Chemico-Biological Interactions Volume 103 Issue 2 1997 (Doi 10.1016/s0009-2797 (96) 03745-3) Dorette T.H. Verhoeven Hans Verhagen R.alexandra Goldbohm Pie - A Review of Mechanisms Underlying

ELSEVIER
Chemica-B~oiogical
Interactions
103 ( 1997) 7%
129
Mini review
A review of mechanisms underlying

anticarcin~genicity by brassica vegetables
Dorette T.H. Verhoeven**, Hans Verhagen,
R. Alexandra Goldbohm, Piet A. van den Brandtb,
Geert van Poppel
TN0
Nutrition and Food Research institute, P.O.Bas 360, 3700 AJ Zeist, The Netherkmds
hUniuersity of Limburg, ~@partm~nt of Epjdem~alag~, Maastricht. The Ne~~~rlunds
Abstract
The mechanisms by which brassica vegetables might decrease the risk of cancer are
reviewed in this paper. Brassicas, including all types of cabbages, broccoli, caulitlower and
Brussels sprouts, may be protective against cancer due to their relatively high glucosinoiate
content. Glucosinolates are usually broken down through hydrolysis catalyzed by myrosinase, an enzyme that is released from damaged plant cells. Some of the hydrolysis products,
viz. indoies and isothiocyanates, are able to influence phase I and phase 2 biotransfor~tion
enzyme activities, thereby possibly influencing several processes related to chemical carcinogenesis, e.g. the metabolism, DNA-binding
and mutagenic activity of promutagens. A
reducing effect on tumor formation has been shown in rats and mice. The anticarcinogenic
action of isothiocyanates and indoles depends upon many factors, such as the test system, the
target tissue, the type of carcinogen challenge and the anti~rcinogeni~
compound, their
dosage, as well as the timing of the treatment. Most evidence concerning anti~arcinogenic
effects of glucosinolate hydrolysis products and bras&a vegetables has come from studies in
animals. Animal studies are invaluable in identifying and testing potential anticarcinogens. In
addition, studies carried out in humans using high but still realistic human consumption
levels of indoles and brassica vegetables have shown putative positive effects on health. 6
1997 Elsevier Science Ireland Ltd.
Ktywords:
Anticarcinogenesis;
Brassica vegetables; Glucosinolates;
Indoles: Isothiocyanates
* Corresponding author. Tel.: + 31 30 6944755: fax: -i- 31 30 6957952.

000%2797/97/$17.00 Q 1997 Elsevier Science Ireland Ltd. All rights reserved
PlI SOOO9-2797(96)03745-3
80
D.T.H.
Verhoeven et al. 1 Chemico-Biological Interactions 103 (1997) 79-129
1. Introduction
The hypothesis that certain components of plant foods are protective against
cancers at many sites has gained interest in the past two decades and is supported
in many studies [l-3]. A large number of potentially anticarcinogenic agents have
been suggested in fruits and vegetables so far, e.g. fiber, vitamins C and E,
carotenoids, flavonoids, phenols, phytoestrogens, diallylsulfides, limonene and hydrolysis products of glucosinolates. The mechanisms by which these agents may act
include dilution and binding of carcinogens in the digestive tract (fiber), antioxidant
effects, inhibition of nitrosamine formation, inhibition of activation of promutagens/procarcinogens,
induction of detoxification enzymes, alteration of hormone
metabolism, and others [4-61.
One group of vegetables that has been widely regarded as potentially cancer
protective are vegetables of the Cruciferae family. Cruciferous vegetables are the
major source of glucosinolates in the diet which distinguishes them from other
vegetables. Brassica vegetables, including all cabbage-like vegetables, are a genus of
the family Cruciferae and contribute most to our intake of glucosinolates [7]. In the
1960s interest emerged in the possibility that certain aromatic and indolic glucosinolate hydrolysis products might influence carcinogenesis. In in vivo experiments
animals were fed glucosinolate hydrolysis products together with a carcinogen and
it was found that fewer animals developed tumors in comparison with control
animals not receiving the glucosinolate hydrolysis products [8,9]. From that time on
many studies have been carried out to examine the possible anticarcinogenic effect
of brassica vegetables and glucosinolate hydrolysis products. This paper now
reviews these experimental studies investigating the effects of brassica vegetables
and glucosinolate hydrolysis products on carcinogenesis and cancer risk.
Searches for papers on brassica vegetables, glucosinolates or hydrolysis products
of glucosinolates were carried out with MEDLINE on CD-ROM (1983-1996),
with Current Contents (1995- 1996), and by checking references to find earlier
reports.
This paper will give a short overview of the occurrence and intake of glucosinolates, and of the chemistry of glucosinolates and their hydrolysis products. This will
be followed by the putative beneficial properties and adverse effects of brassicas,
glucosinolates and their hydrolysis products. Finally, an overall conclusion and
suggestions for further research will be given.
2. Occurrence and intake of glucosinolates

So far, over one hundred glucosinolates have been identified which occur
predominantly, but not exclusively, in vegetables of the family Cruciferae [lo]. In
Table 1 an overview is given of common vegetables of the family Cruciferae.
Vegetables of the genus Brassica, in which 15-20 glucosinolates have been found,
contribute most to our intake of glucosinolates and include all kinds of cabbages,
kale, broccoli, cauliflower, Brussels sprouts, kohlrabi, rapeseed, rutabaga and
turnip. Detailed information on the consumption of brass&as is not readily

available. In Table 2 the ~ons~ption
of some brassicas, as determined from food
cons~ption
surveys in the UK [I l] and in the Netherlands [ 121, in 1992 is given.
The glucosinolate content of plants depends upon variety, cultivation conditions.
climate and the agronomic factors associated with plant growth, while the levels in
a particular plant vary between the parts of the plant [7]. Indolglucosinolates are
found in young shoots and growing leaves [17]. The total glucosinolate content of
a variety of brassica vegetables is also shown in Table 2. Very little is known about
the average daily intake of glucosinolates. An intake of 12- 16 mg glucosinolates
per person per day has been suggested by Fenwiek and I-Ieany [IO].
3. Chemistry of gluc~inolates and their hy~olysis products

3.1. Chemical structure
The chemistry of glucosinolates and their hydrolysis products has been reviewed
extensively by Fenwick and Heany [7,10]. All glucosinolates share a common basic
skeleton containing a j?-r>-thioglucose grouping, a side chain and a sulfonated
oxime moiety, but differ in side chain (R):
S - p - D glucose
/
R-C
\\
N-OSO,-with R = alkyl, alkenyl, arylalkyl, alkylthioalkyl,
a-hydroxyalkyl
or indolylmethyl.
Table 1
Common vegetables of the family Cruciferae
Genus
Species
Common name
Armoracia
Rusticana
Brassica
C~~esr~is
Horseradish
Turnip
Pak choy
Brown mustard
Rape, Swede, rutabaga
Black mustard
Cabbage, kale, Brussels sprouts, cauliflower. broccoli. kohlrabi
Chinese cabbage
Garden cress
Watercress
Radish
Mustard
_-...-._.__
~kine~s~s
Juncea
Napus
Nigra
Oleracea
Pekinensis
Sativum
O~~~ina~e
Satiw
Aha
11
1
10
1
2
4
12
3 (Sauerkraut)
Netherlands [ 121
UK [ll]
Consumption of bras&as
(g/person/day)
;LJ
f?
$j.
2
94-1111 [13]
372 [13]
691 [13]
138-2083 [13], 530-1140 [16], 122 [14]

611 1131,276 [14]
894 [13]
-
z
i2
;
a
;.
6
-G
F
3
K
c%
B
;I;
2
F
205-944 [13]
597-2542 114, 1628 [IS]
548 [13]
Level of total glucosinolates in cooked

vegetables (mg/kg fw)
5G
392-1657 [13], 260 [lo]
PO1
669 [13], 410-1090 [IO]

