272.full

August 2005: 272283Special Article

Soybean Foods and Their Benefits: Potential Mechanisms ofActionAdetayo 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 withthe proteins to protect against cancer, cardiovasculardisease, and osteoporosis. Most of the research activ-ities on the benefits of soybean foods have focused onthe role these isoflavones play in disease prevention ortreatment; however, there is also some evidence thatthe benefits are attributable to certain peptides orprotein fractions from soybeans. This review willfocus on some of the potential mechanisms wherebysoybeans exert their protective effects against heartdisease, cancer, and osteoporosis.

Key words: soybean, isoflavones, peptides, cardiovas-cular disease, cancer 2005 International Life Sciences Institute

doi: 10.1301/nr.2005.aug.272283

INTRODUCTION

Soybean foods have generated a lot of interest re-cently as a result of evidence that populations consuminglarge amounts of soybeans have a lower risk of somechronic diseases, most notably heart disease and can-cer.1-3 Soybean (Glycine max) is an ancient legume thatis 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 madeinto a variety of foods. Asians consume an average of 20to 80 g of traditional soy foods daily, the most commonof which are tofu, miso, and tempeh.4,5 Americans con-sume much less soy, only about 1 to 3 g daily,5,6 and thisis mostly in processed forms such as soy drinks, break-fast cereals, energy bars, and soy burgers.

The consumption of soy foods may reduce the riskof cardiovascular disease and cancer, and this effect isseen particularly among Asian populations, in whomconsumption of soy foods is high, compared with West-ern populations, who eat smaller amounts of soy.1-3 Inaddition to cancer and heart disease, data suggest that soymay also reduce the risk of osteoporosis and help toalleviate menopausal symptoms,3,7,8 both of which aremajor health concerns for women. The aim of this reviewis to discuss current knowledge relating to the possiblemechanisms by which some of the bioactive componentsin soybeans protect against cardiovascular diseases, can-cer, and osteoporosis.

BIOACTIVE COMPONENTS OF SOY AND SOYFOODS

Soy foods contain an array of biologically activecompounds 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 healthbenefits11; and omega-3 fatty acids, which are well rec-ognized for their cardioprotective effects. Of all thebioactive components of soybeans, isoflavones have at-tracted the most attention.4,12

Soy Isoflavones

Soybeans, specifically the isolated soy proteins, areconsidered a rich source of isoflavones.1,7,13 A 25 gportion of soy protein contains approximately 50 mg ofisoflavones, although the amounts vary depending on thevariety of bean and the growing conditions.8 Asianpopulations consume as much as 80 mg of total isofla-vones daily, while in the United States, consumption isusually not more than 5 mg/d.14,15 Isoflavones exist insoybean and unfermented soy foods mostly as glycosides(genistin, diadzin, and, to a lesser extent, glycetin). Infermented soy foods, isoflavones are in the aglyconeform (genistein, daidzein, and glycetein).16 Genistein is

Ms. Omoni and Dr. Aluko are with the Departmentof Human Nutritional Sciences, University of Mani-toba, Winnipeg, Manitoba, Canada.

Address for correspondence: Dr. Rotimi E. Aluko,Department of Human Nutritional Sciences, Universityof Manitoba, H515 Duff Roblin, Winnipeg, Manitoba,Canada, R3T 2N2; Phone: 204-474-9555; Fax: 204-474-7593; E-mail: [email protected].

272 Nutrition Reviews, 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 arethus called phytoestrogens.19 They also have non-hor-monal effects, including signal transduction and antiox-idant activity.19 Isoflavones have been proposed to be theactive component responsible for the beneficial effects ofsoy foods.8,20 They appear to work in conjunction withsoy protein to exert anti-carcinogenic, anti-atherogenic,and anti-osteoporotic effects,7,21 and most of the researchon the benefits of soy foods have focused on the role thatthey play in disease prevention or treatment.19,22 There isalso some evidence that these benefits are attributable tocertain peptides or protein fractions from soybeans.

Biotransformation of Isoflavones in theIntestine

After ingestion, soy isoflavones are biotransformedin the intestinal tract, a process that is highly dependenton intestinal bacterial metabolism.9,16,19,23,24 The glyco-sides diadzin and genistin cannot be absorbed intact intothe peripheral circulation of healthy adults; they have tobe changed to the aglycones genistein and diadzein viathe action of intestinal -glucosidases (Figure 1),16, 23,25

and can be further metabolized into both estrogenic andanti-estrogenic metabolites.16 The extent to which isofla-vone glycosides are bioavailable is therefore dependenton gut microflora.

