August 2005: 272–283
Special Article
Soybean Foods and Their Benefits: Potential Mechanisms of
Action
Adetayo O. Omoni, MSc, and Rotimi E. Aluko, PhD
Isoflavones have been proposed to be the active com-
ponent responsible for the beneficial effects of soy-
bean foods, and appear to work in conjunction with
the proteins to protect against cancer, cardiovascular
disease, and osteoporosis. Most of the research activ-
ities on the benefits of soybean foods have focused on
the role these isoflavones play in disease prevention or
treatment; however, there is also some evidence that
the benefits are attributable to certain peptides or
protein fractions from soybeans. This review will
focus on some of the potential mechanisms whereby
soybeans exert their protective effects against heart
disease, cancer, and osteoporosis.
Key words: soybean, isoflavones, peptides, cardiovas-
cular disease, cancer
© 2005 International Life Sciences Institute
doi: 10.1301/nr.2005.aug.272–283
INTRODUCTION
Soybean foods have generated a lot of interest re-
cently as a result of evidence that populations consuming
large amounts of soybeans have a lower risk of some
chronic diseases, most notably heart disease and can-
cer.1-3 Soybean (Glycine max) is an ancient legume that
is traditionally used to prepare both fermented and non-
fermented foods, and is a staple among Asian popula-
tions. Soybeans are extremely versatile and can be made
into a variety of foods. Asians consume an average of 20
to 80 g of traditional soy foods daily, the most common
of which are tofu, miso, and tempeh.4,5 Americans con-
sume much less soy, only about 1 to 3 g daily,5,6 and this
is mostly in processed forms such as soy drinks, break-
fast cereals, energy bars, and soy “burgers.”
Ms. Omoni and Dr. Aluko are with the Department
of Human Nutritional Sciences, University of Mani-
toba, Winnipeg, Manitoba, Canada.
Address for correspondence: Dr. Rotimi E. Aluko,
Department of Human Nutritional Sciences, University
of Manitoba, H515 Duff Roblin, Winnipeg, Manitoba,
Canada, R3T 2N2; Phone: 204-474-9555; Fax: 204-
474-7593; E-mail: alukor@cc.umanitoba.ca.
272
The consumption of soy foods may reduce the risk
of cardiovascular disease and cancer, and this effect is
seen particularly among Asian populations, in whom
consumption of soy foods is high, compared with West-
ern populations, who eat smaller amounts of soy.1-3 In
addition to cancer and heart disease, data suggest that soy
may also reduce the risk of osteoporosis and help to
alleviate menopausal symptoms,3,7,8 both of which are
major health concerns for women. The aim of this review
is to discuss current knowledge relating to the possible
mechanisms by which some of the bioactive components
in soybeans protect against cardiovascular diseases, can-
cer, and osteoporosis.
BIOACTIVE COMPONENTS OF SOY AND SOY
FOODS
Soy foods contain an array of biologically active
compounds called phytochemicals that may confer im-
portant health benefits.9,10 These include: saponins,
phytates, protease inhibitors, phenolic acids, and lecithin,
all known for their anti-cancer potential;4,6 phytosterols,
which are recognized for their cholesterol-lowering ef-
fects; isoflavones, which are known for several health
benefits11; and omega-3 fatty acids, which are well rec-
ognized for their cardioprotective effects. Of all the
bioactive components of soybeans, isoflavones have at-
tracted the most attention.4,12
Soy Isoflavones
Soybeans, specifically the isolated soy proteins, are
considered a rich source of isoflavones.1,7,13 A 25 g
portion of soy protein contains approximately 50 mg of
isoflavones, although the amounts vary depending on the
variety of bean and the growing conditions.8 Asian
populations consume as much as 80 mg of total isofla-
vones daily, while in the United States, consumption is
usually not more than 5 mg/d.14,15 Isoflavones exist in
soybean and unfermented soy foods mostly as glycosides
(genistin, diadzin, and, to a lesser extent, glycetin). In
fermented soy foods, isoflavones are in the aglycone
form (genistein, daidzein, and glycetein).16 Genistein is
Nutrition Reviews姞, Vol. 63, No. 8
the most abundant isoflavone in soybean17 and is pro-
posed to be the most biologically active.6 Soy isofla-
vones exert both estrogenic and anti-estrogenic effects,
depending on the tissue in which they are acting.12,16,18
They are structurally and functionally similar to 17␤-
estradiol, the most potent mammalian estrogen, and are
thus called phytoestrogens.19 They also have non-hor-
monal effects, including signal transduction and antiox-
idant activity.19 Isoflavones have been proposed to be the
active component responsible for the beneficial effects of
soy foods.8,20 They appear to work in conjunction with
soy protein to exert anti-carcinogenic, anti-atherogenic,
and anti-osteoporotic effects,7,21 and most of the research
on the benefits of soy foods have focused on the role that
they play in disease prevention or treatment.19,22 There is
also some evidence that these benefits are attributable to
certain peptides or protein fractions from soybeans.
Biotransformation of Isoflavones in the
Intestine
After ingestion, soy isoflavones are biotransformed
in the intestinal tract, a process that is highly dependent
on intestinal bacterial metabolism.9,16,19,23,24 The glyco-
sides diadzin and genistin cannot be absorbed intact into
the peripheral circulation of healthy adults; they have to
be changed to the aglycones genistein and diadzein via
the action of intestinal ␤-glucosidases (Figure 1),16, 23,25
and can be further metabolized into both estrogenic and
anti-estrogenic metabolites.16 The extent to which isofla-
vone glycosides are bioavailable is therefore dependent
on gut microflora.
POTENTIAL MECHANISMS OF ACTION
Soy Isoflavones and Cardiovascular Disease
Of all the acclaimed benefits of soy foods, perhaps
the most conclusive one is its protective effects against
cardiovascular disease, which is one of the leading
causes of death worldwide,26,27 with elevated levels of
plasma low-density lipoproteins (LDL) and triglycerides
Figure 1. Biotransformation of soy isoflavones in the intestine.
Nutrition Reviews姞, Vol. 63, No. 8
presenting a higher risk.26 By contrast, high-density
lipoproteins (HDL) are beneficial.28 Postmenopausal