510 [14], 330-840 [lo]
470-1240 [lo]
170-1360 [IO]
145553939 114, 2562 Il.5). 1342 1141,600-3900
Level of total glucosinolates in unprocessed

vegetables (mg/kg fw)
The analyses were conducted in the following countries, with the references in brackets: UK ([lo] only Brussels sprouts, [13, 161);USA ([lo] except Brussels
sprouts); Canada [ 141;Netherlands [ 151.
Turnip-Swede
Cauliflower
Broccoli
Kale
---
Cabbage
Red
White
Savoy
Chinese cabbage
Brussels sprouts
Vegetable
-_
Table 2
Consumption of some brassica vegetables and reported ievels of total glucosinolates in unprocessed and cooked brassica vegetables
D.T.H.
Verhoeven et al. / Ch~~i~~-%~o~o~i~alInteru~ti~tls IO.? [i997] 19-i-79
83
Glucosinolate hydrolysis products make a significant contribution to the typical

flavour of brassica vegetables. The enzyme myrosinase (thioglucoside glycohydrolase EC 3:2:3:1) catalyses the hydrolysis of glucosinolates [lo]. Myrosinase is found
in plant cells in a separate compartment from glucosinolates. When the plant cells
are damaged, e.g. by cutting or chewing, the myrosinase comes in contact with the
glucosinolates and hydrolysis occurs. All kinds of processing lead to a certain
degree of glucosinolate hydrolysis by myrosinase hydrolysis or other chemical
reactions. The effects of processing on glucosinolate levels in vegetables have been
reviewed by De Vos and Bhjleven [18]. When the vegetables are cooked, myrosinase
is inactivated and thermal degradation and wash out occur, leading to a 30 --60(X1
loss of intact glucosinolates.
It should be noted that myrosinase activity has also been found in certain
intestinal microflora. This could be of importance when intact glucosinolates are
digested, although very little is known about this metabolic pathway [lo].
The glucosinolate hydrolysis products consist of equimolar amounts of an
aglucon, glucose and sulphate. The aglucones are unstable and undergo further
reactions to form for instance thiocyanates, nitrites or isothiocyanates. The nature
of the hydrolysis products depends primarily on the side chain of the glucosinolate,
besides the conditions of the hydrolysis and the presence of any cofactors. Glucosinolates with an indole side chain form indoles, whereas oxazolidine-2-thiones are
formed from glucosinolates with a ~-hydroxy-alkyl side chain. Table 3, derived
from De Vos and Blijleven [1X], shows some glucosinolates and their hydrolysis
products that occur in cruciferous vegetables,
Of the indole glucosinolates, which are predominant in brassica vegetables,
glucobrassicin is amongst the most prevalent. At neutral pH glucobrassicin forms
an unstable isothiocyanate which degrades to indole-3-carbinol (13C) and a thiocyanate ion. I3C may condense to 3,3-diindolylmethane (DIM) or react with
ascorbic acid to form ascorbigen. At a more acidic pH, glucobrassicin forms
indole-3-acetonitrile (13A) and elemental sulphur [7,17]. In many publications it was
suggested that 13C and I3A were the most abundant metabolites, but recently it has
been stated that ascorbigen is the major indole-containiIlg product of gluco-brassicin biotransformation
[19].
3.3. Analysis
qf glucosinoiate composition und content
The analysis methods for determining glucosinolate composition and content

have been reviewed by McGregor et al. [20]. Distinction has been made between
total glucosinolates, individual glucosinolates and hydrolysis products. For determination of total glucosinolate content, calorimetric measurement of glucose released
by myrosinase hydrolysis seems most appropriate. Both gas-liquid chromatography
(GLC) and high performance liquid chromatography
(HPLC) can be used to
determine the content of individual glucosinolates. Because of the thermal instability of indolglucosinolates, HPLC is the most suitable method for determination of
Glucocochicarin
Sinigrin
Gluconapin
Glucobrassicanapin
Progoitrin
Gluconapoleiferin
Glucoiberverin
Glncoiberin
Gluc~heiroli~
Glucoerucin
Glueoberteroin
Glueotropaeolin
GIuconastu~un
Glu~brass~cin
Neo-glucobrassicin
Trivial name
+
+
+
+
+
t
+
+
+
+
+
+
+
i+
Nb
c
+
f lndoles
+ Indoles
-I-
-I-
c
+
c
Tb
-
i
i
Xb
Myrosinase hydrolysis products

_-_
Reproduced with permission from De Vos and Blijleven [18].

bN, Nitrile, R-C=N;
I, isothiocyanate, R-N = C = S; T, thiocyanate ion, S-C zN.
CGeneral structure: R-C=N
witb sulphur inserted in the terminal double bond of R.
2-Butyl
2-Propenyl
3-Butenyl
4-Pentenyl
2-Hydroxy-3-butenyl
2Hydroxy-~~nteny1
3Methyltbiopropyl
3-Methylsulfinylpropyf
3-Methylsulfonyipropyl
4-~ethylthjobutyl
5-Methylthiopentyl
Benzyl
2-Phenylethyl
3-Indolylm~thyl
I-Methoxy-3-indolylmethyl
Side chain (R) =
Table 3
Some glucosinolates and their hydrolysis products found in brassica
-__
--
.~
.-
Epithionitrilec
Epithionitrih?
Epithionitrilec
L-5-vinyl-oxazolidine-2-thione
L-~-ailyl-oxazol~dine-2-thione,
Others
1-
(goitrin), Epithionitrile~
~pithionit~lec
_-
5
2
!k?
%
5
B
r*l
ms
3
F;
D
7
&
%
3
b
P
3
3
D.T.H.
Verhoeuw et al. / ~hemico-Biol~gi~ul I~ter~~ti~~ 103 (1997) 79-129
85
these compounds. rsothiocyanates and nitriles can be analyzed by GLC. HPLC

with UV detection may be used for analysis of oxazolidinethiones and indoles.
4. Putative beneficial properties of glucosinolate hydrolysis products and brassicas

4.1. Postulated mechanism of anticarcinogenic action
Carcinogenesis is a multistage process; cells susceptible to genetic changes
(initiation) and epigenetic changes (promotions may gain a growth advantage and
undergo clonal expansion. Genetic changes are considered to result from interactions between DNA and a carcinogen/mutagen, which can be metabolised into an
electrophilic intermediate and bind to DNA. If repair of the damage does not
occur, replication of DNA can lead to permanent DNA lesion, and in presence of
a tumor promotor to preneoplastic cells, neoplastic cells and finally metastases [21].
At each stage of the carcinogenic process a possibility of intervention exists. One
anticarcinogenic action is the modulation of metabolism of carcinogenic/mutagenic
compounds, thereby preventing the formation of electrophilic intermediates. This
modulation of metabolism comprises inhibition of activation of promutagens/procarcinogens, induction of detoxifying mechanisms, and stimulation of activation
coordinated with detoxification and blocking of reactive metabolites [22]. Involved
in this modulation are phase 1 and phase 2 biotransfo~ation
enzymes [23]. Phase
1 involves oxidation, reduction and hydrolysis reactions, thereby making xenobiotics more hydrophilic (which can result in inhibition of activation but also in
activation of the compound) as well as susceptible to detoxification. The most
important phase 1 enzymes are the cytochrome P450 enzymes. Phase 2 metabolism,
a detoxifying mechanism, comprises conjugation reactions making phase 1 metabolites more polar and readily excretable. Examples of phase 2 enzymes are
glutathione S-transferases and UDP-glucuronyl
transferases. Alteration of biotransformation enzyme activities is supposed to be involved, at least partly, in the
alteration of the toxicity, mutagenicity and tumorigenicity of specific chemicals [24].
Isothiocyanates and indoles, both glucosinolate hydrolysis products, are considered to be able to modulate biotransfo~ation
enzyme activities ]17,24-261. Indoles
thereby also affect estradiol metabolism, which is P450 dependent, and may reduce
the risk of estrogen-dependent
diseases such as mammary cancer [27]. Besides
modulators of biotransformation
enzymes isothiocyanates are seen as suppressing
agents [6,28]. Suppressing agents act during the promotion phase of the neoplastic
process via prevention of the evolution of the neoplastic process in cells.
4.2. Results of studies on anticarcinogenic action
In Tables 4-8 the results of studies on the antimutagenic and anticarcinogenic
properties of isothiocyanates, indoles and brassica vegetables are presented. A
distinction has been made between in vitro and in vivo studies. One of the most
In vivo, mouse
In vivo, rat
In vivo, rat
I3C
13C, RXM
I3C, I3A, DIM, ascorbigen,

13CHO
Brussels sprouts, I3C
Benzo[u]pyrene hydroxylase
Aniline p-hydroxylase
Aryl hydrocarbon
hydroxylase
MSPITC
13C, I3A
I3C, DHII, THII
I3C, DHII
Cauliflower
BylITC, BITC, ButITC, PPITC
Brussels sprouts
Brussels sprouts, cabbage
Cabbage
Cauliflower
Broccoli
Brussels sprouts, cabbage,
I3C, I3A, DIM
broccoli, cauliflower, turnips
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
rat
mouse
rat
rat
rat
rat
In vivo, rat
In
In
In
In
In
In
In vivo, rat
rat
mouse
rat
mouse
rat
rat
In
In
In
In
In
In
BylITC, BITC, ButITC, PPITC

vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
In vivo, in vitro,
rat
In vivo, in vitro,
rat
In vivo, rat
PEITC
Alcohol dehydrogenase
Aldehyde dehydrogenase
Aminopyrine Ndemethylase
PEITC
Test systemi
Compound/vegetable
indoles and brassica vegetables
Phase 1 enzyme
Table 4
Alterations of phase 1 enzyme activities by isothiocyanates,
t Small intestine (Brussels sprouts>

cabbage > turnips > broccoli > cauliflower
] Liver, when compounds were given p.o.

