Consumption of soybean and reduced incidence of disease

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East Asian populations that regularly consume soybeans as a part of their dietary intake seem to have lower incidences of cancers and oxidation linked diseases of old age than are prevalent in Western populations. Numerous epidemiological studies have demonstrated an association between the consumption of soybeans and improved health, particularly as a reduced risk for cancers or diseases, such as breast cancer, cardiovascular disease, and atherosclerosis (2-8). Consumption of soy foods has also been associated with a reduced risk of prostate cancer (9,10).

Although soybean protein was first suspected to potentiate the health-promoting benefits of soybean consumption, these properties have more recently been linked to the biological activities of a specific group of phenolic compounds, found mainly in soybeans, known as isoflavonoids (5). While the chemopreventive properties of purified and synthetic isoflavonoids have been heavily investigated, a fermented soybean extract was recently shown to perform better at reducing the incidence of mammary tumor risk than a similar mixture of its constituent isoflavonoids, suggesting that the food background may play a positive role in the chemopreventive actions associated with soybean consumption, in addition to that of isoflavonoids (11-16).

6.2.1 Soybean Isoflavonoids

Isoflavonoids are a unique subgroup of the flavanoids, one of the largest classes of plant phenolics, with more than 5000 compounds currently identified. Isoflavonoids are found mainly in soybeans, and possess a chemical structure that is similar to the hormone estrogen (1). The chief isoflavonoids found in soybeans are genistein and daidzein. Because their structures resemble estrogen and they can interact with the estrogen receptor, soybean isoflavonoids are sometimes referred to as phytoestrogens (17).

Isoflavonoids are flavanoid variants in which the location of one of the phenolic rings is shifted. As diphenolic secondary metabolites, isoflavonoids are synthesized from products of the shikimic acid and malonyl pathways in the fusion of a phenylpropanoid with three malonyl CoA residues (1). Isoflavonoid content in soybeans ranges from 0.14 to 1.53 mg/g, and in soy flour from 1.3 to 1.98 mg/g (18). The Japanese are estimated to consume 25-100 mg of isoflavonoids per day (19). Chinese women are estimated to consume 39 mg of isoflavonoids per day (20). The consumption of isoflavonoids in Western diets is much lower, at less than 1 mg/day in the U.S. and U.K. (18,21).

Phenolic compounds normally occur as glucoside bound moieties called glycones (22,23). However, it is the aglycone (glucoside free) form that is metabolically active (24). After consumption, probiotic enzymes in the intestine cleave the glycoside moieties from glycone isoflavonoids and release the biologically active health-promoting aglycone isoflavonoids. Aglycone phenolic compounds possess higher antioxidant activity and are absorbed faster in the intestines than glucoside bound forms (23,25,26). Interestingly, fermented soy foods are rich in phenolic aglycones due to microbial bioprocessing during fermentation (27,28). However, once inside the bloodstream, biologically active aglycone genistein travels to the liver were it is converted back into an inactive glycone (b-glucuronide) (24). Cellular glucuronidases must remove the glycone moiety before genistein can exert its biological activity (24).

Isoflavonoids have been well studied and possess numerous biological activities (1). For example, genistein possesses inhibitory activity against topoisomerase II, tyrosine kinase, NF-kB, cancer cell proliferation, and nonoxidative pentose-phosphate pathway ribose synthesis in cancer cells (29-33). Many of the health-promoting benefits of isoflavonoids have been linked to the ability of phenolics to serve as antioxidants (34-37).

6.2.2 Major bioactivities of Soybean Isoflavonoids

6.2.2.1 Phytoestrogens and Postmenopausal Activity

The structure of soybean isoflavonoids is uniquely similar to that of estrogen (17) and may account for their weak ability to act as agonists at estrogen receptors (38). Many have speculated that soybean isoflavonoids may be useful for the treatment of somatic, mood, and cognitive disturbances associated with the onset of menopause (39). Diet supplementation with soybean phytoestrogens has been reported to ameliorate hot flashes and other symptoms of menopause (40-43).