POTENTIAL MECHANISMS OF ACTION

Soy Isoflavones and Cardiovascular Disease

Of all the acclaimed benefits of soy foods, perhapsthe most conclusive one is its protective effects againstcardiovascular disease, which is one of the leadingcauses of death worldwide,26,27 with elevated levels ofplasma low-density lipoproteins (LDL) and triglycerides

presenting a higher risk.26 By contrast, high-densitylipoproteins (HDL) are beneficial.28 Postmenopausalwomen are at greater risk for cardiovascular diseasebecause natural or surgical menopause is associated withelevated levels of circulating total and LDL choles-terol.29 The reduction in blood total and LDL cholesterolconcentrations with the consumption of products con-taining soy protein has been shown repeatedly in humansand several animal models (Table 1).30-32 However, theexact component responsible for this action has yet to beclearly defined. Isoflavones have been proposed to be theactive ingredient responsible for the hypocholester-olemic effects of soy.14, 33 A previous study suggestedthat isoflavone-rich soy protein is considerably moreeffective than isoflavone-depleted soy protein, thoughthis finding is controversial.7

The cholesterol-lowering effect is one of severalproposed mechanisms by which soy reduces the risk ofheart disease.34 In a study to evaluate the effects ofisoflavone-rich and isoflavone-depleted soy protein onplasma lipid concentrations in postmenopausal, moder-ately hypercholesterolemic women, isoflavone-rich soyprotein lowered total and LDL cholesterol more than soyprotein depleted of isoflavones, though no significantdifferences were observed in HDL cholesterol or triac-ylglycerol concentrations. This difference in total andLDL cholesterol lowering between the two soy proteinsupplements suggests an effect attributable to the isofla-vone-containing fraction.34

Similar results were observed among 18 postmeno-pausal women with normal and moderately elevatedcholesterol levels in a randomized crossover trial toassess the hypocholesterolemic effects of soy isofla-vones. Subjects were fed isolated soy protein beveragecontaining one of three isoflavone levels, 7.1 mg/disoflavone (control), 65 mg/d isoflavone (low isofla-vone), and 132 mg/d isoflavone (high isoflavone). Thehigh-isoflavone diet lowered plasma LDL cholesterol by6.5%, though there were no significant changes in totalor HDL cholesterol, triacylglycerol, apolipoprotein(Apo) AI, ApoB, lipoprotein(a), or LDL peak particlediameter. Though small, a decrease of LDL cholesterolof this magnitude could be associated with a 16% reduc-tion in cardiovascular disease risk.26

A number of explanations have been put forward forthis 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 thegastrointestinal tract35 and increasing bile acid excre-tion.36 When this happens, hepatic cholesterol metabo-lism shifts to provide cholesterol for enhanced bile acidsynthesis, and cholesterol biosynthesis and LDL receptoractivity increase. The result is an increased removal ofcholesterol from the blood via the LDL receptor, therebyFigure 1. Biotransformation of soy isoflavones in the intestine.

273Nutrition Reviews, Vol. 63, No. 8

Tab

le1.

Cho

lest

erol

-low

erin

gE

ffec

tsof

Soy

Pro

duc

tsR

efer

ence

Pop

ulat

ion

(n)

Soy

Pro

duct

Fed

,D

ose,

Dur

atio

nO

utco

me

Hum

anSt

udie

s

Goo

dman

-Gru

enan

dK

ritz

-Silv

erst

ein,

2001

32

Post

men

opau

sal

wom

en(n

20

8)D

aily

soy

isofl

avon

ein

take

asse

ssed

for

one

year

with

ques

tionn

aire

;av

erag

ein

take

ofge

nist

ein

was

1.3

2.

4m

g/d,

rang

e0

13.9

mg/

d

Wom

enw

ithm

oder

ate

and

high

geni

stei

nco

nsum

ptio

nha

dsi

gnifi

cant

lyim

prov

edH

DL

chol

este

rol

Gar

dner

etal

.,20

0134

Post

men

opau

sal,

mod

erat

ely

hype

rcho

lest

erol

emic

wom

en(n

94

)

Soy

prot

ein

with

trac

eam

ount

sof

isofl

avon

es(S

oy

)or

80m

gag

lyco

neis

oflav

ones

(Soy

)

per

day

for

12w

eeks

Tot

alan

dL

DL

chol

este

rol

conc

entr

atio

nsde

crea

sed

mor

ein

the

Soy

grou

pth

anin

the

Soy

grou

p;no

sign

ifica

ntdi

ffer

ence

sin

HD

Lch

oles

tero

lan

dtr

iacy

lgly

cero

lco

ncen

trat

ions

betw

een

the

grou

psW

ange

net

al.,

2001

26

Nor

moc

hole

ster

olem

ican

dm

ildly

hype

rcho

lest

erol

emic

wom

en(n

18

)

Dai

lyco

nsum

ptio

nof

soy

prot

ein

isol

ate

(SPI

)be

vera

gepo

wde

rspr

ovid

ing

anav

erag

eof

7.1

1.