-+ Liver, when compounds were given i.p.
t Liver > small intestine; ascorbigen least
effective and not by 13CllO
t Intestine, + liver
+ Intestine, + liver
r Small intestine
-+ Liver
t Intestine, -9 liver
-+ Liver
t Liver
1 Small intestine
+ Liver
+ Liver, + small intestine

+ Liver, both given i.p. and p.o.
+ Liver
t Liver only by 13C
t Liver
1 Liver, not by ButITC
1 Liver
1481
[41
1421
[431
PI
1451
[361
[461
1471
1401
1391
[37,381
1321
1331
[341
[351
[361
[31
131
[301
[301
+ Liver
1 Liver
Refs
Effect
N-
7-Ethoxycoumarin
O-deethylase
Estradiol 2-hydroxylase
Cyclooxygenase
Erythromycin Ndemethylase
~enzphetamine
demethylase
WI
[531
1541
[55,561
1571
t Colon
1 Liver
J. Liver
t
t, Only in estrogen-responsive
In vivo, rat
In vivo, rat
[501
1321
1641
1511
WI
[471
I411
[421
[431
t451
T Liver
+ Small intestine, -+ liver
4 Liver
+ Liver
7 Liver
1 Small intestine
1 Intestine, -+ liver
+Intestine, --) liver
t Small intestine
t Intestine. -+ liver
In vivo, rat
In vivo. rat
In vivo. rat
Brussels sprouts
Cabbage
In vitro, chick
embryo
In vivo. rat
rat
rat
rainbow trout
rainbow trout
In
In
In
In
vivo,
vivo,
vivo,
vivo,
l581
1591
[6Wll
[621
[631
[491
t2-hydroxylation, + 16~-hydroxylation
t Liver
f Liver
t Liver (DIM > 13C)
1 Liver
1. Liver

13C, 13A, DIM
Brussels sprouts, 13C
BNITC
MSPITC
I3C
13C, 13-ethanol, Kaldehyde,
13-acetic acid
13C, I3A
13c
13c
13C
13C, DIM
13C ascorbigen
ANITC
13c
In vivo, rat
In vitro, mouse, mammary epithelial cells
In vitro, estrogenresponsive and estrogennonresponsive human
breast cancer ceils
In vitro, MCF-7 cells
In vivo, rat
In vivo, mouse
In vivo, rat
In vivo, rat
In vivo. rat
cells
WI
[331
1511
t Liver
+ Liver, both given i.p. and p.o.
+ Liver, 1 liver only by I3-aldehyde
In viva, rat
In vivo, mouse
In vivo, rainbow trout
BNITC
13C, 13A
13C, I3-ethanol, 13-aldehyde,
I3-acetic acid
PHITC
BITC, PEITC, PBITC,
PHITC
PEITC
13C
1491
vivo.rat
1 Liver
In
ANITC
7-Ethoxyresornfin
deethylased
P450 IA1
N-nitrosodimethylamine demethylase
O-
In vivo, rat
In vivo. rat
In vivo, rat
In vivo, mouse
In vivo, rat
In vivo, mouse
In vitro, estrogenresponsive and estrogen
nonresponsive human
breast cancer cells
In ovo, rainbow trout
embryos; in vivo,
fingerling trout, liver
In vivo, mouse
Cauliflower
BITC, PEITC, PBITC,
PHITC
PEITC
13C
13C, DHII, THII
13C, DHII
13C
1541
[531
F51
[331
1 Liver, 1 nasal mucosa, --$ lung

1 Liver
7 Liver
-+ Liver when given i.p.; 1 Liver
when given p.o. (13C>13A)
-) Liver
1 Liver, but only weak and transient
1 Liver at low doses and 1 liver at
high doses
In vivo, rat
In vivo, rat
In vitro, chick embryo
In vivo, mouse
PEITC
BITC, PEITC, PBITC,
PHITC
13C, 13A
I3C. 13A
f3C
13C
13C
WI
1671
1691
WI
t Liver, but only weak and transient

1 13C showed relatively weak induction
1671
1671
[54&o]
[3gl
1341
[351
[571
1 Liver
-* Liver
1 Liver, only by DHII
-+ Liver
t, Only in estrogen-responsive
cells
1361
[531
t Liver, only by 13C (given p.o. z

given i.p.)
1 Liver
1 Liver
T Liver
PEITC
13C
132, DIM, CTI, RXM
In vivo, rat
In vivo, mouse
PHITC
13C, 13A
1521
1331
PO1
t Liver
In vivo, rat
f Colon
[471
1 Small intestine, not by 13A
In vivo, rat

I3C, I3A, DIM
PEITC
Hexobarbital hydroxylase
Lactate dehydrogenase
Lipoxygenase
p-Nitroanisole Odemethylase
Refs
Effect
Test systemb
Compound/vegetable
Phase 1 enzyme
Table 4 (continued)
7-Ethoxyresorufin
Odeethylased
Sin&in, progoitrin, glucobrassicin, glu~otropaeolin
ICZ
ICZ
t Small intestine, only by ~lucobr~sici~,

liver, + large intestine
-+
[771
f and 1. concentration
dependent
1761
In vitro, Hepa lclc7

murine hepatoma cells
In vitro, Hepa lclc?
murine hepatoma cells
In vitro, human breast
cancer cells
In vivo, rat
ICZ
In vivo. rat
rat
rat, monkey
rat
mouse
rat
13C, NI3C, NCHO, DIM,

indole, 3M1, 13CH0, 13A
vitro,
vitro,
vivo,
vivo,
vivo,
In
In
In
In
In
13C, I3A, DIM, 13CHO

DIM, CTI, BII
13C, DHII, THII
13C, DHII
13C, RXM
1791
[781
1751
[711
[741
I341
1351
1391
f731
[@I
[701
1711
1721
1 Liver
1 Liver
1 Liver, t small intestine
-+ When cotreated with 2,3,7,8-tetrachlorodi~nzo-~-dioxin:
decrease in
induced EROD activity
I3C:t (Liver > small > large intestine)
DIM + 13A:f liver, -t small + large intestine
ascorbigen: + liver, 7 small + large intestine
t Liver, not by 13C and 13CHO
t Liver
t Liver
t Liver
13C + RXM, p.o.: f (small intestine > lung r
liver) 13C, i.p.: -+
RXM, i.p.: t (lung>hver), -+ small intestine
p.o.: 1 Liver, not by indole, 3M1, 13CH0,
I3A
13C, i.p.: + liver
RXM, i.p. or p.0.: t liver
In vivo, mouse
In vivo, rat
In vivo, rat
In vitro, human breast
cancer cells
In vivo, rat
[511
-+ Liver
In vivo. rainbow trout
13C, 13A, DIM, ascorbigen
I3C, I3-ethanol, 13-aldehyde,

13-acetic acid
13C
I3C
13c
I3C, DIM
In vivo, rat
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo.
In
In
In
In
In
In
In
In
In
In vitro, human P450 IA2

expressed in Escherichia roli
In vitro, human P450 IA2
expressed in Escheric~hiu coli
In viva, rat
in vivo, rat
In vivo, rat
In vivo, mouse
In vivo, rat
Cabbage
Brussels sprouts
Brussels sprouts
f3C
13c
13C
13c
13C, DIM
Brussels sprouts
PEITC
PEITC
13c
Brussels sprouts
Broccoli
PEITC
PEITC
P450 IA2
Methoxyresorufin
0-dealkylased
P450 2B
P450 IAI, I450 IA2
In vivo. rat
Cabbage
rat
rat
rat
rat
rat
rat
rat
rat
rat
Test systemb
Compound/vegetabIe~
Phase 1 enzyme
-7-Ethoxyresoru~n
O-deethylase
Table 4 ~continued)
--.--
1 Liver, -+ lung, $ nasal mucosd
T Liver
-t Liver, t small intestine
P450 28 mRNA: -+liver, 1 colon
P450 28 protein: t liver, 1 coion
1 Liver
1 Small intestine, -+ large intestine,

-8 liver
t Small intestine, 1 liver
t Small & large intestine, t liver
t Liver
t Liver, -+ small intestine
P450 1Al: t liver, t colon
P450 1A2: j liver, -+ colon
t Liver
t Liver
t Liver, -+ small intestine
P450 1AI mRNA: t liver, t colon
P450 IA1 protein: t liver, t colon
P450 IA2 mRNA: t liver, colon not
detectable
P4SO IA2 protein: t liver, + colon
1
__t (Small intestine z large intestine > liver)
EffectC
[541
F41
[621
FOI
WI
1831
Refs
-
cl
b
3
f
?
!$
ZY
09
8
k
13
Brussels sprouts
13c
13C
13c
PEITC
Brussels sprouts,
I3C, 13A, DIM
PHITC
P450 3A
P450 3Al
P450 3AI/2
P450 3A2, P450 4Al

