the lowest quintile. A combined analysis of over 100000 participants in the Nurses’ Health Study and the Health Professionals’ Follow-up Study showed that fruit and vegetable intake was inversely associated with risk of CVD, with relative risk for an increment of 5 servings daily of 0.88 (95% CI = 0.81 to 0.95), and green leafy vegetables showed the strongest inverse association (Hung 2004). Heidemann and others (2008) reported that a more prudent diet containing high intakes of fruits and vegetables was associated with a 28% lower risk of cardiovascular mortality (95% confidence interval 13% to 40%) and a 17% lower risk of all-cause mortality (10% to 24%) when comparing individuals in the highest to the lowest quintile of diet prudency. In another cohort study, it was reported that the relative risk of CHD incidence was 0.66 (95% CI: 0.45 to 0.99) for participants with a high intake of fruits and vegetables compared to those with low consumption, and this inverse relationship was present regardless of whether the fruits and vegetables are raw or processed (Oude and others 2010).

Mechanisms for the prevention of atherosclerosis by dietary antioxidants in fruits and vegetables have been proposed. In the LDL oxidation hypothesis, oxidized LDL cholesterol by free radicals has been suggested as the atherogenic factor that contributes to CVD (Berliner and Others 1997; Witztum and Berliner 1998). When circulating LDLs are present at high levels in blood, they infiltrate the artery wall and increase intimal LDL, which can then be oxidized by free radicals. This oxidized LDL in the intima is more atherogenic than native LDL and serves as a chemotactic factor in the recruitment of circulating monocytes and macrophages. Since oxidized LDL plays a key role in the initiation and progression of atherosclerosis, giving dietary phytochemicals with antioxidant activity capable of preventing LDL oxidation has been an important therapeutic approach. Dietary phytochemicals served as antioxidants that are incorporated into LDL are themselves oxidized when the LDL is exposed to free radicals; this occurs before any extensive oxidation of the sterol or polyunsaturated fatty acids can occur (Sanchez-Moreno and others 2000). Therefore, dietary phytochemicals might retard the progression of atherosclerotic lesions.

In addition, C-reactive protein, a marker of systemic inflammation, has been reported to be a stronger predictor of CVD (Ridker and others 2002), suggesting that inflammation is a critical factor in CVD. Inflammation not only promotes initiation and progression of atherosclerosis, but also causes acute thrombotic complications of atherosclerosis (Libby and others 2002). In a 2005 Italian study, the relationship between high-sensitivity C-reactive protein (hs-CRP) and the total antioxidant capacity (TAC) of a diet was studied. Even within groups controlled for dietary factors, TAC was significantly higher among those with a low level of plasma hs-CRP when compared to subjects with high levels of plasma hs-CRP (Brighenti and others 2005). This indicates that the TAC of a specific diet is independently and inversely correlated with hs-CRP, and that this could be one of the mechanisms behind the protective effects of fruits and vegetables against CVD. Dietary phytochemicals can lower C-reactive protein dramatically. An Iranian study in Tehran found that both fruits and vegetables were inversely associated with plasma CRP concentrations (Esmaillzadeh and others 2006), as did a 2004 study in Massachusetts (Gao and others 2004). Therefore, the anti-inflammatory activity of phytochemicals may play an important role in the prevention of CVD. In addition, dietary phytochemicals have been shown to have roles in the regulation of prostaglandin synthesis, reduction of platelet aggregation, regulation of cholesterol synthesis and absorption, and reduction of blood pressure.

Dietary phytochemicals in the prevention of cancer

It has been estimated that over 30% of all cancer deaths in the United States are due to dietary choices (Doll and Peto 1981; Willett 1995). Increasing antioxidant defenses through intake of dietary phytochemicals in fruits and vegetables may reduce or delay the oxidation of DNA and affect cellular signal transduction pathways controlling cell proliferation and apoptosis (Liu 2004). The evidence supporting a high intake of fruits and vegetables to prevent cancer is reviewed below.

Epidemiological studies have consistently shown that regular consumption of fruits and vegetables can reduce cancer risk. Block and others (1992) reviewed about 200 epidemiological studies that examined the relationship between consumption of fruits and vegetables and cancer of the lung, colon, breast, cervix, esophagus, oral cavity, stomach, bladder, pancreas, and ovary, and concluded that the consumption of fruits and vegetables was related to a reduced risk of cancer incidence. High consumption of fruits particularly had significant protection against cancer of the esophagus, oral cavity, and larynx. The risk of cancer was 2-fold higher in persons with a low intake of fruits and vegetables than in those with a high intake. In a meta-analyses conducted by Steinmetz and Potter (1996), 12 out of 20 prospective cohort studies showed that consumption of fruits and vegetables was statistically negatively associated with reduced risk of cancer.