1(c

ontr

ol),

65

11(l

owis

oflav

one)

,or

132

22

(hig

his

oflav

one)

mg

isofl

avon

espe

rda

yfo

rth

ree

93-d

aype

riod

sin

ara

ndom

ized

cros

sove

rde

sign

Hig

h-is

oflav

one

diet

redu

ced

plas

ma

LD

Lch

oles

tero

lby

6.5%

com

pare

dw

ithco

ntro

l;lo

w-

and

high

-iso

flavo

nedi

etre

duce

dL

DL

:HD

Lch

oles

tero

lby

8.5%

and

7.7%

,re

spec

tivel

y;is

oflav

one

cons

umpt

ion

did

not

sign

ifica

ntly

affe

ctpl

asm

aco

ncen

trat

ions

ofto

tal

orH

DL

chol

este

rol,

tria

cylg

lyce

rol,

Apo

AI

,A

poB

,or

lipop

rote

in(a

)or

the

LD

Lpe

akpa

rtic

ledi

amet

erM

erz-

Dem

low

etal

.,20

0027

Nor

moc

hole

ster

olem

icpr

emen

opau

sal

wom

en(n

13

)

SPI

cons

umed

asa

beve

rage

pow

der

with

thre

ele

vels

ofso

yis

oflav

ones

:10

1.

1(c

ontr

ol),

64.7

9.

4(l

ow),

and

128.

7

15.7

(hig

h)m

gpe

rda

yfo

rth

ree

men

stru

alcy

cles

each

ina

rand

omiz

edcr

osso

ver

desi

gn

Hig

h-is

oflav

one

diet

low

ered

LD

Lch

oles

tero

lby

7.6%

to10

%,

tota

l:HD

Lch

oles

tero

lby

10.2

%,

and

LD

L:H

DL

chol

este

rol

by13

.8%

Mitc

hell

and

Col

lins,

1999

43

Hea

lthy

men

(n

10)

Soy

milk

(1L

/d)

for

4w

eeks

No

sign

ifica

ntef

fect

ofso

ysu

pple

men

tatio

non

plas

ma

chol

este

rol,

trig

lyce

ride

leve

ls,

orH

DL

:LD

Lch

oles

tero

lra

tios

com

pare

dw

ithco

ntro

lsPo

tter

etal

.,19

9830

Hyp

erch

oles

tero

lem

ic,

post

men

opau

sal

wom

en(n

66

)

Soy

prot

ein

(40

mg/

d)pl

usm

oder

ate

and

high

erco

ncen

trat

ions

ofis

oflav

ones

(1.3

9an

d2.

25m

gis

oflav

one/

gpr

otei

n,re

spec

tivel

y)fo

r6

mon

ths

Non

-HD

Lch

oles

tero

lw

asre

duce

din

both

grou

psfe

dm

oder

ate

and

high

erco

ncen

trat

ions

ofis

oflav

one

com

pare

dw

ithco

ntro

ls;

HD

Lch

oles

tero

lin

crea

sed

inth

etw

ogr

oups

;L

DL

rece

ptor

mR

NA

was

redu

ced

inth

etw

ogr

oups

com

pare

dw

ithco

ntro

lsW

ong

etal

.,19

9831

Nor

moc

hole

ster

olem

ic(n

13

)an

dhy

perc

hole

ster

olem

ic(n

13

)m

en

Soy

prot

ein

inco

rpor

ated

into

the

Nat

iona

lC

hole

ster

olE

duca

tiona

lPro

gram

Step

Idi

et(c

onst

itutin

g

75%

tota

lpr

otei

nco

nten

t)fe

dfo

ra

tota

lof

10w

eeks

ina

rand

omiz

edcr

osso

ver

desi

gn(a

vera

geda

ilyso

ypr

otei

nco

nsum

ptio

nap

prox

imat

ely

50g)

Plas

ma

conc

entr

atio

nof

LD

Lch

oles

tero

lan

dL

DL

:HD

Lch

oles

tero

lin

both

norm

ocho

lest

erol

emic

and

hype

rcho

lest

erol

emic

men

wer

esi

gnifi

cant

lylo

wer

(app

roxi

mat

ely

6%an

d11

%,

resp

ectiv

ely)

whe

nso

ypr

otei

ndi

etw

asco

nsum

ed


Tab

le1.

(Con

td

)C

hole

ster

ol-l

ower

ing

Eff

ects

ofS

oyP

rod

ucts

Ref

eren

ceP

opul

atio

n(n

)So

yP

rodu

ctF

ed,

Dos

e,D

urat

ion

Out

com

e

Nes

tel

etal

.,19

9740

Men

opau

sal

and

peri

men

opau

sal

wom

en(n

21

)

Soy

isofl

avon

eta

blet

s(8

0m

g/d)

for

5to

10w

eeks

No

effe

cton

plas

ma

lipid

s(p

lasm

ach

oles

tero

l,tr

igly

ceri

dean

dH

DL

chol

este

rol)

;ar

teri

alco

mpl

ianc

eim

prov

edby

26%

Ani

mal

Stud

ies

Ada

ms

etal

.,20

0456

Ath

eros

cler

osis

-sus

cept

ible

mic

e,m

ale

and

ovar

iect

omiz

edfe

mal

eA

poE

-nul

lm

ice,

and

LD

L-

rece

ptor

-nul

lA

poB

tran

sgen

icm

ice

(n

416)

One

offiv

eex

peri

men

tal

diet

s:so

ypl

usis

oflav

ones

,

-con

glyc

inin

(7S

glob

ulin

,a

maj

orso

yst

orag

epr

otei

n),

-

cong

lyci

nin-

devo

idso

ypr

otei

n,gl

ycin

in(1

1Sgl

obul

in,

am

ajor

soy

stor

age

prot

ein)

