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September 1999: (ll)S3-S6 Phytonutrients’ Role in Metabolism: Effects on Resistance to Degenerative Processes Gary R. Beecher, Ph.D. Several “traditional”nutrients and dietary fiber have been associated with both increased and de- creased risk of chronic diseases. However, there are many minor components in foods, particularly plant-derived foods, that elicit biologic responses in mammalian systems that are consistent with reduced risk of one or more chronic diseases (phytonutrients). These phytonutrients have been categorized into ten classes of compounds or bio- logic activities. Representative compounds, typi- cal biologic activities, and common food sources are tabulated for each phytonutrient class. A brief discussion of each category is presented along with several structure-activity relationships. Introduction Dietary components have been identified or purported as risk factors for many chronic degenerative diseases. These diseases include one-half of the ten leading causes of death in the United States,’ immune and inflammatory cell func- tion: adult macular degeneration: and others. Severalof the “traditional” nutrients (nutrients for which Recommended Dietary Allowances [RDAs] have been established)and di- etary fiber have been associated with the risk of chronic disease and the improvementof health outcomes! However, there are many minor components in foods, particularly in plant-derived foods,that elicit biologic responses in mamma- lian systems,some of which are consistentwith reduced risk of one or more diseases.These componentshave been iden- tified with several terms including phytochemicals, phytonutrients,and vitalimins? In this article, only plant de- rived compounds(phyto-) that promote health (nutrient) will be discussed, for which the term phytonutrient has been adopted. A brief overview of several of classes of phytonutrients,examples of their biologic activity, and typi- cal food sources is presented here. Dr. Beecher is a Research Chemist at the Food Composition Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA. Historic Perspective There are several types of medical and scientific observa- tions suggesting that phytonutrients may play a role in health promotion. These include traditional medicine ap- proaches, epidemiologic surveys, intervention and con- trolled human feeding experiments,laboratory animal stud- ies, investigations with cells and sub-cellular organelles, and chemical experiments. The empiric healing of some diseases and ailments with foods, teas, and poultices (tra- ditional medicine) dates to early Egyptian civilizations (circa 1500 BC).6 Traditional medicine approaches have been used extensively in the eastern cultures throughout history, and recently have received considerable interest in the Unite’d States, as evidenced by the development of the Office of Alternative Medicine at the National Insti- tutes of Health. The classic studies of Wattenberg and his colleagues awakened the scientific community to the potential role and power of foods and dietary constituents in the pre- vention of at least one chronic disease4ancer. These investigators examined the inhibition of several chemi- cally induced cancers in laboratory animals by a wide range of human foods and naturally occurring compounds.’J The report of an ad hoc committee of the Food and Nutri- tion Board of the National Academy of Sciences in the early 1980s m h e r strengthenedthe role of diet, including phytonutrients, in decreasing the risk of ~ a n c e r . ~ Over the last two decades, results from a large number of different types of studies strongly suggest that many phyto- nutrients may play an important role in reducing the risk of not only cancer, but of several chronic di~eases?J”-~~ Epidemiologic studies have provided another line of scientific evidence relating diet, foods, and dietary com- ponents to the incidence of chronic disease. Steinmetz and Potter reviewed the associationbetween the consump- tion of fruits and vegetables and cancer prevention.14J5 Along with Dragsted et al., they identified several “tradi- tional” nutrients that appear to be important in reducing the risk of several cancers, but also identified many other substances in fruits and vegetables that may help protect against cancer.”” Other epidemiologic studies indicate that components of diets that are high in fiber-containing Nutrition Reviews@, Vol. 57, No. 9 s3

Phytonutrients' Role in Metabolism: Effects on Resistance to Degenerative Processes

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September 1999: (ll)S3-S6

Phytonutrients’ Role in Metabolism: Effects on Resistance to Degenerative Processes Gary R. Beecher, Ph.D.

Several “traditional” nutrients and dietary fiber have been associated with both increased and de- creased risk of chronic diseases. However, there are many minor components in foods, particularly plant-derived foods, that elicit biologic responses in mammalian systems that are consistent with reduced risk of one or more chronic diseases (phytonutrients). These phytonutrients have been categorized into ten classes of compounds or bio- logic activities. Representative compounds, typi- cal biologic activities, and common food sources are tabulated for each phytonutrient class. A brief discussion of each category is presented along with several structure-activity relationships.

Introduction

Dietary components have been identified or purported as risk factors for many chronic degenerative diseases. These diseases include one-half of the ten leading causes of death in the United States,’ immune and inflammatory cell func- tion: adult macular degeneration: and others. Several of the “traditional” nutrients (nutrients for which Recommended Dietary Allowances [RDAs] have been established) and di- etary fiber have been associated with the risk of chronic disease and the improvement of health outcomes! However, there are many minor components in foods, particularly in plant-derived foods, that elicit biologic responses in mamma- lian systems, some of which are consistent with reduced risk of one or more diseases. These components have been iden- tified with several terms including phytochemicals, phytonutrients, and vitalimins? In this article, only plant de- rived compounds (phyto-) that promote health (nutrient) will be discussed, for which the term phytonutrient has been adopted. A brief overview of several of classes of phytonutrients, examples of their biologic activity, and typi- cal food sources is presented here.

