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439-450.s9791c-messina

Legumes and soybeans: overview of their nutritional profiles andhealth effects1,2 ABSTRACT
Legumes play an important role in the traditional countries beans play a less significant dietary role. In fact, bean diets of many regions throughout the world. In contrast in Western intake has actually declined during the past century in many countries beans tend to play only a minor dietary role despite the fact that they are low in fat and are excellent sources of protein, dietary In the United States, the availability of dry beans, peas, nuts, fiber, and a variety of micronutrients and phytochemicals. Soybeans and soybeans combined has remained fairly constant at 7.3 kg are unique among the legumes because they are a concentrated (16 lb), 7.3 kg (16 lb), and 8.2 kg (18 lb) per person per year dur- source of isoflavones. Isoflavones have weak estrogenic properties ing the time periods 1909–1913, 1967–1969, and 1985, respec- and the isoflavone genistein influences signal transduction. Soyfoods tively (2). For dry edible beans specifically, the annual per capita and isoflavones have received considerable attention for their poten- amount available for consumption (product weight) for the years tial role in preventing and treating cancer and osteoporosis. The low 1972, 1981, 1982, and 1992 was 2.7 kg (6.0 lb), 2.5 kg (5.4 lb), breast cancer mortality rates in Asian countries and the putative 3.0 kg (6.5 lb), and 3.4 kg (7.5 lb), respectively (3). The 1992 antiestrogenic effects of isoflavones have fueled speculation that figure represents less than one-quarter servings of beans per per- soyfood intake reduces breast cancer risk. The available epidemio- son per day. Less than one-third of the adult US population eats logic data are limited and only weakly supportive of this hypothe- beans during any 3-d period (3). The most popular dry bean in sis, however, particularly for postmenopausal breast cancer. The the United States is the pinto bean, followed by the navy, kidney, data suggesting that soy or isoflavones may reduce the risk of great Northern, and lima bean [annual kg per person for 1995: prostate cancer are more encouraging. The weak estrogenic effects 1.5 (3.3 lb), 0.8 (1.7 lb), 0.3 (0.6 lb), 0.2 (0.4 lb), and 0.1 (0.2 lb), of isoflavones and the similarity in chemical structure between soy- respectively] (4). In the US Department of Agriculture food bean isoflavones and the synthetic isoflavone ipriflavone, which was guide pyramid, beans are included in the same group as nuts, shown to increase bone mineral density in postmenopausal women, meat, poultry, fish, and seeds (5). Because the recommendation suggest that soy or isoflavones may reduce the risk of osteoporosis.
is to consume ≥ 2 servings/d from this group, nonvegetarians Rodent studies tend to support this hypothesis, as do the limited pre- have relatively little incentive to make beans an important part of liminary data from humans. Given the nutrient profile and phyto- chemical contribution of beans, nutritionists should make a con- Beans tend to have a poor image and one that stands in stark certed effort to encourage the public to consume more beans in contrast to the nutritional value they offer. Beans have been called general and more soyfoods in particular.
the “poor man’s meat,” a metaphor which is consistent with the inverse relation between bean intake and income. For US malesaged ≥ 20 y, the frequency of bean intake during a 3-d period was KEY WORDS
Legumes, soybeans, beans, phytochemicals, 36.3%, 32.3%, and 25.7% among men with incomes < 131%, isoflavones, genistein, soyfoods, breast cancer, prostate cancer, 131–350%, and > 350% of the poverty level, respectively (3).
cancer prevention, osteoporosis prevention, dietary fiber Given the important role of beans in populations that consume plant-based diets, it is not surprising that legume intake is higher invegetarians than in nonvegetarians, although the data are limited (6, INTRODUCTION
7). Certainly, one would expect the consumption of beans to Legumes include peas, beans, lentils, peanuts, and other pod- increase with the elimination of meat and eggs from the diet by lac- ded plants that are used as food. Legumes have been cultivated tovegetarians and vegans. Appropriately, the vegetarian food guide for thousands of years, although many of the varieties of beans pyramid recently developed by Loma Linda University places and peas that are commonplace today were unknown until rela- legumes in their own group at the bottom of the pyramid (8).
Legumes have played an important role in the traditional diets of many regions throughout the world. It is difficult to think ofthe cuisines of Asia, India, South America, the Middle East, and 1 From Nutrition Matters, Inc, Townsend, WA.
Mexico without picturing soybeans, lentils, black beans, chick- 2 Address reprint requests to MJ Messina, Nutrition Matters, Inc, 1543 peas, and pinto beans, respectively. In contrast, in many Western Lincoln Street, Port Townsend, WA 98368. E-mail: markm@olympus.net.
Am J Clin Nutr 1999;70(suppl):439S–50S. Printed in USA. 1999 American Society for Clinical Nutrition Beans have long been recognized for their protein content and value for protein quality. The PDCAASs of most beans are rea- more recently have been noted for their soluble-fiber content, but sonably good, although their overall value is reduced somewhat in general there has been relatively little research and discussion by their lower digestibility (19). Some types of soy protein prod- about the nutritional attributes of legumes. The glaring exception ucts have PDCAASs of close to one, the highest value possible.
to this is the soybean, which has been investigated intensively dur- Some concerns have been raised about the use of the PDCAAS ing the past 5–10 y. This is largely because soybeans are a unique (20), but it certainly represents an improvement over the protein- dietary source of a group of phytochemicals called isoflavones.