,or

W00

8(a

soy

pept

ide

frac

tion)

for

4m

onth

s

Red

uced

athe

rosc

lero

sis

obse

rved

inal

lm

ice

fed

the

-

cong

lyci

nin

diet

sco

mpa

red

with

mic

efe

dth

eso

ypl

usis

oflav

ones

diet

;ex

tent

ofat

hero

scle

rosi

sre

duce

din

ovar

iect

omiz

edfe

mal

em

ice

fed

all

soy

prot

ein-

cont

aini

ngdi

ets

com

pare

dw

ithco

ntro

ls

Dem

onty

etal

.,20

0233

Mal

eSp

ragu

e-D

awle

yra

ts(n

36

)SP

Ian

dca

sein

with

sim

ilar

isofl

avon

eco

nten

t(1

.82

mg/

gpr

otei

n)fo

r21

days

Plas

ma

tota

ltr

igly

ceri

des

decr

ease

dby

26%

inra

tsfe

dso

ypr

otei

nan

dca

sein

plus

isofl

avon

esco

mpa

red

with

cont

rol

Fuku

iet

al.,

2002

11

Mal

eSp

ragu

e-D

awle

yra

ts(n

30

)20

%SP

I;20

%is

oflav

one-

free

SPI

(IF

SPI)

for

2w

eeks

Plas

ma

tota

lch

oles

tero

lco

ncen

trat

ions

ofra

tsfe

dSP

Ian

dIF

-SPI

wer

eco

mpa

rabl

ean

dsi

gnifi

cant

lylo

wer

than

that

ofra

tsfe

dco

ntro

ldi

et;

high

erfe

cal

ster

oid

excr

etio

nin

the

SPI

grou

pL

ucas

etal

.,20

0129

Ova

riec

tom

ized

fem

ale

gold

enSy

rian

ham

ster

s(n

48

)E

than

olex

trac

ted

isofl

avon

e-de

plet

edSP

I(I

DS

PI)

(240

g/kg

ofdi

et)

for

70da

ysID

-SPI

low

ered

seru

mtr

igly

ceri

deco

ncen

trat

ions

com

pare

dto

cont

rols

,no

sign

ifica

ntdi

ffer

ence

sin

seru

mH

DL

conc

entr

atio

ns,

liver

tota

llip

ids

and

liver

tota

lch

oles

tero

lT

sai

and

Hua

ng,

1999

10

Mal

ego

lden

Syri

anha

mst

ers

(n

24)

SPI

cont

aini

ng1.

24m

gge

nist

ein

and

0.61

mg

diad

zein

/g,

and

etha

nol-

extr

acte

dSP

I(E

SPI

)lo

win

isofl

avon

es(0

.21

mg

geni

stei

nan

d0.

06m

gdi

adze

in/g

)fe

dfo

r10

wee

ks

SPI

grou

pex

hibi

ted

sign

ifica

ntly

low

erse

rum

tota

lch

oles

tero

lco

ncen

trat

ion

com

pare

dw

ithth

eE

SPI

grou

p;bo

thSP

Ian

dE

SPI

grou

psha

dlo

wer

LD

Lch

oles

tero

l,L

DL

Apo

B,

and

LD

L:H

DL

chol

este

rol

com

pare

dw

ithth

eco

ntro

ls


reducing blood cholesterol levels (particularly the LDLfraction). There is evidence that soy protein increasesfecal excretion of bile acids. In rats fed isoflavone-richand isoflavone-depleted soy protein, higher fecal steroidexcretion was observed in the isoflavone-rich group,though both groups had lowered total cholesterol com-pared with the control group. The authors concluded thatthe cholesterol-lowering effects of soy may be attributedto the protein content, with the isoflavones and otherminor constituents playing a role.11

Soy isoflavones are also believed to reduce the riskof heart disease by reducing the susceptibility of LDL tooxidation via its antioxidant action.16,37 The effects of asoy protein diet enriched with isoflavones and one de-pleted of isoflavones on LDL resistance to oxidationwere compared among 24 healthy subjects in a random-ized crossover design. Plasma concentrations of8-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 torisk of atherosclerosis and cardiovascular disease ingeneral.16 Similar results were observed in male goldenSyrian 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 concentrationsof thiobarbituric acid reactive substances, another bi-omarker of lipid oxidation, and the longer lag timerequired for the formation of conjugated dienes. Theisoflavone-enriched group also had significantly higherserum total antioxidant capacity, particularly -tocoph-erol content, showing sparing effects on -tocopherolcontents in both serum and liver. These findings suggestthat the intake of soy isoflavones enhanced the resistanceof LDL to oxidation, contributing to antioxidant defense,and reduced the consumption of -tocopherol in both theserum and liver of hamsters.10

Improvement of arterial compliance is another pos-sible mechanism by which soy isoflavones protectagainst heart disease.38 Arterial compliance (arterialelasticity) is an important cardiovascular disease riskfactor that diminishes with age and menopause.39 Theeffect of soy isoflavones (80 mg daily) on arterial com-pliance was tested in menopausal and perimenopausalwomen over 5- to 10-week periods in a placebo-con-trolled crossover trial.40 Though there was no effect onplasma lipids, systemic arterial compliance improved by26% compared with placebo to about the same extent asthat achieved with conventional hormone replacementtherapy (HRT). The fact that plasma lipids were notchanged suggests that other constituents of soybean

