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7/28/2019 Brassicaceae sulfur nutraceuticals.pdf http://slidepdf.com/reader/full/brassicaceae-sulfur-nutraceuticalspdf 1/7 ~ Pergmnon 0278-6915(95)00017-8 Fd Chem. Toxic'. Vol. 33, No. 6, pp. 537-543, 1995 Copyright © 1995 Elsevier Science Ltd Printedin Great Britain. All rights reserved 0278-6915/95$29.50+ 0.00 Short Review Bioactive Organosulfur Phytochemicals in Brassica oleracea Vegetables A Review G. S. STOEWSAND Department of Food Science and Technology, New York St ate Agricultural Experiment Station, Cornell University, Geneva, NY 14456, USA (Accepted 6 January 1995) Summary--Sulfur-containing phytochemicals of two different kinds are present in all Brassica oleracea (Cruciferae) vegetables (cabbage, broccoli, etc.). They are glucosinolates (previously called thioglucosides) and S-methyl cysteine sulfoxide. The se compounds, which are derived in plant tis sue by amino acid biosynthesis, show quite different toxicological effects and appear to possess anticarcinogenicproperties. Glucosinolates have been extensively studied since the mid-nineteenth century. They are present i n plant foods besides Brassica vegetableswith especially high levels in a number of seed meals fed to livestock. About 100 different kinds of glucosinolates are know n to exist in the plant kingdom, but only about 10 are present in Brassica. The first toxic effects of isothiocyanates and other hydrolytic products from glucosinolates that were identified were goitre and a general inhibition of iodine uptake by the thyroid. Numerous studies have indicated that the hydrolytic products of at least three glucosinolates, 4-methyl- sulfinylbutyl (glucoraphanin), 2-phenylethyl (gluconasturtiin) and 3-indolylmethyl glucobrassicin), have anticarcinogenic activity. Indole-3-carbinol, a metabolite of glucobrassicin, has shown inhibitory effects in studies of human breast and ovarian cancers. Kale poisoning, or a severe haemolytic anaemia, was discovered in cattle in Europe in the 1930s, but its link with the hydrolytic product of S-methyl cysteine sulfoxide was only shown about 35 years later. S-methyl cysteine sulfoxide and its metabolite methyl methane thiosulfinate were shown to inhibit chemically-inducedgenotoxicity in mice. Thus, the cancer chemopreventive effects of Brassica vegetables that have been s hown in human and animal studies may be due to the presence of both types of sulfur-containing pbytochemicals(i.e. certain glucosinolates and S-methyl cysteine sulfoxide). Introduction Two important bioactive, natural sulfur-containing phytochemicals, glucosinolates (GS) and S-methyl cysteine sulfoxide (SMCSO), are present in common Brassica oleracea L. (Cruciferae) vegetables such as broccoli, Brussels sprouts, cabbage, cauliflower, kale, collards and kohlrabi. These organosulfur, secondary plant metabolite compounds are somewhat unusual in that studies with animals fed these substances (initially with the plant food or feed but later with the isolated compound) show numerous kinds of toxico- logical effects (Macfarlane Smith et al., 1990), and yet these compounds appear to have potential value as cancer chemopreventive agents (Wargovich and Eng, 1989). In addition, GS are quite toxic to some insects, and therefore, perhaps could be included as one of many natural pesticides (Ames et al., 1990). However, a small number of specialist insects such as the Abbreviations: DMBA = 7,12-dimethylbenz[a]anthracene; GS = glucosinolates; MMTSO = methylmethane thio- sulfinade; SMCSO= S-methyl cysteine sulfoxide. cabbage aphid use GS as feeding attractants and oviposition stimulants (Harborne, 1989). In addition to their presence in the vegetative tissue and seeds of Brassica, GS (formerly called thioglu- cosides), occur in at least 11 plant families (Daxen- bichler et al., 1991). They are present at rather high levels in oil-seed crops such as rapeseed and in condiments such as mustard seed. Although about 100 different GS have been identified throughout the plant kingdom there are about 10-12 distinct GS found in Brassica (Table 1). A comprehensive review of GS has been written by Fenwick et al. (1989), and a detailed account of GS bioactivities has been summarized by Beier (1990). SMCSO occurs in plant tissue at variable levels but has been reported at a maximum level of almost 4.0% in some plants (Mac et al., 1971; Maw, 1982; Morris and Thompson, 1956). Besides Brassica vegetables, SMCSO has been shown to be present in various beans, Allium (spp. onion, garlic, chives), radish and cowpea. It seems that the amino acid, methionine, methylates cysteine to form S-methyl cysteine which is then converted to SMCSO. A review of SMCSO has been published (Benevenga et al., 1989). 537