Isoflavones are thought to exert a myriad of biological effects and Ironically, the relatively low SAA content of beans may actu- it has been hypothesized that they reduce the risk of a number of ally provide an advantage in terms of calcium retention. The reported hypercalciuric effect of protein is likely to be at least par- This article provides an overview of the nutritional attributes tially due to the metabolism of SAAs. The skeletal system serves of dry beans in general, and then focuses on soybeans in relation as one of the main buffering systems in the body; as a result, the to risk of breast and prostate cancers and osteoporosis. The hydrogen ions produced from the metabolism of SAAs cause dem- reader is referred to other articles in this supplement for reviews ineralization of bone and excretion of calcium in the urine (21, on nuts (9, 10), additional information on legumes (11), and a 22). Thus, bean protein may improve calcium retention relative to discussion of the effects of soy in relation to heart and kidney animal and grain proteins. In general, it has been estimated that every gram of protein consumed causes the loss of 1 mg Ca (23).
Although this may appear to be a trivial amount, every additionalmilligram of calcium excreted may markedly increase dietary cal- NUTRIENT COMPOSITION
cium requirements because net calcium absorption is substantiallyless than the average calcium absorption (Ϸ30%) from foods.
Human studies showed that the consumption of soy protein is The macronutrient composition of selected beans is shown in associated with a markedly lower urinary calcium excretion com- Table 1. The protein content of beans is generally between 20%
pared with the consumption of similar amounts of whey protein and 30% of energy. A serving of beans (Ϸ90 g or 1/2 cup cooked (24) or a mixture of animal proteins (25).
beans) provides Ϸ7–8 g protein or Ϸ15% of the recommended With regard to bone health, the nutritional significance of sub- dietary allowance (RDA) for protein for a 70-kg adult (15).
stituting bean protein for animal protein depends on the relative Although legumes are recognized as being high in protein, the amounts consumed. In general, this process would appear to play quality of bean protein is often underestimated. This is because a minor role because legume protein, even among populations the protein-efficiency ratio, which is based on the growth of lab- eating plant-based diets, comprises only a small percentage of oratory animals (most commonly rats), was the standard method total protein intake. However, the hypocalciuric effect of bean of evaluating protein quality until recently. Rats have a methion- proteins may be quite important for some individuals, such as ine requirement that is Ϸ50% higher than that of humans (16).
those substituting soy protein for animal protein because of its Consequently, because bean proteins are relatively low in sulfur reported hypocholesterolemic effect (12) and athletes using soy amino acids (SAAs), the protein-efficiency ratios of beans are protein supplements. It should be noted, however, that not all studies are in agreement about the effects of protein on calcium However, the World Health Organization (WHO) and the US Food and Drug Administration have adopted an alternativemethod for evaluating protein quality called the protein digest- ibility corrected amino acid score (PDCAAS) (18). This method Most beans are very low in fat, generally containing Ϸ5% of uses the amino acid score (based on the Food and Agriculture energy as fat (Table 1). The primary exceptions are chickpeas and Organization estimated amino acid requirement for 2–5-y-old soybeans, which contain Ϸ15% and 47% fat, respectively. The children) and a correction factor for digestibility to arrive at a predominant fatty acid in beans is linoleic acid, although beans TABLE 1
Nutrient content of selected beans (serving size is Ϸ90 g or 1⁄ c boiled)1
1 From reference 13.
2 Value represents crude fiber. From reference 14.
also contain the nϪ3 fatty acid, ␣-linolenic acid (28). However, index were Ϸ40% more likely to develop diabetes than those because the overall fat content of most beans is so low, the dietary consuming low-glycemic-index diets, even after controlling for contribution of beans to ␣-linolenic acid intake is generally minor.
several diabetes risk factors (55). Thus, beans may be a particu- As noted, soybeans are quite high in fat, and the consumption of larly important food for individuals with diabetes and those with full-fat soyfoods contributes significantly to ␣-linolenic acid an elevated risk of developing diabetes.
intake. The ratio of linoleic to ␣-linolenic acid in soybeans is Ϸ7.5:1 (␣-linolenic acid makes up Ϸ7–8% of the total fat) (28).
Nonnutritive components
nϪ3 Polyunsaturated fatty acids, especially eicosapentaenoic acid Beans contain several components that traditionally have been (EPA) and docosahexaenoic acid (DHA), are being studied for considered to be antinutrients, such as trypsin inhibitors, phytate their health benefits (29–32). Adequate DHA status is particularly (inositol hexaphosphate), oligosaccharides, and saponins. More important for infants (33). ␣-Linolenic acid can be converted into recent information suggests, however, that the antinutrient label EPA and EPA can be converted into DHA, although the rate of may be an oversimplification, especially in the case of oligosac- conversion of ␣-linolenic acid into EPA is relatively inefficient, at charides and saponins. Trypsin inhibitors from beans can cer- 5–10% (34, 35), and is inhibited by linoleic acid (34). The dietary tainly interfere with protein digestion, and in some species of ratio of nϪ6 to nϪ3 fatty acids among vegetarians (36) is at the animals do cause pancreatic enlargement and enhance chemi- high end of the rather conservative recommendations by the WHO cally induced pancreatic tumors (56). However, boiling dry (5:1–10:1) (37). The nϪ3 status of vegetarians is an issue that beans generally reduces the trypsin inhibitor content by 80–90% (57) and there is little reason to think that the amount of trypsininhibitors obtained by eating commonly consumed beans would Micronutrients
exert any adverse effects in humans (58). In contrast to the The folate, iron, zinc, and calcium contents of selected beans trypsin inhibitor, the trypsin and chymotrypsin inhibitor (Bow- are listed in Table 1. Beans are an excellent source of folate, which man-Birk inhibitor) found in beans, especially soybeans, has in addition to being an essential nutrient is thought to reduce the been studied as an anticancer agent (59).