(apart from its isoflavones) may be responsible for lipidlowering.40

Soy Isoflavones and Cancer

The consumption of high levels of soy foods hasbeen shown to be associated with a reduced risk ofseveral 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 haveshown that soy isoflavones are responsible for theseprotective effects.15 This protective effect appears to bestrongest for breast cancer. Administration of soy isofla-vones early in life enhances the early maturation anddifferentiation of the mammary gland of rats, suggestingthat exposure in early life may be important.3,7,17 Table2 shows a summary of previous studies on the effects ofsoy products on cancer and associated DNA damage.

Several possible mechanisms have been identifiedfor the anticarcinogenic activity of soy isoflavones. Oneof the mechanisms by which soy isoflavones are believedto exert their anticarcinogenic effects is via their antiox-idant properties,14 which result in a decrease in lipidperoxidation16 and oxidative DNA damage,14 both im-portant risk factors for carcinogenesis. These antioxidantproperties are suggested to be related to the chemicalstructure 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 plasmaconcentrations of 8-epiprostaglandin F2, a biomarker ofin vivo lipid peroxidation.16 In another study to evaluatethe effects of soy isoflavone supplementation on markersof 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 asignificant decrease in the levels of 5-hydroxymethyl-2-deoxyuridine, a biomarker of oxidative DNA damage;though no significant decrease in lipid peroxidation wasobserved. The results from this study suggest that dietarysupplementation with soy isoflavones can decrease levelsof oxidative DNA damage, which is associated with theprocess of carcinogenesis.14 A similar decrease in oxi-dative DNA damage was also observed among menconsuming 1 L of soy milk daily for 4 weeks.43

Another mechanism by which soy isoflavones mayprotect against cancer is through the induction of phase IIenzymes,44 which is associated with cancer chemopre-ventive potential at both the initiation and promotionphases.44 Induced levels of the phase II enzymes gluta-thione-s-transferase (GST) and quinone reductase (QR)


Tab

le2.

Eff

ect

ofS

oyP

rod

ucts

onC

ance

ran

dO

xid

ativ

eD

NA

Dam

age

Ref

eren

ceP

opul

atio

nSo

yP

rodu

ctF

ed,

Dos

e,D

urat

ion

Out

com

e

Hum

anSt

udie

s

Dju

ric

etal

.,20

0114

Men

(n

6)an

dw

omen

(n

6)N

ovas

oyta

blet

sco

ntai

ning

50m

gis

oflav

ones

;w

omen

took

1ta

blet

daily

and

men

took

2ta

blet

sda

ilyfo

r3

wee

ks

Soy

isofl

avon

esu

pple

men

tatio

nde

crea

sed

leve

lsof

oxid

ativ

eD

NA

dam

age

inm

enan

dw

omen

,ev

iden

ced

byde

crea

sed

leve

lsof

5-hy

drox

ymet

hyl-

2-de

oxyu

ridi

ne,

abi

omar

ker

ofox

idat

ive

DN

Ada

mag

e(4

7%an

d61

%de

crea

sein

wom

enan

dm

en,

resp

ectiv

ely)

Wis

eman

etal

.,20

0016

24he

alth

ysu

bjec

ts(1

9w

omen

and

5m

en)

One

oftw

oex

peri

men

tal

diet

sov

ertw

o17

-day

peri

ods

ina

rand

omiz

edcr

osso

ver

desi

gn:

low

-soy

isofl

avon

edi

et(2

1.2

mg

diad

zein

,34

.8m

gge

nist

ein)

orhi

gh-s

oyis

oflav

one

diet

(0.9

mg

diad

zein

,1.

0m

gge

nist

ein)

Hig

h-is

oflav

one

diet

sign

ifica

ntly

redu

ced

plas

ma

conc

entr

atio

nsof

F 2-i

sopr

osta

ne-8

-epi

pros

tagl

andi

nF 2

,

abi

omar

ker

ofin

vivo

lipid

pero

xida

tion

Mitc

hell

&C

ollin

s,19

9943

Hea

lthy

men

(n

10)

Soy

milk

(1L

/d)

for

4w

eeks

Dec

reas

ein

oxid

ativ

eD

NA

dam

age

byap

prox

imat

ely

67%

Ani

mal

Stud

ies

Con

stan

tinou

etal

.,20

0244

Fem

ale

Spra

gue-

Daw

ley

rats

(n

119)

One

offiv

eex

peri

men

tal

diet

sfo

r12

0da

ys:

geni

stei

n(2

00m

g/kg

diet

);di

adze

in(2

00m

g/kg

diet

);ge

nist

ein

plus

diad

zein

at10

0m

g/kg

diet

each

;16

%so

ypr

otei

nis

olat

epl

usis

oflav

ones

(SPI

);

16%

isofl

avon

e-de

plet

edSP

I(S

PI

)