Voorrips and others (2000) reported that consumption of fruits and vegetables was associated with reduced risk of colon cancer in women. In the Nurses’ Health Study, consumption of fruits was inversely related to polyp formation (Michels and others 2006). Women who consumed 5 or more servings of fruit per day had a reduced risk of developing colorectal adenomas when compared to those who ate 1 or fewer servings (odds ratios = 0.6; 95% CI = 0.44 to 0.81). The risk reduction for vegetable consumption was not significant (odds ratios = 0.82, 95% CI = 0.65 to 1.05).

Cohen and others (2000) reported that vegetable intake was inversely associated with reduced risk of prostate cancer. Consumption of 28 or more servings of vegetables per week exhibited a reduction of 35% for prostate cancer risk when compared to an intake of less than 14 servings per week.

In another study conducted in the San Francisco Bay area, fruit and vegetable consumption was related to the reduced risk of pancreatic cancer (Chan and others 2005). Compared to those in the lowest quartile of total fruit and vegetable intake, those in the highest quartile had a relative risk of 0.47 (95% CI = 0.34 to 0.65). For total fruits and fruit juice, the relative risk was 0.72 (95% CI = 0.54 to 0.98) and for total vegetables it was 0.45 (95% CI = 0.32 to 0.62). Significant inverse associations were also found for dark leafy vegetables, cruciferous vegetables, yellow vegetables, carrots, beans, and onions and garlic.

In a 2003 study of 22043 adults, a higher degree of adherence to the Mediterranean diet, which consists of an increased consumption of fruits and vegetables, was associated with a 0.76 relative risk of death due to cancer (Trichopoulos and others 2003). In a community-dwelling population in Washington, County, Maryland, Genkinger and others (2004) found that participants with the highest quintile of fruit and vegetable intake had a lower risk of cancer-caused mortality (relative risk of 0.65, 95% CI: 0.45 to 0.93) than those in the lowest quintile. Benetou and others (2008) also found a small inverse association between cancer occurrence and fruit and vegetable intake (relative risk of 0.95, 95% CI 0.88 to 0.99) in a Greek cohort. In a European prospective cohort study, overall cancer risk was slightly reduced (relative risk of 0.97, 95% CI: 0.96 to 0.99) when intake of total fruits and vegetables combined increased to 200 g a day (Boffettaand others 2010).

Evidence of reduced cancer risk caused by fruit and vegetable intake is more dramatic in studies of specific cancers. Those that consumed approximately 5.8 portions of fruits and vegetables daily had a significantly reduced risk of cancers of the oral cavity, pharynx, and larynx (relative risk of 0.71, 95% CI: 0.55 to 0.92) when compared with those who only consumed about 1.5 servings a day (Freedman and others 2008). van Duijnhoven and others (2009) found an association between decreased colon cancer risk (relative risk of 0.76, 95% CI: 0.63 to 0.91) and increased fruit and vegetable consumption when comparing those in the highest and lowest quintiles.

The effects of consuming fruits or fruit juices on the antioxidant activity of plasma have been examined in humans. Prior and others (2007) reported that consumption of some fruits (blueberries, grapes, and kiwifruit) increased plasma ORAC values, while cherries and dried plums did not. Ko and others (2005) reported the plasma antioxidant activity of human subjects after a single dose of fruit juice (pear, apple, orange, grape, peach, plum, kiwi, melon, and watermelon). Apple, orange, grape, peach, plum, kiwi, melon, and watermelon juices exhibited potent antioxidant effects in human plasma, but pear juice did not. Orange, melon, grape, peach, plum, apple, and kiwi juices inhibited reactive oxygen species formation by 30 min after consumption and continued to have activity up to 90 min. Grape juice activity persisted to 2 h after ingestion. Watermelon juice did not reduce oxidative stress and pear juice increased radical levels.

It is well accepted that carcinogenesis is a multistep process, and oxidative damage is linked to the formation of tumors through different mechanisms (Ames and Gold 1991; Liu and Hotchkiss 1995). Briefly, oxidative stress induced by free radicals causes DNA damage, which, when left unrepaired, can lead to base mutation, single and double strand breaks, DNA cross-linking, and chromosomal breakage and rearrangement (Ames and Gold 1991). This potentially cancer-inducing oxidative damage might be prevented or limited by dietary phytochemicals found in fruits and vegetables. Studies to date have demonstrated that phytochemicals in common fruits and vegetables can have complementary and overlapping mechanisms of action for cancer prevention (Table 2), including scavenging free radicals and reducing oxidative stress, inhibition of cell proliferation, induction of cell differentiation, inhibition of oncogene expression and induction of tumor suppress gene expression, regulation of gene expression through signal transduction pathways, regulation of cell cycle and induction of apoptosis, modulation of detoxification enzymes, stimulation of the immune system, regulation of hormone metabolism, antiangiogenesis, and antibacterial and antiviral effects (Liu and Finely 2005).