risk of neural tube defects (38). One serving of beans provides As noted above, phytate is thought to contribute to the poor more than half of the current RDA for folate (15). Beans are also mineral bioavailability of beans. On average, the phytate con- high in iron; 1 serving provides Ϸ2 mg. This compares favorably centration in beans is between 1% and 2% (60, 61). Although the with the iron RDAs of 10 and 15 mg for adult men and pre- effect of phytate in reducing mineral bioavailability in plant menopausal women, respectively (15). However, iron bioavail- foods is an important consideration, it has also been postulated ability from legumes is poor and thus their value as a source of that phytic acid may play a role in reducing cancer risk, possibly iron is diminished (39). In acute studies, the addition of vitamin C because of its antioxidant effects (62). Specifically, it has been to foods markedly increased nonheme iron absorption (40), but in suggested that phytic acid may lower the risk of colon cancer longer-term studies the effects of vitamin C intake on iron absorp- (63) and perhaps breast cancer (64).
tion and status were much less pronounced (41). In general, sin- More than 40 y ago, diets containing beans were first shown gle-meal studies overestimate the effects of both inhibitors and to markedly increase flatulence (65). In 1970, it was reported enhancers of nonheme iron absorption (42).
that the oligosaccharides in beans were responsible for gas pro- In contrast to iron bioavailability, zinc bioavailability from duction (66). The oligosaccharide content of dry beans is legumes is relatively good at Ϸ25% (43). Also, many beans are Ϸ25–50 mg/g (67, 68). Because there is no ␣-galactosidase in good sources of calcium, providing on average Ϸ50 mg Ca/serv- the human intestinal mucosa to cleave the ␣-(1–6) galactose ing, although there is quite a bit of variation among the legumes.
linkage present in galactoside-containing oligosaccharides, such Calcium bioavailability from beans in general is Ϸ20%, which is as raffinose and stachyose, these oligosaccharides pass into the lower than that from milk and green leafy vegetables but is still large intestine where bacteria metabolize them and form large reasonably good (44). Calcium bioavailability from soybeans amounts of carbon dioxide, hydrogen, and sometimes methane.
and soyfoods is quite good—essentially equivalent to calcium Because of the discomfort and social embarrassment associated bioavailability from milk—despite the fact that soybeans are with flatulence, some people opt to avoid beans entirely.
Commercial products such as Beano (AkPharma Inc, Pleas- antville, NJ), a digestive aid that contains ␣-galactosidase, are Fiber and the glycemic index
available so that individuals can eat beans without discomfort.
Beans are an excellent source of dietary fiber; 1 serving pro- Additionally, it is possible to remove substantial amounts of vides 2–4 g of a mix of soluble and insoluble fiber (46). High- oligosaccharides and to markedly reduce flatulence by changing fiber, high-bean diets were shown to lower serum cholesterol in the water in which beans are boiled one or more times (69).
hypercholesterolemic individuals (47). In addition, beans have However, there may be some beneficial effects associated with very low glycemic indexes (48, 49). This has been attributed to oligosaccharide consumption. The oligosaccharides, because of many factors including their fiber (50), tannin (51), and phytic their growth-promoting effect on bifidobacteria, have been acid contents (52). Although neither the American Diabetes hypothesized to promote the health of the colon, increase Association nor the American Dietetic Association endorse the longevity, and decrease colon cancer risk (70–72). In fact, for glycemic index as a tool for constructing diets for individuals these reasons researchers in Japan have actually suggested that with diabetes (53), research published during the past decade soybean oligosaccharides be used as a substitute for common makes a persuasive argument that the glycemic index of foods is table sugar (73). For a more detailed discussion of oligosaccha- one factor affecting the overall quality of the diet (54). In sup- rides, see Slavin et al in this supplement (74).
port of this statement are findings from a prospective study Saponins are glycosides composed of a lipid-soluble aglycone showing that women who consumed diets with a high glycemic that consists of either a sterol or, more commonly, a triterpenoid structure attached to water-soluble sugar residues that differ in as the conjugate, whereas in fermented soy products such as their type and amount. The major sources of dietary saponins are legumes, and many types of saponins can be present in the same In addition to the isoflavones found in soybeans, the intestinal bean. Saponins are very poorly absorbed. Most saponins form microflora can convert daidzein into several different products, insoluble complexes with 3-␤-hydroxysteroids and are known to including the isoflavonoids equol (7-hydroxyisoflavan), dihydro- interact with and form large, mixed micelles with bile acids and daidzein, and O-desmethylangolensin (80). However, because of cholesterol. Although saponins were shown to lower cholesterol in differences in intestinal microflora, equol production occurs in some animal species, the hypocholesterolemic effects of saponins only Ϸ1 out of every 3 individuals consuming soyfoods (81, 82).
in humans are more speculative (75). Saponins may have anti- It has been proposed that in humans, genistein is metabolized to cancer properties, as suggested by a recent rodent study that found dihydrogenistein and 6Ј-hydroxy-O-desmethylangolensin (80).