SPI

was

the

mos

tef

fect

ive

diet

,si

gnifi

cant

lyre

duci

ngm

amm

ary

tum

orm

ultip

licity

by50

%;

diad

zein

and

SPI

diet

also

sign

ifica

ntly

redu

ced

tum

orm

ultip

licity

by32

%co

mpa

red

with

cont

rols

;no

sign

ifica

ntre

duct

ion

inm

amm

ary

tum

orin

cide

nce

inan

ydi

et

Coh

enet

al.,

2000

6R

ats

(n

150)

20%

inta

ctso

ypr

otei

n(S

P),

10%

SP,

20%

isofl

avon

e-de

plet

edSP

(ID

SP),

10%

IDSP

for

18w

eeks

No

sign

ifica

ntdi

ffer

ence

sin

mam

mar

ytu

mor

inci

denc

e,la

tenc

y,m

ultip

licity

,or

volu

me

com

pare

dw

ithco

ntro

ls

App

let

and

Rei

cks,

1999

45

Fem

ale

Spra

gue-

Daw

ley

rats

(n

86)

Soy

cont

aini

ngth

ree

leve

lsof

isofl

avon

es(0

.03,

0.4,

0.81

mg/

gdi

et;

low

,m

iddl

ean

dhi

ghle

vel

ofis

oflav

ones

,re

spec

tivel

y)fo

r13

wee

ks

Rat

sfe

dhi

gh-i

sofla

vone

diet

had

low

erm

amm

ary

tum

orin

cide

nce

(40%

)co

mpa

red

with

cont

rols

(71.

4%);

rats

fed

mid

dle

and

low

isofl

avon

edi

etha

dtu

mor

inci

denc

eof

53.3

and

57.1

%,

resp

ectiv

ely


have been proposed as suitable biomarkers for identify-ing compounds likely to inhibit carcinogenesis.45 QRand GST are enzymes that help the body get rid of thetoxic 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 IIenzyme inducers. Soy isoflavones increased antioxidantand phase II enzyme activity, especially QR, GST, andUDP-glucuronosyltransferase, in various tissues of ratsfed 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 ofisoflavone-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 reducedtumor multiplicity compared with the controls, both soygroups (but not the genistein or diadzein groups) upregu-lated transcriptional expression of the antioxidant en-zymes QR and GST. These results suggest that the modeof preventive action of soy protein isolate is distinct fromthat of the main isoflavones, and that isoflavone-depletedsoy may be more beneficial than isoflavone-enriched soyin preventing mammary tumors in these experimentalanimals.44 However, another study evaluating the effectsof 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 thisstudy do not support the hypothesis that the isoflavonecomponents 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 ofbreast cancer have produced conflicting results, and afew have shown stimulatory effects. Petrakis et al.46

reported that prolonged consumption of soy protein iso-late by a group of healthy premenopausal US womenincreased hyperplastic epithelial cells in duct fluid aspi-rates, showing a stimulatory effect on the breast.

Soy Isoflavones and Osteoporosis

The ovarian hormone deficiency associated withmenopause results in an increased rate of bone turnover,which causes an imbalance between bone resorption andbone formation, thereby accelerating bone loss that leadsto osteoporosis.25,47 HRT is an effective treatment inreducing the rate of bone loss and risk of fracture, thoughnot very popular among postmenopausal women becauseof the undesirable side effects and long-term risks ofbreast and endometrial cancer associated with prolongeduse.18,25,47,48 Soy isoflavones have been shown to alle-viate osteoporosis without the side effects of HRT.12 For

this reason, soy isoflavones are called selective estrogenreceptor modulators (SERMs), and may be a possiblealternative to HRT.7,12

Soy isoflavones have been suggested to alleviateosteoporosis by inhibiting bone resorption and stimulat-ing bone formation. Evidence that soy isoflavones reducebone resorption has been demonstrated by a number ofstudies. 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 amodel of postmenopausal women. Soy isoflavones re-duced the urinary excretion of deoxypyridinoline, a spe-cific biomarker of bone resorption.49 Similar results werealso observed among postmenopausal women, in whomsoy protein intake was associated with significantlylower 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 thatIGF-I enhances osteoblastic activity in humans.25 IGF-Iis a protein involved in the bone formation process, andtherefore an increase in IGF-I is indicative of increasedbone formation. In a study by Arjmandi et al.52 using arat model of osteopenia, soy increased the gene expres-sion of IGF-I, as indicated by higher femoral mRNAlevels. Incorporation of soy protein with normal isofla-vone content (2.3 mg/g protein) had a greater effect onfemoral IGF-I mRNA than the isoflavone-depleted soyprotein-based diet (approximately 0.1 mg/g protein).This finding indicates that isoflavones may have a role inenhancing the synthesis of IGF-I at the bone level.