Dr. Beecher is a Research Chemist at the Food Composition Laboratory, Beltsville Human Nutrition Research Center, USDA-ARS, Beltsville, MD 20705, USA.

Historic Perspective

There are several types of medical and scientific observa- tions suggesting that phytonutrients may play a role in health promotion. These include traditional medicine ap- proaches, epidemiologic surveys, intervention and con- trolled human feeding experiments, laboratory animal stud- ies, investigations with cells and sub-cellular organelles, and chemical experiments. The empiric healing of some diseases and ailments with foods, teas, and poultices (tra- ditional medicine) dates to early Egyptian civilizations (circa 1500 BC).6 Traditional medicine approaches have been used extensively in the eastern cultures throughout history, and recently have received considerable interest in the Unite’d States, as evidenced by the development of the Office of Alternative Medicine at the National Insti- tutes of Health.

The classic studies of Wattenberg and his colleagues awakened the scientific community to the potential role and power of foods and dietary constituents in the pre- vention of at least one chronic disease4ancer. These investigators examined the inhibition of several chemi- cally induced cancers in laboratory animals by a wide range of human foods and naturally occurring compounds.’J The report of an ad hoc committee of the Food and Nutri- tion Board of the National Academy of Sciences in the early 1980s m h e r strengthened the role of diet, including phytonutrients, in decreasing the risk of ~ a n c e r . ~ Over the last two decades, results from a large number of different types of studies strongly suggest that many phyto- nutrients may play an important role in reducing the risk of not only cancer, but of several chronic di~eases?J”-~~

Epidemiologic studies have provided another line of scientific evidence relating diet, foods, and dietary com- ponents to the incidence of chronic disease. Steinmetz and Potter reviewed the association between the consump- tion of fruits and vegetables and cancer prevention.14J5 Along with Dragsted et al., they identified several “tradi- tional” nutrients that appear to be important in reducing the risk of several cancers, but also identified many other substances in fruits and vegetables that may help protect against cancer.”” Other epidemiologic studies indicate that components of diets that are high in fiber-containing

Nutrition Reviews@, Vol. 57, No. 9 s3

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foods and the accompanying phytonutrients are also as- sociated with a decreased risk of cancer and several other chronic diseases.I0

Phytonutrients Associated with Health Promotion Several phytonutrient classes, along with selected bio- logical activities, examples of typical compounds, and rep- resentative food sources are tabulated in Table 1. This table is not an exhaustive list of components in foods that

may elicit biologic activities associated with health pro- motion. Instead, it is a list of typical and representative compounds present in many commonly consumed foods in the United States. In general, the phytonutrients are classified by structure or unique molecular content, such as carotenoids, polyphenols, sulfides, and thiols. How- ever, in the case of phytoestrogens and protease inhibi- tors, biologic activity has been selected as the basis of phytonutrient classification and the appropriate food com- ponents have been identified with each class.

Table 1. Phytonutrient Classes Associated with Health Promotion, Examples of Typical Components of Each Class, Representative Biological Activities, and Prominent Food Sources.a Phytonutrient Typical Compounds Biological Class or Components Activitiesb Food Sources' Carotenoids a-Carotene, p-carotene,

P-cryptoxanthin, lutein, lycopene, zeaxanthin

Glucosinolates, Glucobrassicin, isothiocyanates, sulphorophane,

indole-3-carbinol indoles

Inositol phosphates

Phenolics, cyclic compounds

Phytoestrogens

Phytosterols

Polyphenols

Protease inhibitors

Saponins

Sulfides and thiols

Phytate, inositol pentaphosphate, inositol tetra- phosphate, etc.

Chlorogenic acid, ellagic acid, coumarins, limonene

Isoflavones - daidzein, genistein, glycitein Lignans - matairesinol, secoisolariresinol

Campesterol, p-sitosterol, stigmasterol

Flavonoids (-1 5-20 in foods, e.g., quercetin, apigenin, catechin, etc.), theaflavins, thearubigens

Bowman-Birk inhibitor

Soyasaponins, soyasapogenols

Source ofvitaminA (some) Quench singlet oxygen 0 Cell-cell communication U Risk of adult macular degeneration (some)

0 Phase I1 enzyme activity Alter estrogen metabolism through shift in hydroxylation U DNAmethylation

Bind divalent cations-especially copper and iron, which may ~

generate hydroxyl radicals through the Fenton reaction

0 Phase I1 enzyme activity Inhibit N-nitrosation reactions Antioxidant

&

Metabolized in G.I. tract to estrogen-like compounds 0 SHBG synthesis U Tyrosine kinase activity Induce apoptosis

Bind bile acids and cholesterol UColonic cell proliferation

Antioxidant U Capillary fragility and permeability (Vitamin P) Alter tryosine kinase activity