Phenacetin
O-dealkylase
Phospholipase
A2
cabbage,
In
In
In
In
In
In
PEITC
PEITC
Sulforaphane
13C
Broccoli
P450 2El
P450 2D6
P450 2CI 1
P450 2B112
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
mouse
In viva, rat
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
In vivo,
In vivo,
In vivo,
In vivo,
In vivo,
In vivo,
In vivo,
In vivo,
In vivo,
In vivo,
In vitro,
somes
In vivo,
In vivo,
In vitro,
In viva,
In vivo,
P450 2Bl
rat
mouse
rat
rat
rat
rat
rat
rat
rat
rat
human
micro-
1801
1821
WI
1841
1301
1471
1521
T colon
1681
1301
1891
1841
1851
T Liver, 1 lung
1 Liver, after elevation by ethanol
1 Liver
+ Liver
T P450 2E1 proteins liver
+ colon
+ Liver, -+ small intestine
t Liver
T Liver
+ Liver
-+ Liver
t Small intestine, not by DIM
1801
1681
1301
1821
1711
1811
1841
1621
1301
VII
WI
1711
1391
T Liver, T small intestine

T Liver, when 13C was given p.o.,
small intestine,
+ lung
r Liver, 1 small intestine
t Liver, 1 lung
T Liver
t Liver
t Liver, T small intestine
1 Liver
T Liver
T Liver
5_Liver
+ Liver
1 Liver
In vivo, rat
In vivo, rat
+
1531
1 Liver
In vivo. rat
BITC, PEITC,
PHITC
13c
13C, RXM
PBITC,
WI
T Liver
rat
In vivo,
PEITC
Brussels sprouts
PEITC
PEITC
13c
13C
13C
13C
13C, DIM
PEITC
13C
PEITC
7-Ethoxyresorufin
O-dealkylased
I Liver, 1 small intestine, t

esophagus, t forestomach
I (small intestine > forestomach >
liver > lung > kidney), + colon, 1
urinary bladder
7 Liver, + lung, + nasal mucosa
T Liver
t Small intestine, + liver
Erwin: T (small intestine > forestomach > glandular stomach > liver > lung)
Sulforaphane: r (glandular stomach >
small intestine > forestomach > liver), +
lung
Erysolin: + small intestine, +
forestomach, -+ glandular stomach, +
liver, + lung
In vivo, mouse
In vivo, mouse
In vivo, rat
In vivo, rat
In vivo, rat
In vivo, mouse
BITC
PEITC
BylITC, BITC, ButlTC,
PPITC
MSPITC
Erucin, sulforaphane,
erysolin
I Liver
+ Liver
I Liver
I Intestine, only by Brussels sprouts
I Small intestine
1 Liver, only by Brussels sprouts
t Liver, -+ intestine
I Liver
I Esophagus, 7 stomach
1 Liver, not by THII
I Liver, not by THII
+ Liver
I Esophagus, t colon, -+ liver, +
stomach
I Liver, + lung, + nasal mucosa
In vivo, rat
rat
rat
rat
rat
rat
mouse
rat
rat
rat
rat
rat
mouse
rat
BITC, PEITC, PBITC,

PHITC
BITC
Glutathione reductase
Glutathione-S-transferase
Glutathione peroxidase
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
In
In
In
In
In
In
In
In
In
In
In
In
In
ANITC
BNITC
I3C
Brussels sprouts, 13C
Brussels sprouts
Brussels sprouts, cabbage
Cabbage
Broccoli
PEITC
I3C, DHII, THII
13C, DHII, THII
PEITC
PEITC
Epoxide hydrolase
Effect
Compound/vegetables
Test systemb
indoles and brassica vegetables
Phase 2 enzyme
Table 5
Alterations of Phase 2 enzyme activities by isothiocyanates,
1951
~321
[541
1311
1941
[91-931
1531
1341
WI
[901
t901
t341
z
2
g
3
2
2.
P
D
3
r?
0
r;l
6
s
oq.
s
$
,:
%
B
tz
3
2
Q
L-
1411
1431
WI
1451
t461
P
!-I
3
[491
1501
1821
Refs
NAD(P)H-quinone reductase,
also named NAD(P)H-quinone
oxidoreductase, DT-diaphorase
Glutathione-S-transferase
I531
[loll
T Liver, -+ lung, -+ nasal mucosa

T (small intestine z lung> forestomach >
urinary bladder > kidney > liver > colon)
In vivo, rat
In vivo, mouse
BITC, PEITC, PBITC,

PHITC
BITC
[451
[461
w01
WI
In
In
In
In
Cabbage
Broccoli
Rapeseed
PEITC
vivo,
vivo,
vivo,
vivo,
rat
rat
germ-free rat
mouse
Wl
I431
[991
~421
In vivo, rat
In vivo, rat
In vivo, rat
[411
1 Liver & intestine only by Brussels

sprouts
-+ Liver, t intestine only by Brussels
sprouts
t Liver, T small intestine
T small intestine
t Liver, T small intestine, -+ large intestine
T Liver, 1 intestine
T Liver
-+ Liver
-+ Liver, -+lung
vivo, rat
ovo, chick embryo
vivo, rainbow trout
vivo, rat
vivo, rat
vitro, rat
vitro, rat, monkey
vivo, rat
vivo, mouse
vivo, mouse
Brussels sprouts
Brussels sprouts
Brussels sprouts
WI
l971
WI
PSI
1711
1711
[74l
[341
[351
[931
7 Liver
-9 Liver
-+ Liver
t Liver
t Liver, t small intestine
t Liver
+ Liver
t Liver, not by THII
1 Liver
1 Liver, 7 small intestine
In
In
In
In
In
In
In
In
In
In
In vivo. rat
[961
t Liver, t small intestine
In vivo, rat
AITC, goitrin, Brussels

sprouts
13C
13C, 13A
13c
I3C
13C
I3A, DIM, 13CHO
DIM, CTI, BII
13C, DHII, THII
13C, DHII
13C, 13A, cabbage,
Brussels sprouts
Brussels sprouts, I3C
In vitro, Hepa lcIc7 murine

hepatoma cells
In vitro, Hepa lclc7 murine

hepatoma cells
In vivo, mouse
Glucosinolates with(out)
myrosinase, at pH 6.6
or pH 3.t
Erucin, su~foraphane,
erysohn
Erucin, sulforaphane,
erysohn
Erucin: I (smati intestine > Iiver >

gtanduiar stomach > lung > forestomach),
SnIforaphane: 1 (iiver > glandular
stomach = smafi intestine >
forestomach > lung),
Eryaohn: I liver, -) forestomach, -+
glandular stomach, -+ small intestine, -+
lung
t Liver, 7 forestomach, t gIanduIar

stomach, I small intestine
Without myrosinase, pH 6.6: phydroxybenzyl and 2-hydroxybut3-enyI ghrcosinolates induced
activity; with myrosinase at pH
6.6: breakdown products induced
activity (3-methyIsuIphinylpropyl > prop2enyi spent-4enyl + 2-phenethyl t benzyl 3 all
others; without myrosinase,
pH 3.1: breakdown products induced activity (3methyfsulphinyIpropyl + 2-phenethyi > bennyi > all
others
f
1 Liver
t Liver
T Small intestine, + liver
t
In vivo, rat
In vivo, rat
In vivo, rat
In vitro, Hepa lclc7 murine
hepatoma cells
In vivo, mouse
ANITC
BMTC
MSPITC
Ketoisothiocyanate
[951
[IO31
[491
[501
[321
[~021
I541
7 Liver, +Iung,
In vivo, rat
PEITC
NAD(P)Hquinone reductase,
also named NAD(P)H-quinone
--t nasal mucosa
Refs
Effect=
Test systemb
Compound/veg~table~
---_
Phase 2 enzyme
Table 5 (continued)
g
~~__
vivo, rat
vivo, mouse
ovo, chick embryo
vivo, mouse
vivo, germ-free rat
vivo, rat
In
In
In
In
In
In
13C, DHII, THII

13C, DHII
13C, 13A
13C, 13A
Rapeseed
Brussels sprouts
rat
rat
rat
rat
rainbow trout
rat
WI
uw
1331
WI
1341
1351
vivo,
vivo,
vivo,
vivo,
vivo,
vivo,
In
In
In
In
In
in
1 Liver, ] nasal mucosa, -t lung

1 Liver, only by I3C
t Liver, -+ lung, -+ nasal mucosa
3 Liver, + small intestine
-+ Liver
Glucuronyl transferase towards 4ehlorophenoi: T liver, -+ small intestine,
Glucuronyl transferase towards 4-hydroxybiphenyl: --) liver, -+ small intestine
t Liver
T Liver
-+ Liver, both given i.p. and p.o.
-+ Liver
t Liver
-+ Liver, both given i.p. and p.o.