that a saponin-containing diet (3% by wt) inhibited by about two- Estrogenic and antiestrogenic activity thirds the development of azoxymethane-induced preneoplasticlesions in the colon (76). However, given that human intake of Initial interest in the beneficial effects of isoflavones focused saponins is generally ≤ 200–300 mg/d whereas total food intake is on their estrogenic activity and their possible use in the animal Ϸ500 g (dry weight), it is not clear to what extent these results in feed industry as growth promoters (83). On a molar basis relative to physiologic estrogens, isoflavones are quite weak according to Isoflavones make up another group of phytochemicals found both in vitro and in vivo assays, possessing between 1 ϫ 10–4 in beans, but for practical purposes the soybean is the only nutri- and 1 ϫ 10–3 the activity of 17␤-estradiol (84–90). Despite their tionally relevant source of these compounds. Soybeans and soy relatively low potency, isoflavones are likely to exert physiologic products contain Ϸ1–3 mg isoflavones/g protein; 1 serving of effects because it has been shown that in people who consume traditional soyfoods provides Ϸ25–40 mg isoflavones (77, 78).
soyfoods, serum concentrations of isoflavones are several orders Isoflavones have received considerable attention in recent years.
of magnitude higher than those of physiologic estrogens. Studies They are being studied for their potential role in the prevention have found that, in response to the consumption of soyfoods, and treatment of a number of chronic diseases including certain blood isoflavone concentrations can reach the low micromolar forms of cancer, osteoporosis, and heart disease, and also for range (≤ 6 ␮mol/L) (91), although concentrations in free-living their ability to relieve menopausal symptoms.
Japanese men are generally in the high nanomolar range (300–400 nmol/L) (92).
Soybean isoflavones
Although isoflavones are weak estrogens, Folman and Pope Isoflavones are a subclass of the more ubiquitous flavonoids.
(84) showed > 30 y ago that in female mice genistein injected The basic structural feature of flavonoid compounds is the subcutaneously inhibited estrone stimulation of uterine growth; flavone nucleus, which is composed of 2 benzene rings (A and thus, the authors concluded that genistein could function as an B) linked through a heterocyclic pyrane C ring (Figure 1). The
antiestrogen. The prevailing hypothesis has been that isoflavones position of the benzenoid B ring is the basis for dividing the exert antiestrogenic effects when placed in a high-estrogen envi- flavonoid class into flavonoids (2-position) and isoflavonoids ronment, such as exists in premenopausal women, and estrogenic (3-position). The primary isoflavones in soybeans are genistein effects when in a low-estrogen environment, such as exists in (4Ј,5,7-trihydroxyisoflavone) and daidzein (4Ј,7-dihydroxy- postmenopausal women. This hypothesis has some support; for isoflavone) and their respective ␤-glycosides, genistin and example, Mäkela et al (93) found that in ovariectomized mice daidzin (sugars are attached at the 7 position of the A ring).
not given the synthetic estrogen diethylstilbestrol (DES), uterine Much lower amounts of glycitein (7,4Ј-dihydroxy-6-methoxy- weight increased in those fed soy compared with control animals isoflavone) and its glycoside, glycitin, are present in soybeans (0.87 and 0.76 mg/g body wt, respectively; P < 0.001). In mice (79). In nonfermented soyfoods, the isoflavones appear mostly given DES, uterine weight decreased in those fed soy comparedwith control animals (1.01 and 1.49 mg/g body wt, respectively;P < 0.001).
In addition to competing with endogenous estrogens for bind- ing to the estrogen receptor, there are several potential mecha-nisms by which the isoflavones may exert antiestrogenic effects(reviewed in 94). However, there are conflicting results aboutwhen isoflavones and soy exert hormonal effects and whetherthese effects are estrogenic or antiestrogenic in nature (95–106).
This should not be surprising given recent insights into the intri-cacy of the ligand-estrogen receptor binding complex (reviewed in107) and the identification of a novel, second estrogen receptor, ␤,to which isoflavones bind (108). Particularly germane to this issue,however, are the findings of 2 human studies suggesting that soyconsumption exerts estrogenic effects on breast tissue. Epidemio-logic research by Wrensch et al (109) showed that breast-nipple-aspirate fluid is a biomarker for breast cancer risk. Women whosecrete fluid are at increased risk compared with nonsecretors, andwomen who secrete fluid containing cells with abnormal cytology(eg, hyperplastic cells) are also at increased risk. In a 9-mo study FIGURE 1. Structures of the primary isoflavones in soybeans.
by this group, contrary to expectations, breast fluid secretion in both premenopausal and postmenopausal women taking hormone addition to the low breast cancer mortality rates in Asia, 2 other replacement therapy increased in response to soy consumption, as early observations provided a basis for the hypothesis that soy did the number of atypical cells in the breast fluid (110). However, intake decreases breast cancer risk: 1) the potential antiestrogenic this was a pilot study that did not include a control group.
effects of the soybean isoflavones as discussed above, and 2) the In a recent study of premenopausal women by McMichael- reduced number of 7,12-dimethylbenz(a)anthracene–induced Phillips et al (111), the rate of DNA synthesis by breast cells mammary tumors observed in rats fed a diet containing soy (142).