women are at greater risk for cardiovascular disease
because natural or surgical menopause is associated with
elevated levels of circulating total and LDL choles-
terol.29 The reduction in blood total and LDL cholesterol
concentrations with the consumption of products con-
taining soy protein has been shown repeatedly in humans
and several animal models (Table 1).30-32 However, the
exact component responsible for this action has yet to be
clearly defined. Isoflavones have been proposed to be the
active ingredient responsible for the hypocholester-
olemic effects of soy.14, 33 A previous study suggested
that isoflavone-rich soy protein is considerably more
effective than isoflavone-depleted soy protein, though
this finding is controversial.7
The cholesterol-lowering effect is one of several
proposed mechanisms by which soy reduces the risk of
heart disease.34 In a study to evaluate the effects of
isoflavone-rich and isoflavone-depleted soy protein on
plasma lipid concentrations in postmenopausal, moder-
ately hypercholesterolemic women, isoflavone-rich soy
protein lowered total and LDL cholesterol more than soy
protein depleted of isoflavones, though no significant
differences were observed in HDL cholesterol or triac-
ylglycerol concentrations. This difference in total and
LDL cholesterol lowering between the two soy protein
supplements suggests an effect attributable to the isofla-
vone-containing fraction.34
Similar results were observed among 18 postmeno-
pausal women with normal and moderately elevated
cholesterol levels in a randomized crossover trial to
assess the hypocholesterolemic effects of soy isofla-
vones. Subjects were fed isolated soy protein beverage
containing one of three isoflavone levels, 7.1 mg/d
isoflavone (control), 65 mg/d isoflavone (low isofla-
vone), and 132 mg/d isoflavone (high isoflavone). The
high-isoflavone diet lowered plasma LDL cholesterol by
6.5%, though there were no significant changes in total
or HDL cholesterol, triacylglycerol, apolipoprotein
(Apo) A–I, ApoB, lipoprotein(a), or LDL peak particle
diameter. Though small, a decrease of LDL cholesterol
of this magnitude could be associated with a 16% reduc-
tion in cardiovascular disease risk.26
A number of explanations have been put forward for
this cholesterol-lowering effect of soy. It has been sug-
gested that soy reduces blood cholesterol levels by re-
ducing cholesterol and bile acid absorption from the
gastrointestinal tract35 and increasing bile acid excre-
tion.36 When this happens, hepatic cholesterol metabo-
lism shifts to provide cholesterol for enhanced bile acid
synthesis, and cholesterol biosynthesis and LDL receptor
activity increase. The result is an increased removal of
cholesterol from the blood via the LDL receptor, thereby
273
 Table 1. Cholesterol-lowering Effects of Soy Products
274
Reference Population (n)
Human Studies
Goodman-Gruen and Postmenopausal women
Kritz-Silverstein, (n ⫽ 208)
200132
Gardner et al., 200134 Postmenopausal, moderately
hypercholesterolemic
women (n ⫽ 94)
Wangen et al., 200126 Normocholesterolemic and
mildly hypercholesterolemic
women (n ⫽ 18)
Merz-Demlow et al., Normocholesterolemic
200027 premenopausal women
(n ⫽ 13)
Mitchell and Collins, Healthy men (n ⫽ 10)
199943
Potter et al., 199830 Hypercholesterolemic,
postmenopausal women
(n ⫽ 66)
Wong et al., 199831 Normocholesterolemic
(n ⫽ 13) and
hypercholesterolemic
(n ⫽ 13) men
Nutrition Reviews姞, Vol. 63, No. 8
Soy Product Fed, Dose, Duration
Daily soy isoflavone intake assessed for one Women with moderate and high genistein consumption had
year with questionnaire; average intake of
genistein was 1.3 ⫾ 2.4 mg/d, range
0–13.9 mg/d
Soy protein with trace amounts of
isoflavones (Soy⫺) or 80 mg aglycone
isoflavones (Soy⫹) per day for 12 weeks
Daily consumption of soy protein isolate
(SPI) beverage powders providing an
average of 7.1 ⫾ 1.1 (control), 65 ⫾ 11
(low isoflavone), or 132 ⫾ 22 (high
isoflavone) mg isoflavones per day for
three 93-day periods in a randomized
crossover design
SPI consumed as a beverage powder with
three levels of soy isoflavones: 10 ⫾ 1.1
(control), 64.7 ⫾ 9.4 (low), and 128.7 ⫾
15.7 (high) mg per day for three
menstrual cycles each in a randomized
crossover design
Soy milk (1 L/d) for 4 weeks
Soy protein (40 mg/d) plus moderate and
higher concentrations of isoflavones (1.39
and 2.25 mg isoflavone/g protein,
respectively) for 6 months
Soy protein incorporated into the National
Cholesterol Educational Program Step I diet
(constituting ⱖ 75% total protein content)
fed for a total of 10 weeks in a randomized
crossover design (average daily soy protein
consumption approximately 50 g)
Outcome
significantly improved HDL cholesterol
Total and LDL cholesterol concentrations decreased more
in the Soy⫹ group than in the Soy⫺ group; no
significant differences in HDL cholesterol and
triacylglycerol concentrations between the groups
High-isoflavone diet reduced plasma LDL cholesterol by
6.5% compared with control; low- and high-isoflavone
diet reduced LDL:HDL cholesterol by 8.5% and 7.7%,
respectively; isoflavone consumption did not
significantly affect plasma concentrations of total or
HDL cholesterol, triacylglycerol, ApoA–I, ApoB, or
lipoprotein (a) or the LDL peak particle diameter
High-isoflavone diet lowered LDL cholesterol by 7.6% to
10%, total:HDL cholesterol by 10.2%, and LDL:HDL
cholesterol by 13.8%
No significant effect of soy supplementation on plasma
cholesterol, triglyceride levels, or HDL:LDL cholesterol
ratios compared with controls
Non-HDL cholesterol was reduced in both groups fed
moderate and higher concentrations of isoflavone
compared with controls; HDL cholesterol increased in
the two groups; LDL receptor mRNA was reduced in
the two groups compared with controls
Plasma concentration of LDL cholesterol and LDL:HDL
cholesterol in both normocholesterolemic and
hypercholesterolemic men were significantly lower
(approximately 6% and 11%, respectively) when soy
protein diet was consumed
 Table 1. (Cont’d) Cholesterol-lowering Effects of Soy Products
Reference Population (n) Soy Product Fed, Dose, Duration Outcome
40
Nestel et al., 1997 Menopausal and Soy isoflavone tablets (80 mg/d) for 5 to 10 No effect on plasma lipids (plasma cholesterol, triglyceride
perimenopausal women weeks and HDL cholesterol); arterial compliance improved by
(n ⫽ 21) 26%