1331
1 Liver, in monkey hepatocytes only by BII [74]
[341
7 Liver
135J
t Liver, 1 small intestine
1801
1, except by cauliflower
1104j
mouse
rat, monkey
rat
mouse
rat
hepa lclc7 cells
vivo,
vitro,
vivo,
vivo,
vivo,
vitro,
In
In
In
In
In
In
CTI,
BII
I3C, DHII, THII
13C, DHII
Brussels sprouts
Brussels sprouts, cauiiflower, cabbage, broccoli
PEITC
13C, DHII, THII
PEITC
MSPITC
I3C
13C
DIM,
I3C, I3A
(711
1 Liver, 1 small intestine
In vivo, rat
I3C
ANITC, r-naphthyl isothiocyanate; BII, 2,3~bis~3-indolylmethyl]indole, an acid condensation product of DC, BITC, bet@ isothiocyanate; BNITC,
/3naphthyl isothiocyanate; ButITC, butyl isothio~yanate; BylITC, butenyl isothiocyanate; CTI, 5,6,ll,l2,17,18-hexahydrocyclononal[l,2-b:4,5-b:7,8-b]triindole cyclic trimer, an acid couden~tion product of 13C, DHII, 5,iO-d~hydroindeno~l,2-~]-indole; DIM, 3,3-diindolylmethane, an acid condensation
product of f3C; I3-, indole-3-; 13A, indole-3-a~tonit~le;
13C, indole-3~arbjnol; 13CHQ indole-3- ~ar~xaldehyde; ICZ, indoIo[3,2-~~arb~ole;
3M1,
3-methylindole; MSPITC, 3-methylsulfinylpropyi isothiocyanate; NCHO, l-met~oxyindole-3~ar~xaIdehyde;
NI3C, I-methoxyindole-3~rbinol;
PBITC,
4-phenylbutyl isothiocyanate; PEITC, Z-phenethyl isothiocyanate; PHITC, 6phenylhexyl isot~io~yanate; PPITC, 3-phenylpropyl isothiocyanate; RXM,
indale-3-carbinol acid reaction mixture (13C with HCI); THII, 4b,5,9b,lO-tetrahydroinde~o[I,~-~]-indol~.
bWhen the testcompound is added before sacrifice, the test system is called in uioo.
T, increased; 1, decreased; +, no effect; 2, greater effect; i.p., intraperitoneal; po., per 0s.
~~thoxyr~oru~n-~-deethyiase,
methoxyresorufin-~-dealkyla~
and ~ntoxyresorufin-~-deethyi~e
activities are principal markers for P450 lA1, P450 lA2
and P450 2B activities, respectively.
eKetoisothiocyanate, ( + )-e~ff-2-a~tyl-6-isothi~yanatonorbomane.
Also 34 other bifu~ctional isothioc~~nates were found to induce NAD(P)H-quinone
redutiase in vitro.
_-..----_
Su~otransfer~e
Superoxide dismutase
UDP glucuronyl transferase
NAD(P)Hquinone
reductase,
also named NABS-qui~one
96
D.T.H.
Verhoeven et al. 1 Chemico-Biological Interacrions 103 (3997) 79-129
interesting in vitro systems for identifying compounds with potential chemopreventive activity has been developed by Prochaska and colleagues in the laboratory of
Talalay 1291.This resulted e.g. in the identification of sulforaphane as a hydrolysis
product of glucosinolates [95]. Most data originate from experiments using laboratory animals. There is a limited number of studies dealing with effects of isothiocyanates, indoles and brassicas in man. The results of these studies are presented
separately in Table 8.
Tables 4 and 5 presents the alteration of biotransfo~ation
enzyme activities by
isothiocyanates, indoles and brassicas. In various test systems isothiocyanates,
indoles and brassica vegetables induced both phase 1 enzymes and phase 2 enzymes,
although the induction pattern differs among tissues. Isothiocyanates blocked the
activity of some phase 1 enzymes, depending upon the target tissue and the phase
1 enzyme examined.
Table 6 summarizes the modulation of metabolism and mutagenicity of various
agents by isothiocyanates, indoles and brassicas in different test systems. Isothiocyanates decreased the activation of mutagenic compounds, mostly nitrosamines. In
addition, isothiocyanates reduced the DNA adduct formation induced by 4(methylnitrosamino)- 1-(3-pyridyl)-1 -butanone (NNK) and N-nitrosomethylbenzylamine (NMBA), but not the DNA adduct formation induced by benzo(a)pyrene
(B(a)P) and 2-amino-l-methyl-6-phenylimidazoI4,5-~]pyridine
(PhIP). Indoles were
inhibitors of the DNA-binding of aflatoxin B, (AFB,), B(a)P, PhIP and N-nitrosodimethylamine (NDMA), increased nitrosamine metabolism, and reduced the
number of sister chromatid exchanges induced by mutagens, depending on the kind
of mutagen. Brassica vegetables reduced AFB,-DNA binding.
The in vivo alteration of carcinogenicity of various agents by isot~ocyanates,
indoles and brassica vegetables is presented in Table 7. Both isothiocyanates,
indoles and brassicas reduced tumor formation in miscellaneous tissues, test systems
and using various carcinogenic compounds. When added in vitro to human
erythroleukemic KS62 cells various glucosinolates, viz. sinigrin, gluconapin, progoitrin, epi-progoitrin, sinalbin, glucotropaeolin, glucoerucin, glucocheirolin and
glucoraphenin, had no effect on tumor cell growth [194]. Their hydrolysis-delved
products, produced using myrosinase, showed an inhibition of human erythroleukemic K562 cefl growth, which was most evident for the hydrolysis products,
from sinigrin, glucotropaeolin, glucoerucin and glucocheirolin [ 1941. The hydrolysis-derived products from glucoraphenin decreased the growth of several other
tumor ceils, viz. FL (murine erythroleukemic cells), Jurkat (human T-lymphoid
cells), HeLa (human cervix carcinoma cells), H9 (human T-lymphoid cells) and
H3-TI-1 cells (obtained by transfection of HeLa with a LTR-HIV-l-CAT
plasmid)
[194]. 2-Phenethyl isothiocyanate
(PEITC) and its mercapturic acid pathway
metabolites inhibited the growth of HL60 (human leukaemia 60) cells in vitro. The
adduct with L-cysteine was the most potent inhibitor [195].
Table 8 shows the effects of indoles and brassica vegetables given to hnmans. I3C
induced estradiol 2-hydroxylase, a phase I enzyme. Brassica vegetables, mainly
Brussels sprouts, reduced oxidative DNA damage, increased glutathione S-transferase levels, and induced also estradiol 2-hydroxylase. When 11 smokers ate 56.8
NNK
NNK
NNK
NNK
NNK
NNK
NNK
NNK, NNN
NNK
NNK
NNK
NNK
UO81
1 NNK metabolism, 1 NNN metabolism
[111,112]
]I 121
WI
[I31
[531
1 NNK metabolism
1 NNK metabolism (lung> liver)
---t DNA methylation at .V and 0 of guanine
1 NNK oxidative metabolism
[1101
1 DNA methylation (lung>nasal
1 DNA methylation at O6 of guanine
PO91
1 NNK metabolism
mucosa)
[531
J. NNK oxidative metdbohsm
IlO
[68,106]
[541
1871
11051
Refs
1 Formation of a-hydroxylation products

of NNK
1 NNK metabolism (inhibition greater when
pretreated with PEITC)
4 Toxicity towards HT29 after detransformation of the ceils
--_
Effect*
indoles, and brassica vegetables

--
In vitro; rat; lung, liver, nasal

mucosa
In vitro; lung (rat, mouse), nasal
mucosa (rat)
In vitro, in vivo (PEITC
prior to NNK or NNN); rat;
oral tissue
prior to NNK); mouse; lung
prior to NNK); mouse (lung);
rat (lung, nasal mucosa)
In vivo; mouse; lung; PEITC
before NNK
In vivo; mouse; lung; pretreatment with PEITC
In vivo: mouse; lung, liver:PEITC
prior to NNK
In vivo; mouse; lung, liver: PETIC
prior to NNK
In vivo; Iung (rat, mouse),
liver and nasal mucosa (rat); pretreatment with PEITC
In vitro; human colorectal

adenocarcinoma cell line
HT29
In vitro; human liver microsomes
In vitro; mouse; lung
In vitro; rat; lung
PEITC
NNK
Test system
Agentb
Compound/
vegetable
Table 6
Modulation of metabolism and mutagenicity of various agents by isothiocyanates,
__
-~-
NNK
PEITC
NMBA
NMBA
NMAA
NMAA
NNK
NNK
NNK
NNK
NNK
Agentb
Compound/
vegetable
Table 6 (continued)
In vivo; rat; esophagus; PEITC

prior to NMBA
In vitro; rat; esophagus
In vivo; rat; lung, nasal mucosa;