Table 2. Proposed mechanisms by which dietary phytochemicals may prevent cancer (Adapted from Liu and Finely 2005)
• Antioxidant activity
o Scavenge free radicals and reduce oxidative stress
o Inhibit nitrosation and nitration
o Prevent DNA binding and damage
• DNA damage repair
• Inhibition of cell proliferation
• Induction of cell differentiation
• Inhibition of oncogene expression
• Induction of tumor suppress gene expression
• Induction of cell cycle G1 arrest
• Induction of apoptosis
• Regulation of signal transduction pathways
• Enzyme Induction and enhancing detoxification
o Phase II enzyme
o Glutathione peroxidase (GPX)
o Catalase
o Superoxide dismutase (SOD)
• Enzyme Inhibition
o Cyclooxygenase-2 (COX-2) and PGE2 synthesis
o Inducible nitric oxide synthase (iNOS)
o Xanthine oxidase
o Phase I enzyme (block activation of carcinogens)
• Enhancement of immune functions and surveillance
• Anti-angiogenesis
• Inhibition of cell adhesion and invasion
• Regulation of steroid hormone metabolism
• Regulation of estrogen metabolism
• Antibacterial and antiviral effects

Additive and synergistic effects of dietary phytochemicals

Epidemiological studies have consistently shown that consumption of fruits, vegetables, and whole grains is strongly associated with reduced risk of chronic diseases. However, all the evidence for the health benefits of fruits and vegetables is linked to whole foods, not individual dietary supplements, because the actions of the dietary supplements alone do not explain the observed health benefits of diets rich in fruits and vegetables. Taken alone, the individual antioxidants studied in clinical trials do not appear to have consistent preventive effects (Ommen and others 1996; Stephens and others 1996; Yusuf and others 2000). The isolated pure compound either loses its bioactivity or may not behave the same way as the compound in whole foods. In one human clinical trial study, the incidence of malignant cancers was unchanged in patients receiving a β-carotene supplement (Hennekens and others 1996). In other studies, smokers gained no benefit from supplemental β-carotene with respect to lung cancer incidence and may even have suffered a significant increase in lung cancer and total mortality (The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group 1994; Ommen and others 1996). In the Heart Outcomes Prevention Evaluation (HOPE) Study, patients at high risk for cardiovascular events were given 400 I.U. vitamin E per day or a placebo for 4.5 y. No difference was found in deaths from cardiovascular causes, myocardial infarctions, or deaths from CHD or strokes between the 2 groups (The HOPE Investigators 2000). In the Cambridge Heart Antioxidant Study (CHAOS), patients with CHD were given 400 I.U. or 800 I.U. α-tocopherol or a placebo for a median of 510 d. α-Tocopherol intake was associated with a significantly reduced risk of myocardial infarction; however, it insignificantly increased risk of cardiovascular death (Stephens and others 1996). Vitamin E supplementation had no effect on the endpoints of death, myocardial infarction, or stroke for the patients who had recently suffered a myocardial infarction (GISSI-Prevenzione Investigators 1999). Vitamin C supplements also failed to lower the incidence of cancer or CHD (Blot and others 1993; Salonen and others 2000). In another clinical trial, the potential of selenium and vitamin E for prostate cancer prevention (SLECT) was studied (Lippman and others 2009). Both these compounds were beneficial when patterns of increased intake in diet were studied in many previous studies. However, in these clinical trials, an increased risk of prostate cancer was found in the group taking vitamin E and an increased risk of type 2 diabetes mellitus was found in the group taking selenium (Lippman and others 2009). While these were statistically nonsignificant increased risks, they were close enough to be significant (P = 0.06 and P = 0.16) that the clinical trial had to be stopped due to ethical and safety concerns. In longer follow-up studies of SLECT with additional new cases of prostate cancer patients since the primary report, prostate cancer incidence in vitamin E supplementation group was 17% higher (P = 0.008) when compared to the placebo group, indicating dietary supplementation with vitamin E significantly increased the risk of prostate cancer among healthy men (Klein and others 2011).

Why did clinical trials examining the efficacy of beta-carotene, vitamin E, and selenium fail? Why are single antioxidants apparently ineffective? One possible reason is the issue of a single antioxidant compared with antioxidants in balanced food.