taken from biopsies of normal breast tissue from women with Since this hypothesis was initially proposed, several epidemio- benign or malignant breast disease was enhanced by 2 wk of soy logic studies have examined the relation between soy intake and feeding. Although the clinical implications of this study and the study by Petrakis et al (110) are a matter of debate, when the in In 1991, a case-control study conducted by Lee et al (143) in vitro, animal, and human data are considered it is difficult to Singapore (n = 200 case subjects and 420 control subjects) found conclude that soy or isoflavones are necessarily antiestrogenic in that regular consumption of soyfoods was associated with a marked decrease in breast cancer risk in premenopausal women(odds ratio: 0.39; 95% CI for the highest fifth compared with the Effects of soy and isoflavones on cancer risk
lowest fifth of intake of total soy products: 0.19, 0.77; P < 0.02) Data regarding the relation between soy intake and cancer risk, but not postmenopausal women. A Japanese case-control study including in vitro, animal, and epidemiologic results, were (n = 1186 case subjects and 23 163 control subjects) also found reviewed by Messina et al (112). On the basis of this review, it is that tofu intake (≥ 3 times/wk compared with < 3 times/wk) was clear that the data are insufficient to conclude that soy consump- associated with decreased risk of breast cancer in premenopausal tion is protective, and yet the data certainly warrant continued women (odds ratio: 0.81; 95% CI: 0.65, 0.99; P < 0.05), but investigation of this relation. Besides isoflavones, there are a num- again, soy intake was not protective against postmenopausal ber of phytochemicals in soybeans with demonstrated anticarcino- breast cancer (144). In contrast to these studies, a case-control genic activity; these include phytosterols, phytates, saponins, pro- study involving 2 different locations in China [Shanghai (n = 534 tease inhibitors, and a variety of phenolic acids (113). However, case subjects and 534 control subjects) and Tianjin (n = 300 case most of the data point toward the isoflavones as being responsible subjects and 300 control subjects)] failed to find an association for the hypothesized anticancer effects of soy.
between soyfood intake and breast cancer risk in either pre- or Daidzein, one of the 2 primary isoflavones in soybeans, exhibits anticancer effects; eg, it inhibited the growth of HL-60 The only case-control study (n = 596 case subjects and 958 cells implanted in the subrenal capsules of mice (114). However, control subjects) conducted thus far in the United States to exam- genistein has attracted most of the interest. There are literally ine the relation between soy intake and breast cancer risk found hundreds of in vitro studies showing that genistein inhibits the that tofu consumption was protective in both premenopausal growth of a wide range of both hormone-dependent and hormone- (adjusted odds ratio: 0.67) and postmenopausal (adjusted odds ratio: 0.70) Asian women (146). However, the overall intake of (2–10 ␮g/mL), including breast (115–121), prostate (122–124), tofu among the subjects in this study was relatively low; the high- colon (125, 126), and skin (127) cells (reviewed in 94, 128, 129).
est quartile of intake included women who consumed tofu as Also, in vitro, genistein inhibits the metastatic activity of both infrequently as 55 times per year. Also, the protective effect was breast (130) and prostate (131) cancer cells independent of the primarily in Asian women born in Asia who migrated to the West and not in Asian Americans born in the United States (146). One Although the antioxidant properties of genistein may con- interpretation of these findings is that tofu intake per se is not pro- tribute to the anticancer effects observed in vitro (132), it is more tective but rather that it is simply reflective of some protective likely that these effects are due to the inhibitory actions of genis- lifestyle common to women of Asian ancestry born in Asia but tein on several enzymes involved in signal transduction, includ- not those born in the United States. Alternatively, the anticancer ing tyrosine protein kinases (133), MAP kinase (134), and riboso- effects of tofu may be negated by a lifestyle common to women mal S6 kinase (135). Genistein also inhibits the activity of DNA of Asian ancestry born in the United States but not those born in topoisomerase II (136) and Peterson et al (137) recently reported Asia. Finally, in the Iowa Women’s Study, a prospective study that genistein increased the in vitro concentrations of transforming involving > 34 000 women, it was found after 8 y of follow-up growth factor ␤ (TGF␤). This last finding may be particularly that tofu intake was associated with a modest decrease in post- important given the role that TGF␤ may have in inhibiting the menopausal breast cancer risk (adjusted relative risk for any con- growth of cancer cells (138–140). Although there are in vitro, ani- sumption compared with no consumption: 0.76), although this mal, and epidemiologic data supporting a protective role of soy or was not a statistically significant effect (P < 0.22) (147). Not isoflavones against several forms of cancer, this review will con- unexpectedly, only 2.9% of the cohort reported eating any tofu.
sider only breast and prostate cancers because most of the focus Overall, the epidemiologic data are inconclusive. There is rel- atively little epidemiologic support for the notion that soy intakeis associated with a decreased risk of postmenopausal breast can- cer. However, there are some limited data, albeit inconsistent, Research on the relation between soy intake and cancer risk ini- suggesting that soy intake is associated with a decreased risk of tially focused primarily on cancer of the breast. In large part, inter- est in this relation was due to the relatively low breast cancer mor- As noted previously, genistein has been shown to inhibit the tality rates in Asian countries where soyfoods are commonly growth of both estrogen-dependent and estrogen-independent consumed. In Japan for example, the breast cancer mortality rate breast cancer cells in vitro, but it is not clear that cellular con- is only about one-quarter of that of the United States (141). In centrations of genistein in vivo would reach the in vitro concen- trations required to inhibit breast cancer–cell growth. It should soyfoods may be a factor contributing to the low prostate cancer be noted, however, that Peterson and Barnes (148) found that mortality rate in Japan, although the data in support of this genistein inhibits the serum and epidermal growth factor–stimu- hypothesis, while intriguing, are limited.