PEITC before NNK
In vivo; rat; liver, lung, nasal
mucosa; PEITC before and during
NNK
In vivo; rat; PEITC before and
during NNK
In vivo; rat; lung, liver, pancreas,
kidney, stomach, serum, nasla mucosa; PEITC before and throughout
NNK treatment
In vivo; rat; jejenum; PEITC prior
to NNK
In vivo; rat, monkey; blood, uring;
PEITC prior to NNK
In vitro; rat; liver, esophagus
In vivo; rat; liver, esophagus; pretreatment with PEITC
Test systemc
1 NMBA metabolism,
1 Binding of NMBA metabolites to DNA,
1 DNA methylation at N and O6 of guanine
[I211
WI
P191
[1191
V181
1 NNK metabolic activation

1 NMAA metabolism
1 NMAA metabolism (esophagus > liver),
1 DNA methylation at O6 of guanine not
at N7 (esophagus),
1 DNA methylation at N of guanine not
at O6 (liver)
1 DNA methylation at N and O6 of guanine
ill71
[111,114]
P41
Refs
1 NNK metabolism (in $ less than in 9)
1 Levels of cr-hydroxylation metabolites,

not in nasal mucosa
1 DNA methylation at N of guanine in

lung, + liver, + nasal mucosa
Effectd
PEIIC
In vitro; DNA repair assays with

E. coli
In vivo; DNA repair assays with
E. coli, in animal mediated asays
with mice
DMN, PhlP
In vitro; micronucleus assays with

Hep-G-2 cells
In vitro (only with PhIP), in vivo
(PEITC before agents); mouse: liver
DMN, PhIP
DMN, PhlP
In vivo; mutagenicity tests

with Salmonella typhimurium;
PEITC-treated mice
DMN, PhIP
DMN, PhIP
WV
W)P
131WWY
In vitro; DNA repair assays with

E. coli; mouse; liver. In vivo; DNA
repair assays with E. cob; mouse;
liver, kidney, lung; PEITC prior to
nitrosamines
In vitro; human bronchial epithehal
cell line
In vivo; mouse; lung; PEITC prior
to B(a)P
In vitro; mouse; lung, liver
NDMA, NDELA,
NPYR (Ref. 124 only
NDMA)
1I271
1 Deactivation pathways of B(a)P metabolism

(PEITC > BITC)
1 Activation of B(a)P-7,8-diol (BITC > PEITC)
1 Genotoxic effects
4 Genotoxic effects of PhIP in liver and colon,
not in stomach and small intestine; 1 genotoxic
effects of DMN in liver, not in gastrointestinal
tracts
PhIP: 1 number of his+ revertants, with liver
homogenate
DMN:J number of his+ revertants, with liver
and kidney homogenates
1 DMN-induced micronuclei; no effect with
PhIP
J. Metabolism of PhIP and DMN
1IW
+ Formation of B(a)P-DNA adducts
[I281
[I281
[I281
[I281
WI
~251
[122-124)
In vitro: 1 DNA-damage in indicator

bacteria
In vivo: J nitrosamine genotoxicity; 1
nitrosamine metabolism (not examined in ref. 124)
-+ B(a)P-DNA binding
NNK
NNK
PITC
PPITC
NNK
NNK
B(a)P
AAF, MAM acetate,

DMBA, DEN
VHlB(c)P
NNK
NNK
NNK
NNK
PhIP
PEITC
BITC
Agentb
Compound/
vegetable
Table 6 (continued)

In vivo; mouse; lung, liver; PPITC
prior to NNK
In vivo; mouse; liver, colon;

PEITC prior to PhIP
In vivo; mouse; lung; PITC
prior to NNK
HT29
In vitro; human ovarian carcinoma,
human lung carcinoma, murine
leukemia, murine plasmacytoma
cell line
mucosa (rat)
In vivo; mouse; lung; BITC prior to
NNK
In vivo; lung (mouse, rat), liver and
nasal mucosa (rat); pretreatment with
BITC
In vivo; rat; liver; pretreatment with
BITC
In vitro; human bronchial epithehal
cell line
In vitro; mouse; lung, liver
Test system
[109]
[531
[111,112]
1531
V301
11251
[1271
1 NNK metabolism
1 NNK metabolism
+ DNA methylation at O6 of guanine
1 NNK metabolism
JUnscheduled and rephcative DNA synthesis

1 B(u)P-DNA binding
1 Deactivation pathways of B(a)P metabolism
(PEITC > BITC)
1 activation of B(a)P-7,Sdiol (BITC > PEITC)
1 NNK metabolism
1 DNA methylation at O6 of guanine in
lung, + liver
11091
11131
6
3.
11291
Cytotoxic effect of BITC to all the cell lines
1 Toxicity towards HT29 after detransformation of the cells
11091
$
[111,1121 8
2
PO51
;
sa
!-
1 NNK metabolism
+ DNA methylation at O6 of guanine
%
2
G!
$
v)
S
~
a
2
5.
jj
3
K
0
W81
+ Formation of DNA adducts
IJ
Refs
Effectd
NNK
NNK
NDMA
AITC
DDITC
Sulforaphane
NMAA
NNK
NNK
NNK
NNK
NNK
NNK
NNK
NNK
NNK
NNK
PPeITC
PHITC
PBITC
typhimurium
In vivo; mouse; liver, lung; PPeITC

prior to NNK
HT29
In vitro; Salmonella
In vitro: mouse; lung

mucosa (rat)
mucosa (rat)
In vivo; lung (mouse, rat), liver
and nasal mucosa (rat); pretreatment
with PBITC
In vivo; mouse, liver, lung; PBITC
prior to NNK
mucosa (rat)
mucosa (rat)
In vivo; mouse; liver, lung; PHITC
prior to NNK
In vivo; lung (rat, mouse), liver and
nasal mucosa (rat); pretreatment
with PHITC
In vivo; rat; liver, esophagus; pretreatment
with PHITC
[106]
[IlO]
[113]

1 DNA methylation (lung> nasal mucosa)
1 DNA methylation at O6 of guanine in lung,
-+ liver
1 NNK metabolism
I1311
[lo61
1891

1 Mutagenicity of NDMA
(1131
[II91
1 Toxicity towards HT29 after detransformation

of the cells
1 NMAA metabolism (liver > esophagus) 1 DNA

methylation at O6 and N of guanine in liver, +
esophagus
DNA methylation at O6 of guanine
[53]
[53]
11131
1 DNA methylation at O6 of guanine in lung,

-+ liver
1 NNK metabolism
]11]
]531
mucosa)
[lo91
1531
1 NNK metabolism
1 DNA methylation (lung>nasal
j. NNK metabolism
1 NNK metabolism
?
g
g,
$
OS
g
B
;E:
f
g
c,
z
!!?
9
NaN,
NMBA
Sulforaphane
PEITC, BITC,
PPITC, PBITC
I3C
NDMA
NDMA
AFB,
B(a)P, DMN, 2AA,

EMS, DBE
WV
B(a>P
13HlB(a)P
In vitro; mouse; liver
NDMA
Sulforaphane
In vivo; mouse; liver; 13C prior to NDMA

In vivo; mouse; liver; 13C prior to NDMA
In vivo; rainbow trout; liver; I3C prior to
and during AFB,
In vivo; rat; esophagus; testcompounds

prior to NMBA
In vitro; estrogen-responsive and
estrogen-nonresponsive human breast
cancer cells
In vitro; human bronchial epithelial cell
line
In ovo; chick embryo; liver; pretreatment
with 13C
In vivo; mouse; liver; 13C prior to B(a)P
In vitro; chick embryo hepatocytes cocultured with Chinese hamster cells
In vitro; Salmonella
typhimurium
Test systemc
Agentb
Compound/
vegetablea
Table 6 (continued)
1971
f Conversion of B(a)P into water-soluble

metabolites
J B(a)P-DNA binding
1 Number of SCEs induced by B(a)F and
DMN
+ number of SCEs induced by 2AA and
EMS
T number of SCES induced by DBE
1 NDMA-DNA binding
Act as scavenger for reactive electrophiles
1 AFB,-DNA binding
I381
11331
WV341
t37,3gl
t651
[1251
1571
11321
1891
El391
Refs
1 B(u)P-DNA binding
1 DNA methylation at O6 of guanine

(PEITC-PPITC > PBITC > BITC)
JGrowth of estrogen-responsive cells, little
effect on estrogen-nonresponsive cells
J Un~hedul~
DNA synthesis; when
NDMA was not added: unscheduled DNA
synthesis
+ Mutagenicity of NaN,
Effectd
B(a)P, DMN, 2AA,

EMS
B(a)P
13C, I3A
PhIP
PhlP
IQ
CCI,
DMBA
AFB,
AFB,
AFB,
AFB,
AFB,
13A
13c
In vivo; rat; colon, liver, mammary

gland; 13C prior to and during PhIP
In vivo; rainbow trout; liver;