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Page 1: Brassicaceae sulfur nutraceuticals.pdf

7/28/2019 Brassicaceae sulfur nutraceuticals.pdf

http://slidepdf.com/reader/full/brassicaceae-sulfur-nutraceuticalspdf 1/7

~ Pergmnon 0278-6915(95)00017-8

Fd Chem. Toxic ' . Vol. 33, No. 6, pp. 537-543, 1995Copyright© 1995 ElsevierScienceLtd

Printed in Great Britain.All rights reserved0278-6915/95 $29.50 + 0.00

Sho r t Rev iew

Bioactive Organosulfur Phytochemicals inBrass ica o le racea Vegetables A R eview

G. S. STOEWSAND

Department of Food Science and Technology, New York State Agricultural Experiment Station,Cornell University, Geneva, NY 14456, USA

( A c c e p t e d 6 J a n u a r y 1 9 95 )

Summary--Sulfur-containing phytochemicals of two different kinds are present in all B r a s s i c a o l e r a c e a(Cruciferae) vegetables (cabbage, broccoli, etc.). They are glucosinolates(previouslycalled thioglucosides)and S-methyl cysteine sulfoxide. These compounds, which are derived in plant tissue by amino acidbiosynthesis, show quite different toxicological effects and appear to possess anticarcinogenic properties.Glucosinolates have been extensivelystudied since the mid-nineteenth century. They are present in plantfoods besides Brassica vegetables with especially high levels in a number of seed meals fed to livestock.About 100 different kinds of glucosinolates are known to exist in the plant kingdom, but only about 10are present in Brassica. The first toxic effects of isothiocyanates and other hydrolytic products fromglucosinolates that were identified were goitre and a general inhibition of iodine uptake by the thyroid.Numerous studies have indicated that the hydrolytic products of at least three glucosinolates, 4-methyl-sulfinylbutyl (glucoraphanin), 2-phenylethyl (gluconasturtiin) and 3-indolylmethyl glucobrassicin), haveanticarcinogenic activity. Indole-3-carbinol, a metabolite of glucobrassicin, has shown inhibitory effectsin studies of human breast and ovarian cancers. Kale poisoning, or a severe haemolytic anaemia, wasdiscovered in cattle in Europe in the 1930s, but its link with the hydrolytic product of S-methyl cysteine

sulfoxide was only shown about 35 years later. S-methyl cysteine sulfoxide and its metabolite methylmethane thiosulfinate were shown to inhibit chemically-inducedgenotoxicity in mice. Thus, the cancerchemopreventive effects of Brassica vegetables that have been shown in human and animal studies maybe due to the presence of both types of sulfur-containing pbytochemicals (i.e. certain glucosinolates andS-methyl cysteine sulfoxide).

Introduction

Two important bioactive, natural sulfur-containing

phytochemicals, glucosinolates (GS) and S-methyl

cysteine sulfoxide (SMCSO), are present in common

B r a s s i c a o l e r a c e a L. (Cruciferae) vegetables such as

broccoli, Brussels sprouts, cabbage, cauliflower, kale,collards and kohlrabi. These organosulfur, secondary

plant metabolite compounds are somewhat unusual

in that studies with animals fed these substances

(initially with the plant food or feed but l ater with the

isolated compound) show numerous kinds of toxico-

logical effects (Macfarlane Smith e t a l . , 1990), and yet

these compounds appear to have potential value as

cancer chemopreventive agents (Wargovich and Eng,

1989). In add ition, GS are qui te toxic to some insects,

and therefore, perhaps could be included as one of

man y natural pesticides (Ames e t a l . , 1990). However,

a small number of specialist insects such as the

A b b r e v i a t i o n s : DMBA = 7,12-dimethylbenz[a]anthracene;GS = glucosinolates; MMTSO = methylmethane thio-sulfinade; SMCSO = S-methyl cysteine sulfoxide.

cabbage aphid use GS as feeding attractants and

oviposition stimulants (Harborne, 1989).

