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    ~ Pergmnon 0278-6915(95)00017-8Fd Chem. Toxic ' . Vol. 33, No. 6, pp. 537-543, 1995Copyright 1995 ElsevierScienceLtdPrinted in Great Britain.All rights reserved0278-6915/95 $29.50 + 0.00

    Sho r t Rev iewBioactive Organosulfur Phytochemicals inBrass ica o le racea Vegetables A R eview

    G. S. STOEWSANDDepartment 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 cysteinesulfoxide 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).

    IntroductionTwo important bioactive, natural sulfur-containingphytochemicals, glucosinolates (GS) and S-methylcysteine sulfoxide (SMCSO), are present in commonB r a s s i c a o l e r a c e a L. (Cruciferae) vegetables such asbroccoli, Brussels sprouts, cabbage, cauliflower, kale,collards and kohlrabi. These organosulfur, secondaryplant metabolite compounds are somewhat unusualin that studies with animals fed these substances(initially with the plant food or feed but l ater with theisolated compound) show numerous kinds of toxico-logical effects (Macfarlane Smith e t a l . , 1990), and yetthese compounds appear to have potential value ascancer 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 ofman 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 andoviposition stimulants (Harborne, 1989).

    In add ition to their presence in the vegetative tissueand 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 highlevels in oil-seed crops such as rapeseed and incondiments such as mustard seed. Although about100 different GS have been identified throughout theplant kingdom there are about 10-12 distinct GSfound in Brassica (Table 1). A comprehensive reviewof GS has been written by Fenwick e t a l . (1989), anda detailed account of GS bioactivities has beensummarized by Beier (1990).SMCSO occurs in p lant tissue at variable levels bu thas been reported at a m aximu m level of almost 4.0%in some plants (Mac e t a l . , 1971; Maw, 1982; Morr isand Thompson, 1956). Besides Brassica vegetables,SMCSO has been shown to be present in variousbeans, Alli um (spp. on ion, garlic, chives), radish andcowpea. It seems that the amino acid, methionine,methylates cysteine to form S-methyl cysteine whichis then converted to SMCSO. A review of SMCSOhas been published (Benevenga e t a l . , 1989).

    537

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    538 G. S. StoewsandChemistry

    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 nFig . I , and t he m a jo r GS in Bra ss i ca a re l i s t ed i nT 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 theseed 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 dKjae r , 1968; Fenw ick e t a L , 1983) . T he s t ruc tu re ha sb 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 ludea 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 as 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 edu 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 ne 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 600to 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 reo 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 fm yros ina se i soenzym es a re p re sen t i n t he l e aves o fBra ss i ca vege t ab l e s , bu t Pocock e t a l . (1987) foundtha 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 rna 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 mstable i sothiocyanates or ni t r i les as wel l as glucoseand HSO 4 ion . Wh e the r i so th io cyana t e s o r ni tr il es a refo rm ed depend s on t he spec if ic GS , t he pa r t o f t hep 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 sf 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 gp 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 sf 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 lyto 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 ahydroxy 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 sto p rodu ce an oxazo l id ine th ione (G ree r , 1962) . I f G Sc 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 rcond 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 re 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 eq 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 rp roduc t s i nc lud ing i ndo l e -3 -ca rb ino l (E l l i o t t andStowe , 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 st 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 le 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 bed 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 dn 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 oleraceaGlucosinolate R-group Trivial nameProp-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 ~ ' - CH2-1H

    4-Methoxy-3-indolylmethyl ~ cH2-IH

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

    O H4-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 vegetablesj 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

    + SFig. 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 sc 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 rthan 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 ah 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 dp 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 ssu 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 fB 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 mof 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 Brassicav 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 nr 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 sc 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 tw 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 ei 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 swi 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 dt 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 din 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 sgo 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 hthe 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 rex 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 stox 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 here 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 nm 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 y2 - 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 ebeen 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 ee 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 aseed (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 sb 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 andFox , 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 en 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 hc 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 tha 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 ses 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 rs igns o f t he d isease , wh ich i s t he appea ran ce o fs t a inab l e g ranu l e s wi th in t he r ed b lood ce l l s , t hes 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 fSMCSO, 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