There is additional evidence that soy promotes boneformation. Increased levels of bone alkaline phosphatase,a biomarker of bone formation, was observed amongperimenopausal women fed an isoflavone-rich soy pro-tein diet.18 In the same study, lumbar spine bone mineraldensity (BMD) and bone mineral content (BMC) wereassessed at baseline and at the end of the treatment.There was a significant difference in BMD (5.6%) andBMC (10.1%) between the isoflavone-rich and controlgroups, and the authors concluded that soy isoflavonesattenuated bone loss from the lumbar spine in estrogen-deficient perimenopausal women.18 Similar results werealso observed among hypercholesterolemic, postmeno-pausal women assessed for total and regional BMC andBMD before and after administration of 40 mg/d of soyprotein containing moderate and higher concentrations ofisoflavones (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 notelsewhere.30 Increased BMD and mechanical bonestrength and intestinal calcium absorption were alsoobserved in ovariectomized, osteoporotic rats fed soymilk.53 Soy is also a rich source of calcium, and this may


be a possible explanation for the observed increased inintestinal calcium absorption.

From these studies, it is evident that soy foods playa role in attenuating bone loss (Table 3); however, theexact osteoprotective mechanism of soy isoflavones re-mains unclear and requires further elucidation.

Soy Proteins and Peptides in CardiovascularDisease and Cancer

Some evidence exists to support the role of certainisoflavone-free soy protein and peptide fractions in car-diovascular disease and cancer. Sirtori et al.54 haveshown that 7S globulin, a major storage protein insoybean, reduced plasma cholesterol concentration by35% in rats. Similar results were observed by Lovati etal.55 in an in vitro study evaluating LDL receptor activityin Hep G2 cells (a human hepatoma cell line) exposedeither to small natural peptides produced by enzymaticdigestion of CroksoyR70 (a commercial isoflavone-poorsoy concentrate) or to synthetic peptides correspondingto specific sequences of the complete 7S globulin (Table4). The findings from this study demonstrated that 7Sglobulins stimulate the expression of LDL receptors andthe degradation of LDL in the cultured hepatocytes. Thedata also support the hypothesis that there are bioactivepeptides produced from the digestion of soy protein thatare absorbed from the small intestine and have beneficialeffects on lipoprotein metabolism and cardiovascularhealth by up-regulating LDL-receptor activity in livercells. Similar degradation of LDL by an alcohol-ex-tracted 7S globulin was also shown, which demonstratesthat the active molecules are the proteins and not thealcohol-soluble isoflavones.55 The authors concludedthat the isoflavone-free protein component is likely to beresponsible for this biochemical effect of soy.

To further demonstrate this effect in vivo, Adams etal.56 assessed the effects of dietary -conglycinin, a majorsoy storage protein, and other soy peptide fractions on thedevelopment of atherosclerosis in atherosclerosis-suscepti-ble mice. Male and ovariectomized female ApoE-null miceand LDL-receptor-null ApoB transgenic mice were ran-domly assigned to one of six treatment groups differingonly 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 soystorage 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) andplasma lipoprotein cholesterol concentrations of the micewere quantified. Results showed that the extent of athero-sclerosis was reduced in ovariectomized female micefed all soy protein-containing diets compared with

mice fed casein/lactalbumin-based diets. Furthermore,compared with mice fed isoflavone-containing soyprotein isolate, atherosclerosis was reduced only inmice fed the -conglycinin-containing diet. Thesereductions were 39% and 67% in male and ovariecto-mized female ApoE-null mice, respectively, and 66%in the male LDL-receptor-null mice. These observedeffects were unrelated to variations in isoflavone con-tent of the protein source and only minimally relatedto plasma lipoprotein cholesterol concentrations. Theauthors thus concluded that a diet rich in -conglyci-nin has atheroprotective effects that greatly exceedthose of isoflavone-containing soy protein isolate. In-terestingly, however, their results show that theseeffects do not depend on LDL receptors or influenceplasma lipoproteins.

Evidence also shows that dietary soy peptides andsoy protein isolates (without isoflavones) have antioxi-dative properties. Takenaka et al.57 demonstrated thatisoflavone-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 thatfeeding an insoluble, high-molecular weight protein frac-tion (HMF) prepared from a proteinase-treated soybeanprotein isolate suppressed colon and liver tumorigenesisinduced by azoxymethane and dietary deoxycholate inexperimental animals. Bile acid is known to play acritical role in liver and colon tumorigenesis. The authorsproposed that HMF exerted these protective effects incolon and liver tumorigenesis by interfering with theenterohepatic circulation of bile acids, thus inhibitingresorption of bile acids in the intestine and increasingfecal bile acid excretion. Peptides found in the feces ofHMF-fed animals were found to be rich in hydrophobicamino acids, so the authors suggested that the HMFprotein forms non-dissociable complexes with bile acidsin the intestine through hydrophobic binding, which arethen excreted into feces. HMF may therefore be used asa functional food to prevent the tumor-promoting activityof bile acids on the liver and colon.

CONCLUSIONS AND FUTURE DIRECTIONS

The consumption of soy foods has been proven toprotect against heart disease, some forms of cancer, andosteoporosis. However, there is still no conclusive evidenceto date showing whether the protective effects of soy arederived solely from isoflavones, from soy protein itself, orfrom a combination. Research findings are inconsistent;some evidence supports a role for the isoflavones containedin soybeans and many soy foods, while other evidencesupports certain peptides or peptide fractions derived fromsoy. In addition to this, soy foods also contain other bioac-


Tab

le3.