Nutrition Reviews姞, Vol. 63, No. 8

Animal Studies

Adams et al., 200456 Atherosclerosis-susceptible One of five experimental diets: soy plus Reduced atherosclerosis observed in all mice fed the ␤-
mice, male and isoflavones, ␤-conglycinin (7S globulin, a conglycinin diets compared with mice fed the soy plus
ovariectomized female major soy storage protein), ␤- isoflavones diet; extent of atherosclerosis reduced in
ApoE-null mice, and LDL- conglycinin-devoid soy protein, glycinin ovariectomized female mice fed all soy protein-
receptor-null ApoB (11S globulin, a major soy storage containing diets compared with controls
transgenic mice (n ⫽ 416) protein), or W008 (a soy peptide fraction)
for 4 months
Demonty et al., 200233 Male Sprague-Dawley rats SPI and casein with similar isoflavone Plasma total triglycerides decreased by 26% in rats fed soy
(n ⫽ 36) content (1.82 mg/g protein) for 21 days protein and casein plus isoflavones compared with
control
Fukui et al., 200211 Male Sprague-Dawley rats 20% SPI; 20% isoflavone-free SPI (IF–SPI) Plasma total cholesterol concentrations of rats fed SPI and
(n ⫽ 30) for 2 weeks IF-SPI were comparable and significantly lower than that
of rats fed control diet; higher fecal steroid excretion in
the SPI group
Lucas et al., 200129 Ovariectomized female golden Ethanol extracted isoflavone-depleted SPI ID-SPI lowered serum triglyceride concentrations
Syrian hamsters (n ⫽ 48) (ID–SPI) (240 g/kg of diet) for 70 days compared to controls, no significant differences in serum
HDL concentrations, liver total lipids and liver total
cholesterol
Tsai and Huang, 199910 Male golden Syrian hamsters SPI containing 1.24 mg genistein and 0.61 SPI group exhibited significantly lower serum total
(n ⫽ 24) mg diadzein/g, and ethanol-extracted SPI cholesterol concentration compared with the E–SPI
(E–SPI) low in isoflavones (0.21 mg group; both SPI and E–SPI groups had lower LDL
genistein and 0.06 mg diadzein/g) fed for cholesterol, LDL ApoB, and LDL:HDL cholesterol
10 weeks compared with the controls