lated growth of normal human mammary epithelial cells with Genistein inhibits the growth of both androgen-dependent and values 11–15-fold lower than those for human transformed androgen-independent prostate cancer cells in vitro (122, 123).
breast epithelial cells. Thus, soy intake may help to prevent the Genistein also inhibits the metastatic potential of prostate cancer initiation of cancer cells, rather than inhibiting the growth of cells independent of cell growth inhibition, an effect that is asso- ciated with a decrease in the tyrosine phosphorylation of an In a study by Constantinou et al (149), neither genistein nor unidentified molecular species (131).
daidzein (injected intraperitoneally) inhibited N-methyl-N- In addition to the effects of genistein on signal transduction nitrosourea–induced mammary tumor incidence in Sprague- that were noted previously, there are other mechanisms by which Dawley rats, although both isoflavones had a moderate but not genistein or isoflavones could reduce prostate cancer risk. For statistically significant effect on tumor multiplicity (6.7 com- example, even though the precise role of estrogen in prostate can- pared with 4.9 tumors/rat). Because synergistic effects between cer is not well defined, the potential estrogenic effects of iso- genistein and daidzein have been noted in vitro, it would be of flavones may be protective because estrogens have been used suc- interest to examine their combined effects in vivo (150, 151). Of cessfully as a form of hormone therapy for metastatic prostate course there is also the possibility that other components of soy- cancer (156). Also, some data indicate that genistein inhibits the beans, individually or in conjunction with isoflavones, are activity of 5-␣-reductase in genital skin fibroblasts and benign responsible for the hypothesized anticancer effects of soyfoods.
hyperplastic prostate tissue (150). This enzyme converts testos- It is apparent from the human studies by Wrensch et al (109), terone into the more active form of androgen, dihydrotestos- McMichael-Phillips et al (111), and Cassidy et al (103, 104) that terone, which stimulates the growth of prostate tissue. Ross et al soy or isoflavones have the potential to exert physiologic effects (157) showed that biomarkers of 5-␣-reductase activity are higher theoretically related to breast cancer risk. In particular, Cassidy in white and black men compared with Japanese men. The in et al (103) found that the consumption of soy, specifically vitro data from Evans et al (150) are consistent with findings from isoflavone-rich soy (104), extends the length of the follicular Lu et al (158), who reported that after 1 mo of soymilk consump- phase and decreases serum follicle-stimulating hormone and tion (36 oz/d), serum concentrations of 3␣,17␤-androstanediol luteinizing hormone concentrations. It is certainly not possible to glucuronide, a metabolite of dihydrotestosterone, were signifi- conclude at this time that consumption of soyfoods in adulthood is a factor that contributes to the low breast cancer mortality Until recently, there were few animal studies related to soy and rates among Japanese and Asian women, although this hypothe- prostate cancer. In 1995, Mäkela et al (93) reported that after sis still warrants rigorous investigation.
feeding mice a diet containing soy for 9 mo, the incidence of pro- Finally, there are provocative data from Brown and Lamar- static dysplasia, which may viewed as a preneoplastic prostate tiniere (152), Lamartiniere et al (153), and Murrill et al (154) sug- lesion, was markedly reduced compared with the incidence in gesting that the early consumption of soyfoods by young girls mice fed a diet not containing soy (30% and 80%, respectively).
may reduce breast cancer development later in life. This research At 12 mo, however, there was much less difference between the group has shown that early exposure (during the neonatal or pre- 2 groups (64% compared with 86%). These findings are consis- pubertal period of life) to genistein (subcutaneous administration) tent with the epidemiologic data noted above and also with the inhibits the development of dimethylbenz(a)anthracene-induced results of a study of MNU-induced prostate tumors in Lobund- mammary tumors in rodents and increases the latency period Wistar rats (159). Rats fed a diet containing soy with a low (152–154). These findings offer a potential explanation for the amount of isoflavones had a shorter latency period [7.3 mo for findings of Wu et al (146). Perhaps Asian women born in Asia are pre-MNU group and 9.3 mo for post-MNU group] than those fed exposed to tofu at an earlier age than Asians born in the West.
a diet containing soy high in isoflavones [10 mo for pre-MNU Certainly, the work of this group provides the basis for an intrigu- group and 10.6 mo for post-MNU group] (159).
ing line of investigation, especially because recent research indi- Three studies examined the effect of soy or genistein on tumor cates that early dietary exposure to genistein is also effective in development in rats implanted with prostate cancer cells (123, retarding later development of mammary cancer.
160, 161). Zhang et al (160) found that in rats fed a diet contain-ing soy flour (33% by weight) and implanted with Dunning R3327 PAP tumors, tumor growth was significantly retarded at 16 wk As is the case for breast cancer, prostate cancer mortality rates compared with animals fed the control diet. Schleicher et al (161) vary markedly among countries. An interesting observation found that genistein (50 mg/kg body wt) given under the skin in related to the occurrence of prostate cancer is that rates of clini- the dorsal scapular area every 12 h starting at the time of tumor cal prostate cancer vary much more than rates of latent prostate cell transplantation inhibited the development of prostate tumors cancer. For example, the US incidence of clinical prostate cancer in rats implanted with prostate carcinoma cells. Rats given genis- among whites is 10–15-fold higher than the Japanese rate, tein developed fewer tumors and fewer invasive tumors, and no whereas the overall incidence of latent prostate cancer is only genistein-treated animals developed lung metastases.