Eff

ect

ofS

oyP

rod

ucts

onB

one

Hea

lthR

efer

ence

Pop

ulat

ion

Soy

Pro

duct

Fed

,D

ose,

Dur

atio

nO

utco

me

Hum

anSt

udie

sH

oriu

chi

etal

.,20

0050

Post

men

opau

sal

Japa

nese

wom

en(n

85

)D

aily

soy

prot

ein

inta

keas

sess

edov

era

peri

odof

thre

eco

nsec

utiv

eda

ysus

ing

aqu

estio

nnai

re(m

ean

inta

ke12

.6g/

d)

Soy

prot

ein

inta

kesi

gnifi

cant

lyco

rrel

ated

with

high

erbo

nem

iner

alde

nsity

(BM

D)

and

low

erur

inar

yex

cret

ion

ofde

oxyp

yrid

inol

ine

Ale

kel

etal

.,20

0018

Peri

men

opau

sal

wom

en(n

69

)SP

Iw

ithis

oflav

ones

(80.

4m

g/d)

for

24w

eeks

Soy

isofl

avon

esat

tenu

ated

bone

loss

from

the

lum

bar

spin

e:B

MD

and

bone

min

eral

cont

ent

(BM

C)

incr

ease

dby

5.6%

and

10.1

%,

resp

ectiv

ely,

com

pare

dw

ithco

ntro

ls;

incr

ease

dle

vels

ofse

rum

bone

-spe

cific

alka

line

phos

phat

ase,

abi

omar

ker

ofbo

nefo

rmat

ion

Potte

ret

al.,

1998

30

Hyp

erch

oles

tero

lem

ic,

post

men

opau

sal

wom

en(n

66

)

Soy

prot

ein

(40

mg/

d)pl

usm

oder

ate

and

high

erco

ncen

trat

ions

ofis

oflav

ones

(1.3

9an

d2.

25m

gis

oflav

one/

gpr

otei

n,re

spec

tivel

y)fo

r6

mon

ths

Hig

h-is

oflav

one

diet

sign

ifica

ntly

incr

ease

dbo

thB

MC

and

BM

Din

the

lum

bar

spin

ebu

tno

tel

sew

here

Ani

mal

Stud

ies

Pich

erit

etal

.,20

0149

Adu

ltov

arie

ctom

ized

rats

(n

36)

Soyb

ean

isofl

avon

efe

das

pow

dere

dso

yis

oflav

one

conc

entr

ate;

daily

inta

keof

0,20

,40

and

80m

g/kg

body

wei

ght

for

84da

ys

Dai

lyso

ybea

nis

oflav

one

cons

umpt

ion

decr

ease

dbo

netu

rnov

eras

evid

ence

dby

decr

ease

dur

inar

yex

cret

ion

ofde

oxyp

yrid

inol

ine,

asp

ecifi

cbo

nem

arke

rof

bone

reso

rptio

nA

rjm

andi

etal

.,19

9852

Ova

riec

tom

ized

rats

with

esta

blis

hed

bone

loss

(n

36)

Soy

prot

ein

with

norm

alis

oflav

one

cont

ent

(2.3

mg/

gpr

otei

n)an

dre

duce

dis

oflav

one

cont

ent

(app

roxi

mat

ely

0.1

mg/

gpr

otei

n)fo

r65

days

Incr

ease

dex

pres

sion

offe

mor

alin

sulin

-lik

egr

owth

fact

or-I

mR

NA

leve

ls,

anin

dica

tor

ofin

crea

sed

bone

form

atio

n


tive components that could exert beneficial effects: thecholesterol-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, thesecomponents may have synergistic effects.

It is evident that there is still a lot to be learned aboutsoy foods. A question that remains to be answeredconclusively is what component of soy foods is respon-sible for its protective effects against heart disease,cancer, and osteoporosis. This gap in knowledge couldform the basis for more research on the benefits of soy,and further elucidation of its mode of action. Other areasworthy 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, willgo a long way in contributing to the understanding of themechanisms 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.

Table 4. Effect of CroksoyR70, its Enzyme Digests and Subfractions of Different Molecular Weight on LDLReceptor Activity in Hep G2 Cells*

Uptake Degradation

mg 125I-LDL/g cell proteinLipoprotein-deficient Serum (LPDS) 107 12 117 16CroksoyR70, g/L

0.050 105 9 115 100.125 116 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 12CroksoyR70 enzyme digested, g/L

0.050 117 11 119 110.125 136 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/LMW 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 Da0.050 89 10 75 110.125 96 12 84 90.250 90 10 88 120.500 88 15 78 19

MW 1000 Da0.050 88 10 77 110.125 95 22 78 90.250 85 10 70 120.500 80 10 75 9

* Values are means SEM, n 3. P 0.05 compared with LPDS P 0.0001 compared with LPDS P 0.05 compared with CroksoyR70 at the same concentrationReproduced from Lovati et al.55 with copyright permission of the American Society for Nutritional Sciences.


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