    COOHIH 2 N - C HI~ H 28 - ~ 0IC H a

    cystine yase(EC4.4.1.8) C H 3 - S - O HS u l f e n i c a c i d

    + Pyruvate

    O#CH3-S--S-CH 3 m CH3--S-S-CH 3Met 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 + NH3Fig. 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 5g 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 inzb 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 ta 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 sh 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 yanaem ia a l so occur s i n adu l t fowl s f ed d im e thy ld 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 hdepre 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 rereve rs ib le wi th in 2 weeks o f c e ssa t i on o f exposu re t oS 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 yM 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 obe qu i t e t ox i c : 100% l e tha l i t y was no t ed i n m iced 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 sp 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 hi 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 reabo u t t he t he rapeu t i c bene f i ts o f c abb age fo r va r iousc 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 erecen t t im es , num erous l abora to ry an im a l f eed ings 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 and1988; 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 tt 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 vebe 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 hed 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 em 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 ge 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 ytum 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 cp 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 fg 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 onhepa 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 fe 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 lt 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 idaseand supe rox ide d i sm uta se ac t i v i t i e s (She r t ze r andSa insbury , 1991) .

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    Organosulfur compounds in Brassica vegetables 541Recent studies have shown that oestrogens are

    metabolized by specific isozymes of P-450. Since theforma tion of different oestrogen metabolites is linkedto breast and uterine cancer, the use of indole-3-carbinol in women has produced a beneficial effectthrough a modification of oestrogen metabolism. Itseems apparent tha t i ndole-3-carbinol may be a veryuseful preventive agent against hormone-related can-cers (Michnovicz and Bradiow, 1994).In animal studies, it appears that indole-3-carbinolinhibits the initiation of chemical carcinogenesis butacts as a promoter after initiation by aflatoxin B~ or1,2-dimethylhydrazine (Bailey e t a l . , 1987; Dashwoode t a l . , 1991; Pence e t a l . , 1986) (see Table 2). Thecovalent binding to DNA and hepatic macromol-ecules of metabolites of benzo[a]pyrene and N-nitrosodimethylamine, both carcinogens andindirect-ac ting mutagens, was prevented when micewere pretreated by gavage with indole-3-carbinol(Shertzer, 1984). Zhang e t a l . (1992) have shown thatthe isothiocyanate metabolite of 'suiforap hane' (glu-coraphanin, Table 1) isolated from broccoli is amajor inducer of quinone reductase and glutathioneS-transfera se (phase II enzymes) in mouse tissues andmay 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 ofDNA methylation by N-nitrosobenzylmethylaminein cultured explants of rat oesophagus (Stoner e t a l . ,1994).It was discovered more than 10 years ago thatnon-GS fractions of Brussels sprouts can inducecertain P-450-dependent monooxygenases (Millerand Stoewsand, 1983). These fractions are also effec-tive in the induction of rat hepatic glutathione S-transferase (Godlewski e t a l . , 1985), thus indicatingthat Brassica vegetables may contain anticarcino-genic compounds other than GS. Studies had shownthat thiosulfinate compounds from garlic possessdistinct carcinogenesis-inhibitingproperties (DiPaoloand Carruthers, 1960; Weisberger and Pensky, 1957).Subsequent studies showed that both SMCSO andMMTSO (Fig. 2) inhibited the induction by ben-zo[a]pyrene of mouse micronucleated polychromaticerythrocytes (Marks e t a l . , 1993). The induction ofmicronuclei is one measure of genotoxicity (Heddlee t a l . , 1983), and this assay appears to be an appro-priate test for screening for potent ial anticarcinogeniccompounds (Abraham, 1991; Marks e t a l . , 1992a;Toth and Casaba, 1988).The two types of organosulfur phytochemicaisfound 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 beuseful as cancer chemopreventive agents in humans.A recent case-control study indicated that the risk ofsecondary primary cancers in patients with oral can-

    cer was about 40-60% lower among those who atethese vegetables than among those who did not (Daye t a l . , 1994). These phytochemicals, perhaps in con-cert with other constituents such as vitamins whichare also present in brassicas, could be the majorefficacious agents.

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