In add ition to their presence in the vegetative tissue

and seeds of Brassica, GS (formerly called thioglu-

cosides), occur in at least 11 plant families (Daxen-

bichler e t a l . , 1991). They are present at rather high

levels in oil-seed crops such as rapeseed and incondiments such as mustard seed. Although about

100 different GS have been identified throughout the

plant kingdom there are about 10-12 distinct GS

found in Brassica (Table 1). A comprehensive review

of GS has been written by Fenwick e t a l . (1989), and

a detailed account of GS bioactivities has been

summarized by Beier (1990).

SMCSO occurs in p lant tissue at variable levels bu t

has been reported at a m aximu m level of almost 4.0%

in some plants (Mac e t a l . , 1971; Maw, 1982; Morr is

and Thompson, 1956). Besides Brassica vegetables,

SMCSO has been shown to be present in variousbeans, Alli um (spp. on ion, garlic, chives), radish and

cowpea. It seems that the amino acid, methionine,

methylates cysteine to form S-methyl cysteine which

is then converted to SMCSO. A review of SMCSO

has been published (Benevenga e t a l . , 1989).

537

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538 G. S. Stoewsand

Chemistry

Very few GS have been i so l a t ed i n t he pure s t a t e .

T h e c o m m o n s k e l e t a l s t r u c t u r e f o r G S i s s h o w n i n

Fig . I , and t he m a jo r GS in Bra ss i ca a re l i s t ed i n

T ab le I . T he f ir s t c rys t a l li ne GS w as i so la t ed f ro m the

seed o f wh i t e m u s t a rd i n 1831 and s ince t hen r e sea rcho n t h e c h e m i s t r y o f G S h a s c o n t i n u e d ( E t t li n g e r a n d

Kjae r , 1968; Fenw ick e t a L , 1983) . T he s t ruc tu re ha s

b e e n co n f i r m e d b y X - r a y s t u d i es ( M a r s h a n d W a s e r ,

1970).

As seen i n T ab l e I , t he GS s ide -cha ins i nc lude

a l ip h a t ic , a r o m a t i c o r h e t e r o a r o m a t i c g r o u p i n g s . I n -

d o l e G S h a v e b e e n k n o w n t o b e p r e s e n t i n B r a s s i c a

s ince t he 1960s (Gm e l in and V i r t anen , 1961 and 1962)

but the re la t ive ly high level present in Brassica ,

especia l ly glucobrassic in in Brusse ls sprouts

( G o o d r i c h e t a l . , 1988) , was no t fu l ly app rec i a t ed

u n t il t h e d e v e l o p m e n t o f t he o n - c o l u m n d e s u l f a ti o nm e t h o d f o l l o w e d b y H P L C a n a l y s i s ( M i n c h i n t o n

e t a l . , 1982 ; T rusco t t e t a l . , 1983).

O f the B ra ss i ca vege t ab le s , Brusse ls sp rou t s co n-

t a in t he h ighes t l eve l o f t o t a l G S, w i th a r ange o f 600

to 3900 #g /g (H eaney an d Fenw ick , 1980) . T he s ide -

cha in de t e rm ines t he chem ica l and b io log i ca l na tu re

o f t h e p r o d u c t s o f m y r o s i n a s e ( t h i o g l u c o s id e g l u c o h y -

d ro l a se E C 3 .2.3.1) hydro lys i s (F ig . 1 ). Di s t i nc t m y-

ros in cel ls con t a in ing l a rge quan t i ti e s o f a num b er o f

m yros ina se i soenzym es a re p re sen t i n t he l e aves o f

Bra ss i ca vege t ab l e s , bu t Pocock e t a l . (1987) found

tha t t he re we re va r i a t i ons be tween cabbage cu l t i va r s

in t he cy to lo gy o f the se cel ls and t he enzym e pa t t e rn

a n d a c t i v it y . O n m y r o s i n a s e h y d r o ly s i s m o s t G S f o r m