Soybean isoflavonoids may also have potential in natural chemoprevention therapies against long term health problems associated with menopause, particularly for osteoporosis (44-47). After menopause, the ovaries stop producing estrogen. Because estrogen positively affects the metabolism of calcium, lack of sufficient estrogen can lead to bone loss and osteoporosis (48). Hormone replacement therapy (HRT) can reduce bone loss and the risk of osteoporosis in postmenopausal women, but unfortunately appears to also increase the risk for certain estrogen linked cancers (49-51).

Current osteoporosis prevention research is focused on the development of estrogenlike compounds (selective estrogen receptor modulators, or SERMs) that can selectively act against bone loss without causing negative estrogenic action against the uterus (52). The soybean isoflavonoid genistein has shown SERM activity in ovariectomized mice (53). When provided at optimal dosages, soybean isoflavonoids (especially genistein and daidzein) have been shown to improve bone mass and reduce bone resorption (54,55).

6.2.2.2 Cancer Chemoprevention

Soybean isoflavonoids also possess various biological activities that may help to explain the cancer chemopreventive properties associated with the consumption of soybean foods (3,8,49,56). In in vitro studies, daidzein was reported to activate the catalase promoter, to stimulate caspase-3 and apoptosis, and to down regulate the activities of Bcl-2 and Bcl-xL (57,58). Genistein can stimulate p53, antioxidant enzyme activities, BRCA2, caspase-3 and apoptosis, and chloride efflux (59-63). Genistein has also been reported to suppress activation of NF-kB, matrix metalloproteinases, lipogenesis, and COX-2 (31,64-66).

The exact mechanism by which these compounds exert their chemopreventive properties is not yet clear.

6.2.2.3 Prevention of Cardiovascular Disease

Soybean consumption has also been linked to a reduced risk for cardiovascular disease (47). Addition of soybean to foods has been shown to result in reduced cholesterol (67). In 1999, the US Food and Drug Administration reported that the consumption of soy protein as part of a healthy diet could help reduce the risk of coronary heart disease by lowering blood cholesterol levels (68). Soy protein isolates typically contain soybean isoflavonoids, which are believed to be largely responsible for the health benefits assigned to soy protein. Related herbal flavanoids prevented in vitro platelet aggregation and in vivo thrombogen-esis in mouse arteries (69). Inclusion of isoflavonoid rich soybean in diets was also reported to protect against coronary heart disease by causing reductions in blood lipids, oxidized LDL, homocysteine, and blood pressure (7).

6.2.3 Approaches Toward Isoflavone Enrichment of Soybean

6.2.3.1 Genetic Modulation of Soybean

Throughout recorded history, man has used conventional breeding and selection techniques to improve crop species for desired traits. When modern genetic engineering techniques became available, agricultural scientists sought to improve crop species' phenolic content through the use of genetic technologies. At first, progress was slow, as knowledge of the biosynthetic pathways responsible for producing beneficial phenolic phytochemi-cals was limited.

One of the most studied pathways is the anthocyanin biosynthesis pathway, as phe-notypic changes in flower color aided genetic analysis and metabolic understanding. Study of anthocyanin biosynthesis has also aided in the understanding of isoflavonoid biosynthesis as both pathways share a dependence on substrate flux through the flavanoid biosynthetic pathway. The isoflavonoid biosynthetic pathway is now almost completely characterized and genetic manipulation techniques have matured enough that it is now possible to alter synthesis at many different stages (70).

Knowledge of key enzymes involved in isoflavonoid biosynthesis in legumes led to attempts to engineer isoflavonoid biosynthesis in nonlegumes through genetic manipulation, in order to expand the delivery of dietary isoflavonoids as well as to develop new sources for their isolation (1). Unfortunately, initial attempts to incorporate key enzymes involved in isoflavonoid synthesis, such as soybean isoflavone synthase (IFS) and alfalfa chalcone isomerase in Arabidopsis, corn, and tobacco resulted in little to no formation of genistein or daidzein, the major isoflavonoids produced by soybean (71-73). Significant accumulation of isoflavonoids in nonlegumes was thought to be hindered by limited activity of the introduced IFS enzyme, by precursor pool limitations, and by competition (flux partitioning) between IFS and other enzymes that use the flavanoid naringenin as a substrate (73,74). More recent attempts to engineer flavanoids in bacteria and increased iso-flavonoid content in soybean have been more successful, with the latter largely by coengineering the suppression of the naringenin-utilizing enzyme flavanone-3-hydroxy-lase to block competing pathways (72,75).