Ϸ50% higher (155). This suggests that in some populations, Insight into a possible mechanism for the inhibitory effects of such as the Japanese, the growth of prostate tumors is slower, the genistein came from Dalu et al (162), who found that in Lobund- onset of prostate tumors occurs later in life, or both. Delaying the Wistar rats, dietary genistein (1 mg genistein/g diet) reduced the appearance of clinical prostate tumors by even a few years could weight of the dorsolateral and ventral prostates and inhibited the have a marked impact on mortality because prostate cancer typ- expression of tyrosine-phosphorylated proteins. This study was ically occurs in older men. There is speculation that the intake of the first to show that in vivo, genistein inhibits a key cellular path- way. Related to this finding are those of Geller et al (163), who larger, follow-up study is currently underway. Interestingly, the found that genistein (at concentrations of 1–15 ␮g/mL) inhibited genes in which hereditary hemorrhagic telangiectasia mutations the incorporation of 3H-thymidine (a measure of tissue growth) have been mapped thus far all encode for proteins that are involved in cultured benign prostatic hypertrophy tissue by 44–86% in a in TGF␤ signaling (169) and as noted previously, Peterson et al showed that in vitro, genistein increases TGF␤ levels (137).
In contrast to the favorable results discussed above, Naik et al (123) found that although genistein inhibited prostate cancer cell Soy and bone health
growth in vitro, when Copenhagen rats were injected in the right The similarity in structure between the isoflavones and estro- flank with the metastatic MAT-Lylu prostate cancer line, oral gen and the findings that isoflavones possess weak estrogenic doses of genistein (0.07, 0.143, and 0.285 mg/d) failed to inhibit properties as shown by various experimental models provided the the development of prostate tumors. These doses more closely initial basis for speculation that isoflavones may promote bone approximated human dietary intake than the amounts used by health. Speculation about the potential benefits of isoflavones Schleicher et al (161) and Dalu et al (162). Higher doses of genis- was also fueled by the similarity in chemical structure between tein (0.143, 0.285, and 0.428 mg/kg) injected by the intraperi- the soybean isoflavones and the synthetic isoflavone, 7-isoprop- toneal route also had little effect on tumor growth (123).
oxyisoflavone (ipriflavone), which was shown to increase bone Not surprisingly, there are limited human data available for use mass in postmenopausal women (170, 171).
in evaluating the soy–prostate cancer hypothesis, although a Interestingly, for ipriflavone to be maximally effective it prospective study by Severson et al (164) found that consumption requires metabolism, and one of the metabolites of ipriflavone is of tofu was associated with a markedly reduced risk of prostate the soybean isoflavone daidzein (166). The usual dose of ipri- cancer (age-adjusted relative risk: 0.35 for subjects who ate tofu flavone is between 600 and 1200 mg/d. Reportedly, daidzein ≥5 times/wk compared with those who ate tofu ≤1 time/wk).
comprises 10% of the metabolic products of ipriflavone (171), However, this difference did not quite reach statistical significance although it is not clear to what extent daidzein is actually respon- (P < 0.054) and the number of men with tumors in each of the ter- sible for the effects of ipriflavone on bone resorption; it appears tiles was small (164). Of potential relevance to the effects of to be one of several metabolites able to inhibit osteoclast activity isoflavones on prostate cancer risk is the finding that isoflavones appear in the prostatic fluid, and that concentrations are highest in The lower rate of hip fracture among Japanese women in com- men from soyfood-consuming countries (165). Furthermore, rela- parison to US women (173, 174) is often cited as providing sup- tive to plasma concentrations, isoflavones are concentrated sev- port for a protective effect of isoflavones, but this line of reason- eral-fold in the prostatic fluid. Interestingly, a recent case study ing appears to be without merit. The bone density of Japanese reported significant apoptosis in a prostatic specimen from a man women is similar to or lower than that of US women, whose hip with adenocarcinoma who had taken isoflavones (160 mg/d) fracture rate is twice as high (175–177). Furthermore, the Japan- derived from red clover 1 wk before surgery. The red clover ese vertebral fracture rate is actually much higher than that of US extract contains both genistein and daidzein as well as the methy- women (176). The low Japanese hip fracture rate is thought to be lated isoflavones, biochanin-A and formononetin, from which due at least in part to anatomical differences between white and genistein and daidzein, respectively, are derived (166).
Japanese women, such as the shorter hip axis length of Japanesewomen (178), and perhaps also to other factors such as a lower There has been some speculation that soy or isoflavones could Until recently there were no direct data indicating that the soy- be used in the treatment of existing tumors, either alone or in con- bean isoflavones affect bone density. In 1995, Anderson et al (180) junction with conventional chemotherapeutic agents. Support for reported that genistein exhibited a biphasic effect on bone in 2 dif- this speculation comes from work by Fotsis et al (167) who found ferent models of ovariectomized rats, young growing rats and lac- that at high concentrations (IC , 150 ␮mol), genistein inhibited tating rats, both of which were fed low-calcium diets. These stud- the ability of bovine microvascular cells to invade collagen gels ies used 3 different doses of genistein: 1.0, 3.2, and 10 mg/d. After and generate capillary-like structures when stimulated by basic 2 wk of treatment for the young growing rats and 5 wk of treatment fibroblast growth factor. Development of antiangiogenesis agents for the lactating rats, genistein at the lowest dose helped to prevent is a highly promising area of cancer treatment because inhibiting ovariectomy-induced, bone-related changes to an extent similar to the tumor-stimulated growth of new blood vessels prevents the effects of conjugated equine estrogens (5 ␮g/d).