Different species and varieties of fruits, vegetables, and grains have different phytochemical profiles (Adom and Liu 2002; Chu and others 2002; Sun and others 2002; Adom and others 2003, 2005; Chu and Liu 2005; He and Liu 2007, 2008). The additive and synergistic effects of phytochemicals in fruits and vegetables have been proposed to be responsible for their potent antioxidant and anticancer activities. The benefit of a diet rich in fruits and vegetables is attributed to the complex mixture of phytochemicals present in these and other whole foods (Eberhardt and others 2000; Chu and others 2002; Sun and others 2002; Chu and Liu 2005; Wolfe and others 2008; Song and others 2010). This partially explains why no single antioxidant can replace the combination of natural phytochemicals in fruits and vegetables in achieving the observed health benefits. Thousands of phytochemicals are present in whole foods. These compounds differ in molecular size, polarity, and solubility, which may affect the bioavailability and distribution of each phytochemical in different macromolecules, subcellular organelles, cells, organs, and tissues. This balanced natural combination of phytochemicals present in fruits and vegetables cannot simply be mimicked by pills or tablets.

Liu and others (2005) reported that whole apple extracts prevented mammary cancer in a rat model in a dose-dependent manner at the doses comparable to human consumption of 1, 3, and 6 apples a day. Apple supplementation decreased mammary cancer incidence, tumor yield, and tumor burden in a dose-dependent manner when compared to the control, indicating apple consumption may be an accessible method of cancer prevention. Recently, a study examining the possible additive, synergistic, or antagonistic interactions among phytochemicals yielded results, suggesting that the apple phytochemical extracts and quercetin 3-beta-D-glucoside (Q3G) in combination possesses a synergistic effect against MCF-7 human breast cancer cell proliferation (Yang and Liu 2009).

A recent human nutrigenomics study also confirmed the importance of whole food instead of a single phytochemical. Milenkovich and others (2011) investigated the effects of orange juice and pure citric phytochemical hesperidin on the expression of genes in leukocytes in healthy volunteers after consumption of orange juice, hesperidin, or placebo for 4 wk. Global gene expression profiles were determined using human whole genome cDNA microarrays. Both orange juice and hesperidin consumption significantly affected leukocyte gene expression. Orange juice consumption induced changes in the expression of 3422 genes, hesperidin intake modulated the expression of 1819 genes, and 1582 genes were in common in both groups. Many of these affected genes were involved in chemotaxis, adhesion, infiltration, and lipid transport, suggesting lower recruitment and infiltration of circulating cells to vascular wall, lower lipid accumulation, and formation of the atherosclerotic plaque.

Therefore, consumers should obtain their phytochemicals from a wide variety of fruits, vegetables, and whole grains for optimal health benefits. To improve their nutrition and health, consumers should be obtaining antioxidants from their diet and not from expensive dietary supplements, which do not contain the balanced combination of phytochemicals found in fruits and vegetables and other whole foods. More importantly, obtaining antioxidants from dietary intake by consuming a wide variety of foods is unlikely to result in consumption of toxic quantities because foods originating from plants contain many diverse types of phytochemicals in various quantities. Fruits and vegetables eaten in the recommended amounts (9 to 13 servings of fruits and vegetables per day) are safe. Furthermore, health benefits from the consumption of fruits and vegetables extend beyond lowering the risk of developing cancers and CVD: benefits also include preventive effects on other chronic diseases such as cataracts, age-related macular degeneration, central neurodegenerative diseases, and diabetes (Liu 2004).

Conclusions

There is strong scientific evidence suggesting that regular consumption of fruits and vegetables is negatively associated with reduced risk of developing chronic diseases such as CVD, cancer, diabetes, Alzheimer's disease, cataracts, and age-related functional decline. The 2010 Dietary Guidelines for Americans (United States Department of Agriculture 2010) recommend most people should eat at least 9 servings (4½ cups) of fruits and vegetables a day, 4 servings (2 cups) of fruits and 5 servings (2.5 cups) of vegetables, based on a 2000 kcal diet. The key is to increase the total up to 9 to 13 servings of fruits and vegetables in all forms. Fresh, cooked, and processed fruits and vegetables including frozen and canned, 100% fruit juices, 100% vegetable juices, and dry fruits are all considered as servings of fruits and vegetables a day. More and more evidence suggests that the health benefits of fruits and vegetables are attributed to the additive and synergistic interactions of the phytochemicals present in whole foods by targeting multiple signal transduction pathways. Therefore, consumers should obtain nutrients and bioactive phytochemicals from a wide variety of whole foods for optimal nutrition and health well-being, not from expensive dietary supplements. Further research on the health benefits of phytochemicals in whole foods is warranted.

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