Dietary safety of genetically engineered foods remains a major concern of potential consumers. Although genetically modified (GM) foods appear no more harmful than conventionally produced foods, concerns remain as to the safety of the newly added DNA, its gene product, the overall safety of the rest of the food, the potential toxicology of the expressed protein, potential changes in allergenicity, changes in nutrient composition, unintended effects that could give rise to allergens or cause toxicity, and the safety of antibiotic resistance marker encoded proteins included with the transgene (76).

6.2.3.2 Enrichment of Soybean Isoflavone Content via Nongenetic Approaches

The technological challenge of stably introducing a foreign gene into a food crop and having that gene product function as desired, the problems of controlling substrate flux partitioning to drive a desired biosynthetic pathway, and the potential risks posed by transgenic food crops are troublesome issues that have underscored the need for continued research on and development of nongenetic approaches for the enrichment of isoflavonoids in soybean foods and food ingredients (1). Major nongenetic approaches for increasing phenolic content in dietary plants include bioprocessing of soybean substrates and stimulation of the plant defense responses, which is known to result in the stimulation of phenolic synthesis. Both of these approaches could potentially be used to increase isofla-vonoid content in soybeans.

Bioprocessing of various plant based foods by dietary fungus is a technology that has been used throughout history in the context of producing fermented foods, such as tempeh. Currently, this technology is being utilized in conjunction with specific dietary fungi to produce certain desired products. In this context, fungal bioprocessing (also known as solidstate fermentation) has been employed to enrich various solid food substrates such as grape pomace, cornmeal, mango, date, wheat bran, and wine for products such as protein, C/N ratio, b-glucan, and pectinase (77-81). The use of dietary fungal bioprocessing of fruit and legume food substrates for enrichment of aglycone phenolic antioxidants such as ellagic acid in cranberry and isoflavonoids from soybeans has been reported (27,28,82-84). Enhanced isoflavonoid content in soybeans and soybean meal following bioprocessing by Aspergillus species has also been reported (85,86). The number of different microbial species and substrates available for isoflavonoid and other phenolic enrichment by fungal bioprocessing is likely to grow as knowledge of dietary microbial species increases.

One of the results of elicitor mediated activation of the plant defense system is an increase in phenolic secondary metabolite biosynthesis (87,88). Exogenous application of salicylic acid, a phenolic metabolite thought to act as a chemical signal in the defense response system, can stimulate phenolic content in peas (89). Similarly, pure dietary phe-nolics and phenolic rich extracts have been reported to stimulate phenolic content in legumes (90-96). Further, application of bacteria, bacterial polysaccharides, and UV and microwave radiation (all of which are known inducers of plant defense responses) have been shown to stimulate plant phenolic content (96-99). The type of phenolics elicited by activation of the defense response is largely determined by the nature of the treated plant (i.e., phenolic profiles vary from plant to plant). Therefore, application of plant defense response elicitors to soybean may potentially stimulate higher isoflavonoid content without the need for genetic manipulation.

6.2.4 Toward a Model Mechanism for Action of Soybean Isoflavonoids and Related Phenolic antioxidants against Cancer

6.2.4.1 Metabolism of Dietary Isoflavonoids

As stated earlier, genistein and daidzein occur in soybeans as glucoside conjugates that must be converted into aglycones to be metabolically active (22,24). In humans, this can be performed by intestinal flora. Interestingly, fermented soy foods are rich in phenolic aglycones due to microbial bioprocessing during fermentation, which may allow for rapid intestinal absorption upon consumption (27,28).

6.2.4.2 Control of Energy Metabolism and Oxidative Stress in a Healthy Cell

In cells, the production of energy adenosine triphosphate (ATP) occurs in mitochondria by reduced nicotinamide adenine dinucleotide (NADH)-mediated oxidative phosphorylation (oxPHOS) (100). The tricarboxylic acid (TCA) cycle produces NADH to support mitochondrial ATP synthesis. Although some reactive oxygen species (ROS) are generated during mitochondrial oxPHOS, cells possess an extensive antioxidant response system which operates to scavenge ROS and protect cellular components from oxidative damage (100,101).