275
reducing blood cholesterol levels (particularly the LDL
fraction). There is evidence that soy protein increases
fecal excretion of bile acids. In rats fed isoflavone-rich
and isoflavone-depleted soy protein, higher fecal steroid
excretion was observed in the isoflavone-rich group,
though both groups had lowered total cholesterol com-
pared with the control group. The authors concluded that
the cholesterol-lowering effects of soy may be attributed
to the protein content, with the isoflavones and other
minor constituents playing a role.11
Soy isoflavones are also believed to reduce the risk
of heart disease by reducing the susceptibility of LDL to
oxidation via its antioxidant action.16,37 The effects of a
soy protein diet enriched with isoflavones and one de-
pleted of isoflavones on LDL resistance to oxidation
were compared among 24 healthy subjects in a random-
ized crossover design. Plasma concentrations of
8-epiprostaglandin F2␣, a biomarker of lipid oxidation,
were significantly lower after the high-isoflavone diet
(21.2 mg diadzein, 34.8 mg genistein), showing in-
creased resistance of LDL to Cu2⫹-induced oxidation.
This antioxidant action may be significant with regard to
risk of atherosclerosis and cardiovascular disease in
general.16 Similar results were observed in male golden
Syrian hamsters.10 The resistance of LDL to Cu2⫹-
induced oxidation was greater in hamsters fed isofla-
vone-rich soy protein than in those fed isoflavone-
depleted protein, as assessed by the lower concentrations
of thiobarbituric acid reactive substances, another bi-
omarker of lipid oxidation, and the longer lag time
required for the formation of conjugated dienes. The
isoflavone-enriched group also had significantly higher
serum total antioxidant capacity, particularly ␣-tocoph-
erol content, showing sparing effects on ␣-tocopherol
contents in both serum and liver. These findings suggest
that the intake of soy isoflavones enhanced the resistance
of LDL to oxidation, contributing to antioxidant defense,
and reduced the consumption of ␣-tocopherol in both the
serum and liver of hamsters.10
Improvement of arterial compliance is another pos-
sible mechanism by which soy isoflavones protect
against heart disease.38 Arterial compliance (arterial
elasticity) is an important cardiovascular disease risk
factor that diminishes with age and menopause.39 The
effect of soy isoflavones (80 mg daily) on arterial com-
pliance was tested in menopausal and perimenopausal
women over 5- to 10-week periods in a placebo-con-
trolled crossover trial.40 Though there was no effect on
plasma lipids, systemic arterial compliance improved by
26% compared with placebo to about the same extent as
that achieved with conventional hormone replacement
therapy (HRT). The fact that plasma lipids were not
changed suggests that other constituents of soybean
276
(apart from its isoflavones) may be responsible for lipid
lowering.40
Soy Isoflavones and Cancer
The consumption of high levels of soy foods has
been shown to be associated with a reduced risk of
several types of cancer, including breast, endometrial,
and prostate cancers, particularly among Asian popula-
tions.5,6,15,41,42 This is in contrast to Western popula-
tions, where there is a higher incidence of these cancers.
A number of in vivo studies are supportive of a protec-
tive role for soy foods in cancer and some studies have
shown that soy isoflavones are responsible for these
protective effects.15 This protective effect appears to be
strongest for breast cancer. Administration of soy isofla-
vones early in life enhances the early maturation and
differentiation of the mammary gland of rats, suggesting
that exposure in early life may be important.3,7,17 Table
2 shows a summary of previous studies on the effects of
soy products on cancer and associated DNA damage.
Several possible mechanisms have been identified
for the anticarcinogenic activity of soy isoflavones. One
of the mechanisms by which soy isoflavones are believed
to exert their anticarcinogenic effects is via their antiox-
idant properties,14 which result in a decrease in lipid
peroxidation16 and oxidative DNA damage,14 both im-
portant risk factors for carcinogenesis. These antioxidant
properties are suggested to be related to the chemical
structure of soy isoflavones. Consumption of soy con-
taining naturally occurring amounts of isoflavones re-
duced lipid peroxidation in vivo among 24 healthy sub-
jects, as evidenced by lower levels of plasma
concentrations of 8-epiprostaglandin F2␣, a biomarker of
in vivo lipid peroxidation.16 In another study to evaluate
the effects of soy isoflavone supplementation on markers
of oxidative stress in men and women, soy supplemen-
tation was given in the form of Novasoy tablets contain-
ing 50 mg of isoflavones daily for 3 weeks. There was a
significant decrease in the levels of 5-hydroxymethyl-2-
deoxyuridine, a biomarker of oxidative DNA damage;
though no significant decrease in lipid peroxidation was
observed. The results from this study suggest that dietary
supplementation with soy isoflavones can decrease levels
of oxidative DNA damage, which is associated with the
process of carcinogenesis.14 A similar decrease in oxi-
dative DNA damage was also observed among men
consuming 1 L of soy milk daily for 4 weeks.43
Another mechanism by which soy isoflavones may
protect against cancer is through the induction of phase II
enzymes,44 which is associated with cancer chemopre-
ventive potential at both the initiation and promotion
phases.44 Induced levels of the phase II enzymes gluta-
thione-s-transferase (GST) and quinone reductase (QR)
Nutrition Reviews姞, Vol. 63, No. 8
 Table 2. Effect of Soy Products on Cancer and Oxidative DNA Damage
Reference Population Soy Product Fed, Dose, Duration Outcome
Human Studies