stable i sothiocyanates or ni t r i les as wel l as glucose

and HSO 4 ion . Wh e the r i so th io cyana t e s o r ni tr il es a re

fo rm ed depend s on t he spec if ic GS , t he pa r t o f t he

p l an t wh e re t hey a re l oca t ed , the t r e a tm en t o f p l an tm a t e r ia l b e f o r e t h e h y d r o l y s i s o f G S , a n d c o n d i t io n s ,

e spec i a l l y pH, du r ing hydro lys i s . T he SCN ion i s

f o u n d i n a t l e as t s m a ll a m o u n t s i n a ll G S - c o n t a i n i n g

p l a n t s a f t e r m y r o s i n a s e h y d r o l y s i s u n d e r c o n d i t i o n s

f a v o u r a b l e f o r i s o t h i o c y a n a t e f o r m a t i o n ( C o l e, 1 9 80 ;

Va nE t t en and T ook ey , 1983) . Ni t r i le s a re m ore l i ke ly

to be fo rm ed in f r e sh t is sue t han a f t e r hea t i ng . I f a

hydroxy l g roup i s i n t he ag lucon (e .g . p rogo i t r i n ;

T ab le I ) , t he i so th iocyana t e i s uns t ab l e and cyc l i z e s

to p rodu ce an oxazo l id ine th ione (G ree r , 1962) . I f G S

c o n t a i n t e r m i n a l u n s a t u r a t i o n , o n h y d r o l y s i s u n d e r

cond i t i ons t ha t f avour n i t r i l e fo rm a t ion , t he su l fu rm a y be re t a ined a s an ep isu lf ide g ro up (D axenb ich l e r

e t a l . , 1 9 7 7 ). G l u c o b r a s s i c i n a n d o t h e r i n d o l y l m e t h y l -

G S f o r m u n s t a b l e i s o t h i o c y a n a t e s w h i c h d e c o m p o s e

q u a n t i ta t i v e ly t o g i v e i n o r g a n i c S C N a l o n g w i t h o t h e r

p roduc t s i nc lud ing i ndo l e -3 -ca rb ino l (E l l i o t t and

Stowe , 1971 ; Gm e l in and V i r t anen , 1961) .

M o s t G S a p p e a r t o b e d e r i v e d f r o m a m i n o a c i d s

t h r o u g h a c o m m o n b i o s y n t h e t i c p a t h w a y ( U n d e r h i l l

e t a l . , 1973) . GS wi th t e rm ina l m e thy l th io , m e thy l -

su lf iny l o r m e thy l su l fony l g roup s a re cons ide red t o be

d e r i v e d f r o m m e t h i o n i n e , t h e s a m e a m i n o a c i d

n e c e s s a r y f o r t h e s y n t h e s i s o f S M C S O .

Table 1. Glucosinolates commonly found in Brassica oleracea

Glucosinolate R-group Trivial name

Prop-2-enyl (allyl) CH2~-CH--CH 2 -But-3-enyl CH2~------CH--CH2-~CH2 -3-Methylthiopropyl CH3--S---CH2--CH:--CH2 -3-Methylsulfinylpropyl CH3--S O~CH2~ H2--CH 2-4-Methylsulfinylbutyl CH3 --SO---CH 2--CH 2-~CH2 -CH 2 -4-Methylthiobutyl CH~--S--(CH 2)4-2-Hydroxybut-3-enyl ?2-Phenylethyl C6H 5CH~ CH 2-

3-1ndolylmethyl ~ ' - CH2-1

H

4-Methoxy-3-indolylmethyl ~ cH2-IH

l-Methoxy-3-indolylmethyl ~ H 2-IOCH

O H

4-Hydroxy-3-indolylmethyl ~ - - ~ O H 2-v - N -

IH

SinigrinGluconapinGlucoiberverinGlucoiberinGlucoraphaninGlucoerucinProgoitrinGluconasturtiin

Glucobrassicin

4-Met hoxyglucobrassicin

Neoglucobrassicin

4-H ydroxyglucobrassicin

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Organosulfur compounds in B rassica vegetables

j u c o s s ) a u c o s e NR - C (E .C .3 .2 .3 .1 ) ~ R - C

~ N _ O S O 3 - + H S O 4 "

R - N = C = S R - - C = = N R - S - - C = = NG l u c o s i n o l a t e s I s o t h i o c y a n a t e N i t r il e T h i o c y a n a t e

+ S

Fig. 1. General structure and enzymatic hydrolysis of glucosinolates through myrosinase activity.