Colored fruits and vegetables, dairy products, eggs, margarines

Cruciferous vegetables (broccoli), horseradish

Cereals, soybeans, soy-based foods

Citrus, fruits, vegetables

Isoflavones - soybeans, soy-based foods Lignans - flax, rye, vegetables

Vegetable oils, nuts, seeds, cereals, legumes

Fruits, vegetables, tea, red wine Theaflavins and thearubigens exclusively in black and oolong tea

Bind to trypsin and chymotrypsin Soybeans, soy-foods, other U Growth oftransformed cells legumes, cereals, vegetables U Tumors in animals

Bind bile acids and cholesterol Cytotoxic toward tumor cells Antioxidant

Soybeans, soy-based foods, other legumes, nuts

Diallyl sulfides, ally1 methyl 0 Phase I1 enzyme activity trisulfides, dithiolthiones

Sulfides - Allium vegetables (onions) Dithiolthiones - Cruciferous U Bacterial activity - nitrate to

nitrite conversion Vegetables (broccoli)

"Information for the development of this table was drawn primarily from references 15-1 7 and 24-27. bThe biological activities listed are representative of the entire class of phytonutrients. 'The food sources listed are representative of the entire class of phytonutrients.

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The observations tabulated in Table 1 suggest there is a variety of compounds in foods that elicit an array of biologic activities that may be associated with depressed rates of degenerative processes. These activities range from scavenging of reactive oxygen species, and presum- ably reactive nitrogen species (antioxidants), to alteration of such cellular functions as growth and apoptosis through, as yet, unknown mechanisms. Another form of antioxidant activity may be the sequestering of the diva- lent cations copper and iron by inositol phosphates, which prevents them from reacting in Fenton-type reactions to produce hydroxyl radicals. Several classes of phyto- nutrients-including isothiocyanates, phenolics, and sul- fides-stimulate the activity of phase I1 enzymes, the se- ries of P45O enzymes responsible for the biologic detoxi- fication of compounds. In the case of some phytonutrients such as phytosterols, protease inhibitors, and saponins, one beneficial biologic activity occurs presumably through physical binding to other molecules such as cholesterol and trypsin inhibitors, which alters their metabolism and results in a positive health effect. Isoflavones and lignans are structurally modified by microflora in the gastrointes- tinal tract to compounds that are similar in structure to the hormone estradiol. They subsequently elicit their effect by associating with estradiol binding sites, but do not cause the same biologic response as estradiol. Isoflavones are also absorbed directly and elicit additional biologic activities. Polyphenols undergo metabolism in the gas- trointestinal tract, which may explain why only small amounts ofpolyphenol doses (less than 5%) are absorbed and excreted in human The polyphenol meta- bolic products-phenolics-should be absorbed and may account for some of the biologic activity of the polyphe- no1 phytonutrients. Only limited human studies have been conducted on the measurement of these metabolic com- pounds.20 A number of compounds in several different classes of phytonutrients alter intracellular and cell-cell communication. This is accomplished through alteration of tyrosine kinase activity and gap-junction communica- tion, respectively. Several other biological activities ben- eficial to health have been identified with various phytonutrients (Table 1). This list is sure to grow as re- search continues to elucidate the mechanism of action of many of these naturally occurring compounds.

Although strict structure-activity relationships are not apparent across all phytonutrient classes, a few are be- ginning to emerge (Table 1). For example, those compounds that have considerable electronic resonance, i.e., caro- tenoids, phenolics, polyphenols, have excellent antioxi- dant activity, measured in ~ i t r ~ . ~ ~ - ~ ~ Similarly, phytosterols and saponins-both of which have cyclic structures simi- lar to cholesterol-possess the ability to bind cholesterol and bile salts, thereby decreasing the absorption of cho- lesterol, one of the key risk factors in cardiovascular dis- ease. Most of the phytonutrients that contain sulfur, such

as isothiocyanates, sulfides, and dithiolthiones, appear to increase phase I1 enzyme activity. In addition to con- taining sulfur compounds, several phenolics also stimu- late phase I1 enzyme activity. Both subclasses of phytoestrogens-isoflavones and lignans-are metabo- lized to compounds that are structurally similar to estra- diol (equol, o-desmethylangolensin, enterodiol, enterolactone) in the gastrointestinal tract, and as a re- sult, alter the metabolism of naturally occurring estrogens. While structure-activity relationships have not been iden- tified for many of the phytonutrient-biologic activities tabu- lated in Table 1, the current research activity in this field will continue to elucidate more of these relationships.

The foods that supply phytonutrients in the diet are from all types of plant sources. While the phytonutrients found in fruits and vegetables have received consider- able attention for their potential to reduce the risk of can- cer, foods such as cereals, legumes, nuts and seeds pro- vide a wide variety of phytonutrients that may have a significant role in reducing the risk of several other chronic diseases, as well as ~ancer.’OJ~~’ There are only a few examples where a limited number of foods supply a spe- cific phytonutrient. Two such examples are soybeans and soy foods, which provide isoflavones, and cruciferous vegetables, which supply isothiocyanates. In general, fol- lowing the dietary guideline to “Eat a Variety of Foods”- especially if theyare plant-derived foods-will result in a diet rich in phytonutrients that will have a positive impact on health.28

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