Djuric et al., 200114 Men (n ⫽ 6) and Novasoy tablets containing 50 mg Soy isoflavone supplementation decreased levels of oxidative
women (n ⫽ 6) isoflavones; women took 1 tablet daily DNA damage in men and women, evidenced by decreased
and men took 2 tablets daily for 3 weeks levels of 5-hydroxymethyl-2-deoxyuridine, a biomarker of

Nutrition Reviews姞, Vol. 63, No. 8

oxidative DNA damage (47% and 61% decrease in women and
men, respectively)
Wiseman et al., 24 healthy subjects One of two experimental diets over two High-isoflavone diet significantly reduced plasma concentrations
200016 (19 women and 17-day periods in a randomized crossover of F2-isoprostane-8-epiprostaglandin F2␣, a biomarker of in
5 men) design: low-soy isoflavone diet (21.2 mg vivo lipid peroxidation
diadzein, 34.8 mg genistein) or high-soy
isoflavone diet (0.9 mg diadzein, 1.0 mg
genistein)
Mitchell & Collins, Healthy men Soy milk (1 L/d) for 4 weeks Decrease in oxidative DNA damage by approximately 67%
199943 (n ⫽ 10)

Animal Studies

Constantinou et al., Female Sprague- One of five experimental diets for 120 days: SPI⫺ was the most effective diet, significantly reducing
200244 Dawley rats genistein (200 mg/kg diet); diadzein (200 mammary tumor multiplicity by 50%; diadzein and SPI⫹ diet
(n ⫽ 119) mg/kg diet); genistein plus diadzein at also significantly reduced tumor multiplicity by 32% compared
100 mg/kg diet each; 16% soy protein with controls; no significant reduction in mammary tumor
isolate plus isoflavones (SPI⫹); 16% incidence in any diet
isoflavone-depleted SPI (SPI⫺)
Cohen et al., 20006 Rats (n ⫽ 150) 20% intact soy protein (SP), 10% SP, 20% No significant differences in mammary tumor incidence, latency,
isoflavone-depleted SP (IDSP), 10% multiplicity, or volume compared with controls
IDSP for 18 weeks
Applet and Reicks, Female Sprague- Soy containing three levels of isoflavones Rats fed high-isoflavone diet had lower mammary tumor
199945 Dawley rats (0.03, 0.4, 0.81 mg/g diet; low, middle incidence (40%) compared with controls (71.4%); rats fed
(n ⫽ 86) and high level of isoflavones, middle and low isoflavone diet had tumor incidence of 53.3
respectively) for 13 weeks and 57.1%, respectively