Antioxidant enzymes play a key role in cellular antioxidant response (100). Chief among these enzymes are superoxide dismutase (SOD) and catalase. SOD converts superoxide (O;T) into hydrogen peroxide (H2O2), which is less reactive. Catalase converts H2O2 into water (H2O) and oxygen (O2). Manganese superoxide dismutase (MnSOD) occurs within mitochondria to protect the organelle from oxidative damage, while copper-zinc SOD (CuZnSOD) and catalase occur in the cytosol, both to protect cytosolic bound cellular components from oxidative damage and to maintain a proper redox environment, because redox imbalances can activate certain cellular activities (102).

It has been proposed that phenolic antioxidants may have chemopreventive potential through modulation of the antioxidant enzyme response through the proline linked pen-tose-phosphate pathway (103). Exogenous antioxidants, such as dietary plant phenolic compounds, have been shown to scavenge ROS in cells in vitro and may help protect cells against oxidative damage in vivo (103,104).

6.2.4.3 Control of Energy Metabolism and Oxidative Stress in a Tumorigenic Cell Many of the diseases for which a reduced risk of incidence has been associated with soy food consumption are oxidation linked diseases, such as cancer and cardiovascular disease (100). Oxidation linked diseases have been linked to a general breakdown in the regulation of cellular activities (such as growth or energy production), an accumulation of ROS such as superoxide and hydrogen peroxide, a cellular redox imbalance, and accumulated oxida-tive damage in normal cells (106).

Evidence indicates that, similar to healthy cells, tumor cells obtain much of their ATP for energy requirements via NADH linked mitochondrial oxPHOS (107). However, in tumorigenic cells, energy generation is inefficient as mitochondrial respiration activities are defective compared to healthy cells (108-110). Interestingly, in many cancer cells the activity of glucose-6-phosphate dehydrogenase (G6PDH), the key regulatory enzyme of the oxPPP, is reduced by up to 90%, while the nonoxidative pentose-phosphate pathway (nonoxPPP) flux is increased, possibly to support higher glycolytic flux toward the TCA cycle to support additional demand for NADH (111,112).

In addition to an abnormal energy metabolism, tumor cells possess a reduced antioxidant response system. Catalase and CuZnSOD activities, important for controlling cytosolic ROS levels, are decreased in numerous cancer cell lines (113,114). Low activity of antioxidant enzymes leaves cancer cells particularly susceptible to increased oxidative damage upon ROS accumulation, and eventually apoptosis (cell death) or necrosis (113,114).

6.2.5 Stress Response and the Proline Linked Pentose-Phosphate Pathway

Healthy cells possess a mechanism that couples increased mitochondrial ATP synthesis to increased glucose flux through the oxPPP for biosynthetic substrates (glucose phosphates, reduced nicotinamide adenine dinucleotide phosphate (NADPH) that support cellular energy demands during times of stress (100). In this mechanism, mitochondrial ATP generation and oxPPP activity are coupled through the biosynthesis of proline (115). Proline biosynthesis provides a mechanism for the transfer of reducing equivalents from NADPH into mitochondria (via proline oxidation) and is linked to glucose oxidation in the oxPPP by NADPH turnover, a coupling known as the proline linked pentose-phosphate pathway (PL-PPP) (116). Notably, in this mechanism mitochondrial oxPHOS switches its dependence on NADH to proline as a source of reducing equivalents to support ATP synthesis while maintaining cellular NADPH biosynthesis for anabolic reactions. Increased proline metabolism has been shown to stimulate oxPPP activity via NADP mediated redox regulation (117).

As the activity of several antioxidant enzymes depends on the availability of NADPH, activity of the cellular antioxidant response system in stressed cells may depend directly upon flux through the oxPPP and, therefore, indirectly upon the activity of a functional proline cycling mechanism (100). Increased oxPPP activity has been shown to protect cells against H2O2 and NO stresses (118,119). Similarly, a phagocyte derived ROS increase occurs during the immune response and is followed by an increase in G6PDH activity (120). G6PDH and oxPPP activity protected cells from oxidant and radiation induced apoptosis (121). Recently, antioxidant enzymes were found to be essential for protecting cells against ROS mediated damage (122).

6.3 A HYPoTHETICAL MoDEL FoR THE CANCER CHEMoPREvENTIvE

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