539

M a r k s e t a l . (1992b) r epor t ed t ha t Brusse l s sp rou t s

c o n t a i n e d a b o u t 7 0 m g S M C S O / 1 0 0 g f r e s h t i s s u e .

T h i s concen t ra t i on i s abou t t h ree t o f i ve t im es h ighe r

than i n o the r Bra ss i ca vege t ab l e s . On d i s rup t ion o fp l an t t i s sue t he e nzym e cys t i ne lya se , i n it i a ll y cha rac -

t e r i z ed by Maze l i s (1963) , conve r t s SMCSO to a

h igh ly r eac t ive i n t e rm ed ia t e , su l f en ic ac id t ha t d im er -

i z e s t o m e t h y l m e t h a n e t h i o s u l f i n a t e ( M M T S O ) a n d

p y r u v a t e ( F i g . 2 ) . M M T S O t h e n f o r m s v a r i o u s

su l f i de s . T hese m e tabo l i t e s we re fo rm ed in an enzy-

m a t i c m ode l sys t em a s we l l a s i n a wa te r ex t r ac t o f

B r u s s e l s s p r o u t s t h a t a p p e a r s t o b e s t r o n g l y d e p e n -

d e n t o n p H ( M a r k s e t a l . , 1 9 9 2 b ) . T h e p H o p t i m u m

of cys t i ne lya se is r epor t ed t o be be tween 8 .0 and 8 .5

( H a m a m o t o a n d M a z e l i s , 1 9 8 6 ) .

T o x i c o l o g i c a l e f fe c t s

The f i rs t harmful e ffec t in animals fed Brassica

v e g e t a b l e s w a s r e p o r t e d a l m o s t 7 0 y e a r s a g o , w h e n

r e la t iv e l y l ar g e a m o u n t s o f c a b b a g e f e d t o r a b b i t s

c a u s e d g o i t r e d e v e l o p m e n t ( C h e s n e y e t a l . , 1928) . I t

w a s 1 5 y e a r s l at e r w h e n t h e S C N p r o d u c t o f t h e

i n d o l y l G S w a s s h o w n t o c a u s e g o i t r e i n a n i m a l s

wi th a d i e t a ry i od ine de f i c i ency (As twood , 1943) .

A d d i t i o n a l w o r k b y A s t w o o d a n d c o ll e ag u e s sh o w e d

t h a t a b r e a k d o w n p r o d u c t o f al k en y l G S f o u n d

in t u rn ips and Bra ss i ca seeds , 5 -v iny l -2 -oxazo-

l idine thione , had a s imi lar goi t rogenic effec t butc o u l d b e m o d e r a t e d b y t h y r o x i n e ( A s t w o o d e t a l . ,

1949) . T he t r iv i a l nam e o f th i s cyc l i z ed p ro du c t i s

go i t r i n , wh ich i s p roduced f rom progo i t r i n (T ab l e 1 ) .

T h e r e h a v e b e e n n u m e r o u s s t u d i e s c o n c e r n e d w i t h

the an t i nu t r i t i ona l e ff ec ts o f r apeseed and , t o a l e sse r

ex t en t , m us t a rd and c ram be seeds i n l i ve s tock and

p o u l t r y a s w e l l a s in l a b o r a t o r y a n i m a l s . T h e v a r i o u s

tox i c e f f ec t s have been gene ra l l y a t t r i bu t ed t o t he

re l a ti ve ly h igh l eve ls o f GS wi th in t he se p rodu c t s .

Growth r e t a rda t i on , l i ve r l e s ions /nec ros i s , and t hy -r o i d h y p e r t r o p h y o r h y p e r p l a s i a a p p e a r t o o c c u r i n

m o s t a n i m a l s w h e n t h e d i e t c o n t a i n s a p p r o x i m a t e l y

2 - 5 m g G S / g d i e t ( F e n w ic k e t a l . , 1 9 8 9 ) . M i n k h a v e

been adve r se ly a f f ec t ed by r apeseed f l ou r d i e t s con-

t a in ing GS l eve ls o f on ly 0 .5 m g /g o f d i e t (Be lz il e

e t a L , 1974).