277
have been proposed as suitable biomarkers for identify-
ing compounds likely to inhibit carcinogenesis.45 QR
and GST are enzymes that help the body get rid of the
toxic products of oxidative metabolism of aromatic hy-
drocarbons.44 There is evidence to support the mecha-
nism of soy isoflavones as antioxidants and as phase II
enzyme inducers. Soy isoflavones increased antioxidant
and phase II enzyme activity, especially QR, GST, and
UDP-glucuronosyltransferase, in various tissues of rats
fed a high-isoflavone diet for 2 weeks.45
Similar results were found in a study by Con-
stantinou et al.44 comparing the anti-tumor effects of
isoflavone-enriched soy protein isolate and isoflavone-
depleted soy protein isolate with those of its isoflavones,
genistein and diadzein. Although the diadzein and isofla-
vone-enriched soy groups showed significantly reduced
tumor multiplicity compared with the controls, both soy
groups (but not the genistein or diadzein groups) upregu-
lated transcriptional expression of the antioxidant en-
zymes QR and GST. These results suggest that the mode
of preventive action of soy protein isolate is distinct from
that of the main isoflavones, and that isoflavone-depleted
soy may be more beneficial than isoflavone-enriched soy
in preventing mammary tumors in these experimental
animals.44 However, another study evaluating the effects
of intact and isoflavone-depleted soy protein on N-
nitroso-N-methylurea (NMU)-induced rat mammary tu-
morigenesis showed no effect on tumor incidence, la-
tency, multiplicity, or volume. The results from this
study do not support the hypothesis that the isoflavone
components of soy protein, or the soy protein itself,
inhibit chemically induced mammary tumor development.6
As with animal experiments, studies in human pop-
ulations relating soy consumption to reduced risk of
breast cancer have produced conflicting results, and a
few have shown stimulatory effects. Petrakis et al.46
reported that prolonged consumption of soy protein iso-
late by a group of healthy premenopausal US women
increased hyperplastic epithelial cells in duct fluid aspi-
rates, showing a stimulatory effect on the breast.
Soy Isoflavones and Osteoporosis
The ovarian hormone deficiency associated with
menopause results in an increased rate of bone turnover,
which causes an imbalance between bone resorption and
bone formation, thereby accelerating bone loss that leads
to osteoporosis.25,47 HRT is an effective treatment in
reducing the rate of bone loss and risk of fracture, though
not very popular among postmenopausal women because
of the undesirable side effects and long-term risks of
breast and endometrial cancer associated with prolonged
use.18,25,47,48 Soy isoflavones have been shown to alle-
viate osteoporosis without the side effects of HRT.12 For
278
this reason, soy isoflavones are called selective estrogen
receptor modulators (SERMs), and may be a possible
alternative to HRT.7,12
Soy isoflavones have been suggested to alleviate
osteoporosis by inhibiting bone resorption and stimulat-
ing bone formation. Evidence that soy isoflavones reduce
bone resorption has been demonstrated by a number of
studies. Picherit et al.49 investigated the ability of long-
term daily intake of soy isoflavones in reversing osteope-
nia in the adult ovariectomized rat, which was used as a
model of postmenopausal women. Soy isoflavones re-
duced the urinary excretion of deoxypyridinoline, a spe-
cific biomarker of bone resorption.49 Similar results were
also observed among postmenopausal women, in whom
soy protein intake was associated with significantly
lower urinary deoxypyridinoline excretion.50,51
Soy isoflavones appear to stimulate osteoblastic ac-
tivity through the promotion of insulin-like growth fac-
tor-I (IGF-I) production.52 It is well recognized that
IGF-I enhances osteoblastic activity in humans.25 IGF-I
is a protein involved in the bone formation process, and
therefore an increase in IGF-I is indicative of increased
bone formation. In a study by Arjmandi et al.52 using a
rat model of osteopenia, soy increased the gene expres-
sion of IGF-I, as indicated by higher femoral mRNA
levels. Incorporation of soy protein with normal isofla-
vone content (2.3 mg/g protein) had a greater effect on
femoral IGF-I mRNA than the isoflavone-depleted soy
protein-based diet (approximately 0.1 mg/g protein).
This finding indicates that isoflavones may have a role in
enhancing the synthesis of IGF-I at the bone level.
There is additional evidence that soy promotes bone
formation. Increased levels of bone alkaline phosphatase,
a biomarker of bone formation, was observed among
perimenopausal women fed an isoflavone-rich soy pro-
tein diet.18 In the same study, lumbar spine bone mineral
density (BMD) and bone mineral content (BMC) were
assessed at baseline and at the end of the treatment.
There was a significant difference in BMD (5.6%) and
BMC (10.1%) between the isoflavone-rich and control
groups, and the authors concluded that soy isoflavones
attenuated bone loss from the lumbar spine in estrogen-
deficient perimenopausal women.18 Similar results were
also observed among hypercholesterolemic, postmeno-
pausal women assessed for total and regional BMC and
BMD before and after administration of 40 mg/d of soy
protein containing moderate and higher concentrations of
isoflavones (1.39 and 2.25 mg isoflavone/g of protein,
respectively). The high-isoflavone diet significantly in-
creased both BMC and BMD in the lumbar spine but not
elsewhere.30 Increased BMD and mechanical bone
strength and intestinal calcium absorption were also
observed in ovariectomized, osteoporotic rats fed soy
milk.53 Soy is also a rich source of calcium, and this may
Nutrition Reviews姞, Vol. 63, No. 8
be a possible explanation for the observed increased in
intestinal calcium absorption.
From these studies, it is evident that soy foods play
a role in attenuating bone loss (Table 3); however, the
exact osteoprotective mechanism of soy isoflavones re-
mains unclear and requires further elucidation.
Soy Proteins and Peptides in Cardiovascular
Disease and Cancer
Some evidence exists to support the role of certain
isoflavone-free soy protein and peptide fractions in car-
diovascular disease and cancer. Sirtori et al.54 have
shown that 7S globulin, a major storage protein in
soybean, reduced plasma cholesterol concentration by
35% in rats. Similar results were observed by Lovati et
al.55 in an in vitro study evaluating LDL receptor activity
in Hep G2 cells (a human hepatoma cell line) exposed
either to small natural peptides produced by enzymatic