tumors from becoming larger than 1–2 mm. Tumors limited to In 1996, Arjmandi et al (98) studied the effects of soy protein this size are clinically insignificant (168). The concentration of on bone loss due to ovariectomy. Sprague-Dawley rats were genistein required to inhibit angiogenesis in vitro, as reported ini- divided into 4 groups: 1) sham operated, 2) ovariectomized plus tially (167), is certainly much higher than the genistein concen- casein, 3) ovariectomized plus soy (0.227 g/g diet, isoflavone tration likely to be achieved in vivo. However, it has since been content not indicated), and 4) ovariectomized plus estrogen. The reported that a much lower genistein concentration is required for bone density of the right femur was highest in the group given angiogenesis inhibition in vitro (IC , 8 ␮mol) (94), and that the estrogen and lowest in the ovariectomized animals fed casein.
initial higher concentration was a result of incomplete solubiliza- The bone density of the soy group was significantly lower than that of the estrogen and sham groups, but significantly higher There is some preliminary support from in vivo research for than that of the ovariectomized group fed casein. Bone density of the antiangiogenic potential of genistein. In a small study of the fourth lumbar vertebra of the soy group was equal to that of patients with hereditary hemorrhagic telangiectasia, soy intake the estrogen group and significantly higher than that of both the led to a marked reduction in nosebleeds and gastrointestinal bleed- casein and sham groups. This suggests that soy is more protec- ing (JR Korzenik, S Barnes, unpublished observations, 1996). A tive of trabecular bone than cortical bone. Similar conclusions were reached by Anderson et al (180). In a follow-up study by also worth noting that estrogen and tamoxifen, both of which Arjmandi et al (181), in which a similar experimental model as inhibit bone resorption, cause osteoclast apoptosis, an effect that described above (98) was used, a soy product low in isoflavones is inhibited in vitro by the addition of antibodies to TGF␤ (188).
did not affect bone density favorably but a soy product high in As noted previously, genistein was shown to increase TGF␤ in isoflavones did, clearly suggesting that the isoflavones are vitro, and thus an effect of genistein on bone resorption may be responsible for these beneficial effects of soy.
Two other rat studies suggest that genistein in particular affects The relation between isoflavones and bone health is provoca- bone density (182, 183). Blair et al (182) fed ovariectomized rats tive. Thus far, no long-term human studies have examined the an AIN-76 diet (ICN Pharmaceuticals Inc, Cleveland) or the same
effects of either soy or isoflavones on bone density or even mark- diet containing 30 ␮mol genistein/d for 4 wk. The dry femoral ers of bone formation and resorption, let alone fracture risk.
mass of the animals fed genistein was 12% higher (P < 0.05) than Consequently, although the effect of soy and isoflavones on bone that of the controls. In a study by Fanti et al (183), after 21 d of health constitutes an exciting area of research, no firm conclu- treatment with genistein in ovariectomized rats, 5 and 25 ␮g genis- sions can be reached at this time. Fortunately, because of the tein/g body wt injected subcutaneously significantly reduced number of studies underway, it is likely that a much better under- ovariectomized tibial bone mineral loss; however, 1 ␮g genistein/g standing of this issue will be obtained within a relatively short In contrast to the favorable effects observed in rat studies (98, 180–183), Jayo et al (100) found that in ovariectomized cyno-mogulus monkeys, feeding diets containing soy with or without SUMMARY AND CONCLUSIONS
isoflavones for 23 mo did not retard the loss of lumbar spine Legumes have traditionally been an important part of the diets bone mineral content, whereas monkeys given conjugated equine of many cultures throughout the world. In contrast, in developed estrogens had an increase in bone mineral content during this countries beans currently have only a minor dietary role. The period. Also, in rats a diet containing an amount of soy that nutritional profile of beans shows that they have much to offer; retarded ovariectomy-induced bone loss when administered beans are high in protein, low in saturated fat, and high in complex immediately after surgery had no effect when diet administration carbohydrates and fiber. Beans are also a good source of several was delayed until 35 d after ovariectomy (184). The implications micronutrients and phytochemicals. Soybeans are unique among of this finding may be quite significant given that recent research the legumes because they are a concentrated source of isoflavones.
suggests that estrogen can exert favorable effects on bone density It has been hypothesized that isoflavones reduce the risk of cancer, even when administration is delayed for many years after heart disease, and osteoporosis, and also help relieve menopausal symptoms. Although there is much to learn about the effects of Two human studies that examined the effects of soy consump- isoflavones on chronic disease risk, this area of research holds tion on bone mineral loss in postmenopausal women have been considerable potential. Given the nutrient profile and phytochem- reported thus far (186, 187). In both studies, soy was associated ical contribution of legumes, nutritionists should make a concerted with favorable effects on bone density or content; however, the effort to encourage the public to consume more beans in general results of these studies should be considered preliminary. Potter et al (186) reported that after 6 mo of treatment, lumbar spinebone mineral density increased significantly compared with base-line values in postmenopausal women who consumed 40 g soy REFERENCES
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