T ab l e 2 de sc r ibe s t he m a jo r t ox i c e f f ec t s o f hydro -

ly t i c p roduc t s f rom spec i f i c GS com m on in Bra ss i ca .

T h e r e a r e t w o i s o m e r s o f p r o g o i tr i n . T h e e p i - p r o -

go i t r i n i som er was d i scove red i n C r a m b e a b y s s i n i c a

seed (Daxenb ich l e r e t a l . , 1 9 6 5 ) . E p i - P r o g o i t r i n h a s

b e e n f o u n d i n b r o c c o l i b u t , i n c o n t r a s t t o p r o g o i t r in ,

i s qu i t e uns t ab l e du r ing hea t i ng o r f r eez ing (Be t z and

Fox , 1994) . Go i t r i n (L -5 -v iny loxazo l id ine -2 - th ione ) ,

t h e p r o d u c t o f p r o g o i t r i n i s o t h i o c y a n a t e c y c l iz a t io n ,

h a s b e e n f o u n d i n m i l k a t a b o u t 0 . 1 % o f th e p r o -

g o i t r i n c o n t e n t o f r a p e s e e d m e a l f e d t o c o w s ( B a c h -

m a n n e t a l . , 1 9 8 5 ) . G o i t r i n h a s b e e n s h o w n t o b e

n i t r o s a t e d b y t r e a t m e n t w i t h n i t r i t e u n d e r s t o m a c h

c o n d i t i o n s t o f o r m N - n i t r o s o - o x a z o l i d o n e , a m u t a -

g e n ( L u t h y e t a l . , 1984).

C a t t le f e d l a rg e q u a n t i ti e s o f k a le c a m e d o w n w i th

a seve re haem oly t i c anaem ia , t e rm ed ' ka l e po i son ing '

( R o s e n b e r g e r , 1 9 39 ) a n d a li n k w i th S M C S O w a s

es t ab l ished (Sm i th , 1974) . Af t e r 1 -3 weeks o f ka l efeed ing m os t rum inan t an im a l s p roduce t he f i r s t c l e a r

s igns o f t he d isease , wh ich i s t he appea ran ce o f

s t a inab l e g ranu l e s wi th in t he r ed b lood ce l l s , t he

s o - c a l l e d H e i n z - E h r l i c h b o d i e s . T h e p r o d u c t o f

SMCSO, d im e thy l d i su l f i de (F ig . 2 ) , wh ich i s p ro -

d u c e d b y r u m e n o r g a n i s m s , a n d r e a c t s w i t h r e d u c e d

COOHI

H 2 N - C HI~ H 2

8 - ~ 0IC H a

cystine yase(EC4.4.1.8) C H 3 - S - O H

S u l f e n i c a c i d

+ Pyruvate

O#

CH3-S--S-CH 3 m CH3--S-S-CH 3

Met h y l m et h a n e D im et h y ld lsu l fid et h io su l fln a t e an d o t h e r su l f id es

SMCSO + NH3

Fig. 2. Sequence for the breakdown of S -methylcysteine sulfoxide through cystine lyase activity.

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540 G .S . Stoewsand

, , ,a

. -

: = l o °

° 1 1 '~ 4

I. - .

g=2

I '1

~ = 2 5

g x :

- - = ~ 1

z z ~ ; ~ ~ - ~ a~-

d

~ ~ " - = - ~ - " ~

~ ~ " ~ ' - ' ' " ~ ' e . = o " = = l , o d

=2.&

~ 25

.~ ._ .= .= n '~, , ' E ~ ,

- a ~ " g g g

e 9 , .

_6 I-~-II o

.. o

~ o

g lu t a th ione a nd i n i t ia t e s t he fo rm a t ion o f t he se He inz

b o d i e s ( S m it h , 1 9 8 0 ) . S M C S O i n t a k e i n g o a ts , a t

a b o u t 1 5 - 1 9 g / 1 0 0 g b o d y w e i g h t , e l i c i t s t h i s

h a e m o l y t i c r e s p o n s e ( S m i th , 1 9 7 8 ) . H e i n z b o d y

anaem ia a l so occur s i n adu l t fowl s f ed d im e thy l

d i su lf i de (Maxwe l l , 1981) . How eve r , t h i s cond i t i ondoes no t occur i n gu inea p igs o r r abb i t s f ed ka l e

( G r e e n h a l g h e t a l . , 1969).