digestion of CroksoyR70 (a commercial isoflavone-poor
soy concentrate) or to synthetic peptides corresponding
to specific sequences of the complete 7S globulin (Table
4). The findings from this study demonstrated that 7S
globulins stimulate the expression of LDL receptors and
the degradation of LDL in the cultured hepatocytes. The
data also support the hypothesis that there are bioactive
peptides produced from the digestion of soy protein that
are absorbed from the small intestine and have beneficial
effects on lipoprotein metabolism and cardiovascular
health by up-regulating LDL-receptor activity in liver
cells. Similar degradation of LDL by an alcohol-ex-
tracted 7S globulin was also shown, which demonstrates
that the active molecules are the proteins and not the
alcohol-soluble isoflavones.55 The authors concluded
that the isoflavone-free protein component is likely to be
responsible for this biochemical effect of soy.
To further demonstrate this effect in vivo, Adams et
al.56 assessed the effects of dietary ␤-conglycinin, a major
soy storage protein, and other soy peptide fractions on the
development of atherosclerosis in atherosclerosis-suscepti-
ble mice. Male and ovariectomized female ApoE-null mice
and LDL-receptor-null ApoB transgenic mice were ran-
domly assigned to one of six treatment groups differing
only in their source of dietary protein: 1) casein/lactalbu-
min, 2) isoflavone-containing soy protein isolate, 3) ␤-con-
glycinin, 4) glycinin (11S globulin, another major soy
storage protein), 5) ␤-conglycinin-devoid soy protein, or 6)
W008 (a peptide fraction produced by hydrolysis and pre-
cipitation of soy protein isolate). After 4 months of feeding,
the aortic atherosclerosis (cholesteryl ester content) and
plasma lipoprotein cholesterol concentrations of the mice
were quantified. Results showed that the extent of athero-
sclerosis was reduced in ovariectomized female mice
fed all soy protein-containing diets compared with
Nutrition Reviews姞, Vol. 63, No. 8
mice fed casein/lactalbumin-based diets. Furthermore,
compared with mice fed isoflavone-containing soy
protein isolate, atherosclerosis was reduced only in
mice fed the ␤-conglycinin-containing diet. These
reductions were 39% and 67% in male and ovariecto-
mized female ApoE-null mice, respectively, and 66%
in the male LDL-receptor-null mice. These observed
effects were unrelated to variations in isoflavone con-
tent of the protein source and only minimally related
to plasma lipoprotein cholesterol concentrations. The
authors thus concluded that a diet rich in ␤-conglyci-
nin has atheroprotective effects that greatly exceed
those of isoflavone-containing soy protein isolate. In-
terestingly, however, their results show that these
effects do not depend on LDL receptors or influence
plasma lipoproteins.
Evidence also shows that dietary soy peptides and
soy protein isolates (without isoflavones) have antioxi-
dative properties. Takenaka et al.57 demonstrated that
isoflavone-free soy protein isolate and soy peptide re-
duced paraquat-induced oxidative stress in rats.
Soy protein may also have cancer-protective effects.
Azuma et al.58 and Kanamoto et al.59 demonstrated that
feeding an insoluble, high-molecular weight protein frac-
tion (HMF) prepared from a proteinase-treated soybean
protein isolate suppressed colon and liver tumorigenesis
induced by azoxymethane and dietary deoxycholate in
experimental animals. Bile acid is known to play a
critical role in liver and colon tumorigenesis. The authors
proposed that HMF exerted these protective effects in
colon and liver tumorigenesis by interfering with the
enterohepatic circulation of bile acids, thus inhibiting
resorption of bile acids in the intestine and increasing
fecal bile acid excretion. Peptides found in the feces of
HMF-fed animals were found to be rich in hydrophobic
amino acids, so the authors suggested that the HMF
protein forms non-dissociable complexes with bile acids
in the intestine through hydrophobic binding, which are
then excreted into feces. HMF may therefore be used as
a functional food to prevent the tumor-promoting activity
of bile acids on the liver and colon.
CONCLUSIONS AND FUTURE DIRECTIONS
The consumption of soy foods has been proven to
protect against heart disease, some forms of cancer, and
osteoporosis. However, there is still no conclusive evidence
to date showing whether the protective effects of soy are
derived solely from isoflavones, from soy protein itself, or
from a combination. Research findings are inconsistent;
some evidence supports a role for the isoflavones contained
in soybeans and many soy foods, while other evidence
supports certain peptides or peptide fractions derived from
soy. In addition to this, soy foods also contain other bioac-
279
280
Table 3. Effect of Soy Products on Bone Health
Reference Population Soy Product Fed, Dose, Duration Outcome
Human Studies
Horiuchi et al., Postmenopausal Japanese women Daily soy protein intake assessed over a period Soy protein intake significantly correlated with higher
200050 (n ⫽ 85) of three consecutive days using a bone mineral density (BMD) and lower urinary
questionnaire (mean intake 12.6 g/d) excretion of deoxypyridinoline
Alekel et al., Perimenopausal women SPI with isoflavones (80.4 mg/d) for 24 weeks Soy isoflavones attenuated bone loss from the lumbar
200018 (n ⫽ 69) spine: BMD and bone mineral content (BMC)
increased by 5.6% and 10.1%, respectively,
compared with controls; increased levels of serum
bone-specific alkaline phosphatase, a biomarker of
bone formation
Potter et al., Hypercholesterolemic, Soy protein (40 mg/d) plus moderate and High-isoflavone diet significantly increased both
199830 postmenopausal women higher concentrations of isoflavones (1.39 BMC and BMD in the lumbar spine but not
(n ⫽ 66) and 2.25 mg isoflavone/g protein, elsewhere
respectively) for 6 months
Animal Studies
Picherit et al., Adult ovariectomized rats Soybean isoflavone fed as powdered soy Daily soybean isoflavone consumption decreased
200149 (n ⫽ 36) isoflavone concentrate; daily intake of 0, 20, bone turnover as evidenced by decreased urinary
40 and 80 mg/kg body weight for 84 days excretion of deoxypyridinoline, a specific bone
marker of bone resorption
Arjmandi et al., Ovariectomized rats with Soy protein with normal isoflavone content Increased expression of femoral insulin-like growth
199852 established bone loss (2.3 mg/g protein) and reduced isoflavone factor-I mRNA levels, an indicator of increased
(n ⫽ 36) content (approximately 0.1 mg/g protein) for bone formation
65 days