I3C prior to and during AFB,
13C prior to, during and after
AFB,
In vitro; rainbow trout; liver
13C prior to AFB,
In vivo; rat; liver; 13C prior to
AFB,
In vitro; mouse mammary epithelial
cell line
In vitro, In vivo (13C prior to CCL,);
mouse; liver
In vivo; rat; colon, liver; 13C prior to
and during IQ
In vivo; rat; colon; 13C prior to and
during PhIP; 13C after PhIP; 13C
prior, during and after PhIP
binding
1 Number of SCEs induced by B(a)P;

+number of SCEs induced by DMN, 2AA
and EMS
1 number of SCEs
]I391
[70]
$
6
;
f
a
2.
2.
B
[I381
In vitro: 1 lipid peroxidation

in vivo: protection against hepatotoxicity
1 Number of total aberrant crypts in colon; 1
IQ-DNA adducts in liver
all 3 experiments: 1 aberrant crypt foci 13C
prior, during and after PhIP: t PhIP-DNA
adducts at 6 h, 1 at 24 h and 7 days after PhIP
treatment
1 PhIP-DNA adduct formation
CA
1981
1551
binding
binding
[135,136]
1 DNA repair synthesis
1 AFB,-DNA
+ AFB,-DNA binding
1 AFB,-DNA binding
-+ AFB, metabolism, 1 AFB,-DNA
1 AFB,-DNA
In vivo; rat; liver, lung; testcompounds before AFB,

In ovo; rainbow trout embryo;
coinjection
In vitro; in vivo (testcompounds
before CCL,); rat; liver
In vivo; rat; liver; testcompounds
before agents
AFB,
AFB,
AFB,
ccl,
NNK, NDMA
I3C, RXM
I3C, RXM, DIM
RXM, 01, DIM

I3C, DHII, THII
13C, I3A, indole,

BITC, AITC,
PEITC, PITC,
AFB,
Cabbage
[4451
1 AFB,-DNA
binding
[42]
P431
~421
I.341
11411
i391
WI
Refs
No scavenging of electrophiles
1 AFB,-DNA binding by RXM, not by 13C
J AFB,-DNA binding in lung when given p.o.,
not when given i.p.;
J AFB,-DNA binding by RXM and DIM, not
by 13C
1_AFB, activation and AFB,-DNA binding
In vitro: 1 lipid peroxidation (THII>DHIb~I3C)
in vivo: protection against hepatoxicity (THII >
DHII > 13C)
13C, 13A, indole, BITC: 1 NNK and NDMA
metabolism AITC, PEITC, PITC,
sinigrin: 1 NNK and NDMA metabolism PEITC,
PI-I-C,
sin&in: J, formation of 7-methylguanine and 06methylguanine
1 AFB,-DNA binding only by Brussels sprouts
Effectd
AITC, ally1 isothiocyanate; BITC, benzyl isothiocyanate; CTI, 5,6,1 1,12,17,18-hexahydrocyclononal[l,2-b;4,5-b;7,8-~]tri-indole

cyclic trimer of 13C
DDITC I-dodecyl isothiocyanate; DHII, 5,10-dihydroindeno[l,2-b]-indole;
DIM, 3,3-diindolylmethane, an acid condensation product of 13C; 13A,
indole-3-acetonitrile; 13C, indole-3-carbinol; PBITC, 4-phenylbutyl isothiocyanate; PEITC, 2-phenethyl isothiocyanate; PHITC, 6-phenylhexyl isothiocyanate; PITC, phenyl isothiocyanate; PPeITC, 5-phenylpentyl isothiocyanate; PPITC, 3-phenylpropyl isothiocyanate; RXM, indole-3-carbinol acid reaction
mixture (13C with HCI); THII, 4b,5,9b,lO-tetrahydroindeno[l,Zb]-indole.
b2AA, 2-aminoanthra~ne;
AAF, 2acetylamino~uorene; AFB,, aflatoxin B,; B(a)P, ~nzo(u)pyrene; CCI,, carbon tetradoride DBE dibromoethane DEN,
diethylnitrosamine; DMBA 9,lO-dimethyl-1,2-be~nthr~ne;
DMN, dimethylnitro~mine;
EMS, ethyl methanesulphonate:
IQ, 2-amino-3-methylimidazo]4,5-flquinoline; MAM, methy lazoxymethanol; NaN,, sodium azide; NDELA, N-nitrosodiethanolamine;
NDMA, N-nitrosodimethylamine; NMAA,
N-nitrosomethylamylamine;
NMBA, N-nitrosomethylbenzylamine;
NNK, 4-(N-nitrosome-thylamino)-l-(3-pyfldyl)-t-butanone;
NNN, N-nitrosonornicotine; NPYR, N-nitrosopyrrolidine; PhIP, 2-amino-l-methyl-6-phenylimid~o[4,5-~]pyridine.
When the testcompound is added before sacrifice, the test system is called in vivo.
1, increased; 1, decreased; -+ , no effect; >, greater effect; SCEs, sister ehromatid exchanges; i-p., intra~ritoneal; ~,a., per OS.
AFB,
I3C, Brussels sprouts
In vivo; rat; liver; testcompounds

before AFB,
In vivo; rat; liver; cabbage before
AFB,
AFB,
I3C, RXM
sinigrin
Test system
Agentb
Compound/
vegetablea
Table 6 (continued)
Hamster; PEITC before BOP
Mouse;
DEN
BOP
BOP
DEN
PEITC
before
and aftet
BOP
BGlP
Hamster;
before
Mouse; PEITC prior to and after
B(a)P
PEITC
Mouse; PEITC prior to B(a)P
BW
NMBA
NMBA
NNK
NNK
and multiplicity
1 Incidence and multiplicity

of lung adenomas
and/or adenocarcinomas,
1 pancreatic
tumorigenesis
1 Incidence and multiplicity
of lung and
pancreas tumors,
+ incidence of liver and
renal tumors
1 Yield of foci of altered hepatocytes
and
hepatocellular
adenomas
1 Esophagus
tumor incidence and multiplicity
when given before, during but not following
NMBA
1 Forestomach
tumor multiplicity,
-+ lung, +
skin
+ Lung tumor incidence and multiplicity
incidence
Rat; PEITC prior to and during

NNK treatment
Rat; PEITC prior to and during
NNK treatment
Rat; PEITC before and throughout
NNK reatment
Rat; PEITC prior to, during and
after NMBA
Rat; PEITC after NMBA or before,
during and after NMBA
NNK
tumor
Mouse; PEITC after NNK
NNK
1 Esophageal
1 Lung tumor incidence and multiplicity

1 Lung tumor multiplicity,
+ incidence
A/J mice: 1 lung tumors/mouse,
+ lung tumor
incidence other mice: 1 lung tumor incidence
and multiplicity
-+ % Mouse with lung tumors + no. lung
tumors/mouse
1 Lung tumor incidence,
-+ liver, -+ nasal
cavity
1 Lung tumor incidence, 1 progression
of
benign to malignant
pancreatic
tumors
1 Lung tumorigenesis
Mouse; PEITC prior to NNK

Mouse; PEITC prior to NNK
A/J mice, A/J x TSG-p53FI mice;
PEITC prior to NNK
PEITC
NNK
NNK
NNK
Agentb
Compound/
vegetable
Effect
indoles, and brassica vegetables
Test system
Table I
In vivo modulation of carcinogenicity of various agents by isothiocyanates,
U541
11531
]l521
11261
I1511
ll501
[120,121,132]
11491
Ll51
[111,114]
2
S
31
P
2
S
2
3.
a
!k
0
S
09
g
s!
,:
%
0
5
b
F
[l461
U471
H4gl
5:
[Ill-113,144,145]~
Refs
Rat; PEITC prior to DMBA

Mouse; PEITC together with DMBA
DMBA
DMBA
BITC
PITC
Rat; BITC prior to, during and after

NMBA
Rat; BITC before or after DMBA
Mouse; BITC together with DMBA

Rat, BITC after DMBA
Mouse, BITC after DMH
Mouse; BITC prior to DEN
Rat; BITC before and after DEN
Mouse; BITC together with B(a)P
Mouse; BITC prior to B(a)P
Mouse; BITC prior to B(a)P
NMBA
DMBA
DMBA
DMBA
DMH
DEN
DEN
B(a)P
B(c)P
B(a)P
NNK
NNK
Mouse; PITC prior to NNK

Rat; PEITC prior to DMBA
Mouse; implanted plasmacytoma
subcutaneous tumor; BITC after
implantation
Mouse; BITC prior to NNK
Mouse, BITC after NNK
NNK
DMBA

+ % Mouse with lung tumors
1 no. lung tumors/mouse
+ Esophagus tumor incidence and little
effect on multiplicity
Rat, BITC before DMBA: J mammary
tumor formation rat, BITC after DMBA:
inhibition was diminished
1 Formation of neoplasms of forestomach
and pulmonary adenomas
1 Occurrence of neoplasia of breast
1 Occurrence of neoplasia of large bowel
1 Forestomach tumor formation, --+
pulmonary tumor formation
1 Carcinogenesis of forestomach and lung
(lung > forestomach)
1 Carcinogenesis of forestomach and lung
(lung > forestomach)
1 Lung tumor multiplicity, + forestomach,
+ skin
+ Mammary tumor incidence and multiplicity