R a t s f e d S M C S O a t 2 % i n th e d ie t s h o w e d g r o w t h

depre ss ion , anaem ia and sp l en i c hype r t rophy

( U c h i n o a n d I t o k a w a , 1 9 7 2 ; U c h i n o a n d O t o k a m i ,

1972) . Ad d i t i ona l s t ud i e s wi th r a ts f ed SM CS O a t 4%

in the d i e t showed th a t a l l o f the sy m p tom s a re

reve rs ib le wi th in 2 weeks o f c e ssa t i on o f exposu re t o

S M C S O ( U c h i n o , 1 9 8 0 ) . I n m o r e r e c e n t s t u di e s b y

M a r k s e t a l . ( 1 9 9 3 ) t h e i n t e r m e d i a t e M M T S O ,

f o r m e d f r o m S M C S O ( F i g . 2 ) , h a s b e e n s h o w n t o

be qu i t e t ox i c : 100% l e tha l i t y was no t ed i n m ice

d o s e d a t a b o u t 5 5 m g / k g b o d y w e i g h t a n d g r o s s

p a t h o l o g y i n d i c a t e d g e n e r a l d i a r r h o e a , s t o m a c h

i r r i t a t i on wi th pe t ech i ae (m inu te b lood pa r t i cu l a t e s ) ,

and ex t ens ive u l ce ra t i on o f t he s t om a ch wa l l ( e cchy-

mosis).

A n t i c a r c i n o g e n i c e f f e c ts

T here a re c l a im s i n t he anc i en t he rba l l i t e r a tu re

abo u t t he t he rapeu t i c bene f i ts o f c abb age fo r va r ious

c a n c e r o u s c o n d i t i o n s ( A l b e r t - P u le o , 1 9 8 3 ) . I n m o r e

recen t t im es , num erous l abora to ry an im a l f eed ing

s tud i e s have shown tha t Bra ss i ca vege t ab l e s do i n -

deed posse ss an t i c a rc inogen ic p rope r t i e s (Boyd e t a l . ,

1982; Bresnick e t a l . , 1990; S toewsan d e t a l . , 1978 and

1988; W a t t enbe rg , 1983) . Speci fi c GS m e tab o l i t e s - -

i n i t i a l l y t he i so th iocyana t e s - -we re shown to i nh ib i t

t h e g r o w t h o f H e L a c el ls i n c i t r o , wi th t he m os t a c t i ve

be ing t he g lucoraphan in (4 -m e thy l su l f i ny lbu ty l )

i s o t h io c y a n a t e , w h i c h w a s s h o w n t o h a v e c h e m o t h e r -

apeu t i c p rope r t i e s a t l evel s o f le ss t han I pp m in t he

d i e t ( H o r a k o v a e t a l . , 1 9 6 8 ) . W a t t e n b e r g ( 19 7 7)

found tha t va r ious i so th iocyana t e s i nh ib i t ed 7 ,12-

d i m e t h y l b e n z [ a ] a n t h r a c e n e ( D M B A ) - i n d u c e d m o u s e

m a m m a r y t u m o r i g e n es i s . B o t h b e n z y l i s o t h i o c y a n a t ea n d c a b b a g e p o w d e r w e r e s h o w n t o h a v e a b l o c k i n g

e f f e c t a g a i n s t D M B A - i n d u c e d m a m m a r y c a r c i n o g e n -

e sis a n d a l s o to s u p p r e s s t h e f o r m a t i o n o f m a m m a r y

tum ours (Wa t t enbe rg , 1990) .