Nutrition Reviews姞, Vol. 63, No. 8

Table 4. Effect of CroksoyR70, its Enzyme Digests and Subfractions of Different Molecular Weight on LDL
Receptor Activity in Hep G2 Cells*
Uptake Degradation
125
mg I-LDL/g cell protein
Lipoprotein-deficient Serum (LPDS) 107 ⫹ 12 117 ⫹ 16
CroksoyR70, g/L
0.050 105 ⫾ 9 115 ⫾ 10
0.125 116 ⫾ 8† 123 ⫾ 7‡
0.250 132 ⫾ 11‡ 145 ⫾ 11‡
0.500 144 ⫾ 7‡ 166 ⫾ 8‡
0.750 139 ⫾ 10‡ 146 ⫾ 8‡
1.000 108 ⫾ 7† 120 ⫾ 12
CroksoyR70 enzyme digested, g/L
0.050 117 ⫾ 11† 119 ⫾ 11
0.125 136 ⫾ 9‡§ 180 ⫾ 9‡§
0.250 153 ⫾ 10‡§ 191 ⫾ 22‡§
0.500 182 ⫾ 13‡§ 249 ⫾ 19‡§
0.750 192 ⫾ 11‡§ 250 ⫾ 20‡§
1.000 220 ⫾ 13‡§ 266 ⫾ 8‡§
Fractions from CroksoyR70 enzyme digested, g/L
MW ⬎ 3000 Da
0.050 125 ⫾ 11† 153 ⫾ 11‡§
0.125 145 ⫾ 13‡§ 190 ⫾ 15‡§
0.250 169 ⫾ 9‡§ 210 ⫾ 12‡§
0.500 137 ⫾ 10‡ 226 ⫾ 19‡
1000 ⬍ MW ⬍ 3000 Da
0.050 89 ⫾ 10 75 ⫾ 11
0.125 96 ⫾ 12 84 ⫾ 9
0.250 90 ⫾ 10 88 ⫾ 12
0.500 88 ⫾ 15 78 ⫾ 19
MW ⬍ 1000 Da
0.050 88 ⫾ 10 77 ⫾ 11
0.125 95 ⫾ 22 78 ⫾ 9
0.250 85 ⫾ 10 70 ⫾ 12
0.500 80 ⫾ 10 75 ⫾ 9
* Values are means ⫾ SEM, n ⫽ 3.
†
P ⱕ 0.05 compared with LPDS
‡
P ⱕ 0.0001 compared with LPDS
§
P ⱕ 0.05 compared with CroksoyR70 at the same concentration
Reproduced from Lovati et al.55 with copyright permission of the American Society for Nutritional Sciences.

tive components that could exert beneficial effects: the
cholesterol-lowering effects of soluble fiber and phytoster-
ols; the anti-carcinogenic potential of saponins, phytic acid,
Bowman-Birk inhibitor, and lecithin; and the cardioprotec-
tive effects of omega-3 fatty acids. Furthermore, these
components may have synergistic effects.
It is evident that there is still a lot to be learned about
soy foods. A question that remains to be answered
conclusively is what component of soy foods is respon-
sible for its protective effects against heart disease,
cancer, and osteoporosis. This gap in knowledge could
form the basis for more research on the benefits of soy,
and further elucidation of its mode of action. Other areas
worthy of research are the possible variations in effects
of the form of soy foods consumed (fermented, non-
fermented) on different tissues and the possible syner-
gistic effects of the many bioactive components of soy.
Furthermore, tissue-specific metabolism and biotransfor-
mation of soy isoflavones, and the effects and mecha-
nisms of action of its different metabolites in vivo, will
go a long way in contributing to the understanding of the
mechanisms of action of soy isoflavones.
ACKNOWLEDGEMENT
The authors thank the Natural Sciences and Engineer-
ing Research Council of Canada for financial support pro-
vided to the research program of Dr. Aluko.

Nutrition Reviews姞, Vol. 63, No. 8 281

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