T he i n t ake o f i ndo l e -3 -ca rb ino l , a hydro ly t i c

p r o d u c t o f g l u c ob r a s s ic i n , c a n l e a d t o m a r k e d i n-

c rea se s i n t he ac ti vi ti es o f cy toch rom e P-450 -

d e p e n d e n t m o n o o x y g e n a s e s ( B a b is h a n d S t o e w s a n d ,

1978 ; L oub e t a l . , 1975) a s we l l a s t he i ndu c t ion o f

g lu t a th ione -S- t r ansfe ra se (Bradf i e ld and Bje ldanes ,

1984) . T h i s com pound a l so ha s o the r e f f ec t s on

hepa t i c enzym es , i nc lud ing i nc rea s ing t he ac t i v i ti e s o f

e t h o x y r e s o r u f i n O - d e e t h y l a s e , U D P - g l u c u r o n o s y l

t r ansfe ra se , g lu t a th ione r educ t a se and qu inone r e -

duc t a se , and dec rea s ing g lu t a th ione pe rox idase

and supe rox ide d i sm uta se ac t i v i t i e s (She r t ze r and

Sa insbury , 1991) .

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Organosulfur compounds in Brassica vegetables 541

Recent studies have shown that oestrogens are

metabolized by specific isozymes of P-450. Since the

forma tion of different oestrogen metabolites is linked

to breast and uterine cancer, the use of indole-3-

carbinol in women has produced a beneficial effect

through a modification of oestrogen metabolism. Itseems apparent tha t i ndole-3-carbinol may be a very

useful preventive agent against hormone-related can-

cers (Michnovicz and Bradiow, 1994).

In animal studies, it appears that indole-3-carbinol

inhibits the initiation of chemical carcinogenesis but

acts as a promoter after initiation by aflatoxin B~ or

1,2-dimethylhydrazine (Bailey e t a l . , 1987; Dashwood

e t a l . , 1991; Pence e t a l . , 1986) (see Table 2). The

covalent binding to DNA and hepatic macromol-

ecules of metabolites of benzo[a]pyrene and N-

nitrosodimethylamine, both carcinogens and

indirect-ac ting mutagens, was prevented when micewere pretreated by gavage with indole-3-carbinol

(Shertzer, 1984). Zhang e t a l . (1992) have shown that

the isothiocyanate metabolite of 'suiforap hane' (glu-

coraphanin, Table 1) isolated from broccoli is a

major inducer of quinone reductase and glutathione

S-transfera se (phase II enzymes) in mouse tissues and

may be a significant component of the anticarcino-

genic action of broccoli. Phenylethyl isothiocyanate,

a hydrolysed produc t of gluconasturt iin (Table 1),

was shown to be effective against nitrosamine-

induced oesophageal cancer in F-344 rats. This com-

pound also produced a dose-dependent inhibition of

DNA methylation by N-nitrosobenzylmethylamine

in cultured explants of rat oesophagus (Stoner e t a l . ,

1994).

It was discovered more than 10 years ago that

non-GS fractions of Brussels sprouts can induce

certain P-450-dependent monooxygenases (Miller

and Stoewsand, 1983). These fractions are also effec-

tive in the induction of rat hepatic glutathione S-

transferase (Godlewski e t a l . , 1985), thus indicating

that Brassica vegetables may contain anticarcino-

genic compounds other than GS. Studies had shown

that thiosulfinate compounds from garlic possess

distinct carcinogenesis-inhibitingproperties (DiPaoloand Carruthers, 1960; Weisberger and Pensky, 1957).

Subsequent studies showed that both SMCSO and

MMTSO (Fig. 2) inhibited the induction by ben-

zo[a]pyrene of mouse micronucleated polychromatic

erythrocytes (Marks e t a l . , 1993). The induction of

micronuclei is one measure of genotoxicity (Heddle

e t a l . , 1983), and this assay appears to be an appro-

priate test for screening for potent ial anticarcinogenic

compounds (Abraham, 1991; Marks e t a l . , 1992a;

Toth and Casaba, 1988).

The two types of organosulfur phytochemicais

found in all B r a s s i c a o l e r a c e a vegetables, GS andSMCSO, or, more specifically, many of their metab-

olites, show anticarcinogenic action an d could be

useful as cancer chemopreventive agents in humans.

A recent case-control study indicated that the risk of

secondary primary cancers in patients with oral can-

cer was about 40-60% lower among those who ate

these vegetables than among those who did not (Day

e t a l . , 1994). These phytochemicals, perhaps in con-

cert with other constituents such as vitamins which

are also present in brassicas, could be the major

efficacious agents.

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