1 Mammary tumor formation
1 Formation of neoplasms of forestomach
and pulmonary adenomas
-+ Lung tumor incidence and multiplicity
-+ Tumor mass
Rat; PEITC before and after DMBA
DMBA
PEITC
Effect
Test system
Agentb
Compound/
vegetable
Table 7 (continued)
11511
115g1
[I591
11561
11571
11571
11581
11561
[I561
11321
[111,112,146]
11481
[111,112,146]
]1561
~1291
11561
11561
]1551
Refs
Hamster; PPITC prior to BOP
BOP
Rat; PHITC prior to NMBA

Mouse; PPeITC prior to NNK
Mouse; DDITC prior to NNK
Rat; testcompounds prior to and after
DMBA
NMBA
NNK
NNK
DMBA
PPeITC
DDITC
Sulforaphane, 3
synthetic analogs
NNK
NNK
NNK
NNK
OPBITC
PyBITC
PHITC
AOM
B@P
Mouse; PBITC prior to NNK

Rat; PBITC prior to, during and after
NMBA
Mouse; OPBITC prior to NNK
Mouse; PyBITC prior to NNK
Mouse; PHITC prior to NNK
Rat; PHITC before and throughout
NNK treatment
Mouse; PHITC prior to B(a)P
Rat; PHITC pre-, during and postinitation
NNK
NMBA
PBITC
BOP
Mouse; PPITC prior to NNK

Rat; PPITC prior to, during and after
NMBA
Hamster; PPITC prior to BOP
NNK
NMBA
prior to agents
PPITC
Mouse; testcompounds
B(a)P & NNK
BITC & PEITC
r Skin tumor multiplicity

t Incidence of intestinal adenocarcinomas
and multiplicities of invasive and noninvasive adenocarcinomas of the colon
T Esophagus tumor multiplicity
1 Mammary tumor incidence and multiplicity
--, Lung tumor incidence, 1 lung tumor

multiplicity, 1 stomach tumor incidence
and multiplicity
1 Esophagus tumor incidence and multiplicity
1 Incidence and multiplicity of lung
adenomas and/or adenocarcinomas, +
pancreatic umorigenesis
1 Incidence and multiplicity of lung
adenomas and/or adenocarcinomas; no
modulation of developments of neoplastic
lesions in pancreas, kidney or liver
+ Esophagus tumor incidence and little
effect on multiplicity
-P Lung tumor incidence
J Lung tumor incidence and multiplicity
1 Lung tumorigenesis
[I641
[I131
[IO61
[I651
[I511
[163,52]
[111,146]
[I131
[113,144,162]
U491
[111,113,146]
~321
P611
v521
[111,113,146]
v321
[I@1
Rat; I3C after agents
Rat; 13C before or after DEN
Rat; I3C prior to and after MNIJ

Rat; I3C only during initiation or also
during promotion phase
Rat; testcompounds prior to DMBA
DEN & MNU &

DBN
DEN
MNU
DMBA
DMBA
WN
AFB,
DEN
4NQ0
I3C, DIM, I3A

I3C, DIM, RXM
13C, sin&in
I3C, sinigrin
Mouse; testcompounds prior to B(u)P

In ovo, rainbow trout embryo; coinjection
Rat; testcompounds before, during and
after DEN
Rat, testcompounds before, during and
after 4NQ0, or only after 4NQ0
1 Occurrence of mammary tumors, not

by I3A
1 Occurrence of neoplasms of forestomach
1 Hepat~arcinog~esis
1 Liver tumor incidence and muitiplicity
(sinigrin > 13C)
1 Incidence of tongue neoplasms and of
preneoplastic lesions of the tongue
11671
Wgl
1 Liver tumor incidence

I3C before and during AFB,: 1 hepatocehuiar carcinomas I3C after AFB,: t
hepatic tumor incidence
t Tumorigenesis, f colonic and small
intestinal CanCer incidence
1 Hyperplastic nodules of the liver, 1
lung, + thyroid, -+ kidney, -+ urinary
bladder
13C before DEN: 1 number of GST-Ppositive liver cell foci, 13C after DEN: t
number of and area of GST-P-positivef
liver ceII foci
1 Mammary tumor multiplicity
1 Mammary tumor multipii~ity
AFB,
AFBi, or IEC
[I741
11721
II411
11731
II721
1g21
WI
11711
11701
II691
11361
1 Tumor incidence
Rat; I3C before, during and after DMH
W61
1 Development of papillomas; when I3C

was added to normal cells of the larynx
of mice, it abrogated prohfertive effects of
estradiol
1 Liver tumor incidence
11371
Refs
Effete
to and during
DMH
AFB,
AFB,
AFB,
to, during and
Rainbow trout; I3C prior

after AFB,
Rainbow trout; I3C prior
AFB,
Rainbow trout; I3C after
Rainbow trout; 13C after
before and during AFB,
Mouse; HPV-11 infected laryngeal tissue
Test system
AFB,
Agentb
13C, DIM, I3A
I3C
Compound/
vegetable*
Table 7 (continued)
Rat; cabbage together with AFB,

Mouse; cabbage together with DMH
Rat; cabbage after MNU
Mouse; cabbage before injection with cells
AFB,
AFB,
DMH
MNU
Mammary tumor
cells
Cauliflower
Cabbage
Cabbage
Cabbage
Cabbage
Rat; Brussels sprouts during initiation or

progression period
Rat; cauliflower together with AFB,
DMBA
1 Mammary tumor incidence, when given
during initiation period
Small localii
hepatic tumors instead of
very large ones & metastasis when treated
only with AFB,
1 No. of tumors/liver
1 Tumor frequency
1 Incidence of mammal cancer
1 No. of pulmonary metastases
WI
WY
I1781
1179)
[361
I1771
(175,176)
aBITC, benzyl isothiocyanate; DDITC, I-dodecyl isothiocyanate; DIM, 3,3-diindolylmethane, an acid condensation product of 13C; I3A, indole-3-acetonitrile; 13C, indole-3-carbinol; OPBITC, oxopyridylbutyl isothiocyanate; PBITC, phenylbutyl isothiocyanate; PEITC, 2-phenethyl isothiocyanate; PHITC,
~phenylhexyl isothiocyanate; PITC, phenyl isothio~yanate; PPeITC, S-phenylpentyl isothiocyanate; PPITC, 3-phe~yl~ropy1 isothiocyanate; PyBITC,
4-(3-pyridyl)butyl isothiocyanate; RXM, indole-3-carbinol acid reaction mixture (I3C with HCI).
bAFB,, aflatoxin B,; AOM, azoxymethane; B(a)P, benzo(u)pyrene; BOP, N-nitrosobis(2-oxopropyl)amine;
DBN, NJ-dibutyl
nitrosamine; DEN, N-t&
tro~d~ethylamine; DMBA, 7,12dimethy~~nz(u)anthra~ne;
DMH, symmetri~ai l,Z-dimethylhydrazine dihydr~hloride;
MNU, ~-methylnitrosoure~;
NMBA, ~-nitrosomethyl~nzylamine;
NNK, 4-(N-nitrosome-thylamino)-l-(3-pyridyl)-l-butanone;
4NQ0, 4-njtroquinol~ne l-oxide.
5, increased; 1, decreased; -t , no effect; no., number; >, greater effect.
dAlso isothiocyanates with larger alkyd chain length or secondary isothioeyanates showed to reduce tumor incidence and multiplicity (secondary>primary,
larger chain >shorter chain).
3 analogs are ego-2-acetyl-ego-6-isothiocyanatonorbo~ane,
e~~o-2-acetyi-e~~-6-isothi~yanatonorbomane
ego-2-a~tyl-e~o~5-isothi~yanatonorbornane,
GST-P, ~lutathione 5-transferase placental form.
Rat, vegetables after DMBA
DMBA
Cabbage,
cauliflower,
broccoli
Brussels sprouts
;;
tw
2
8
,u
;;:
ij
2,
$
Y
g
@_
W
110
D.T.N. Verhoeven et ai. / Chemico-BiologicalInferactions 103 (1997) 79-129
g watercress, a eruciferous vegetable, at each meal for 3 days, an increase in the

urinary excretion of detoxification metabolites of NNK was found [196]. In a study
of Caporaso et al. [SS], no inhibition of P450 2D6 activity was found in males and
females after consumption of 50 g watercress. When PEITC, a constituent of
watercress, was added in vitro to human liver microsomes, an inhibition of P450
2D6 activity was shown [88].
4.3. ~~scuss~o~ on anticarc~nogen~c action
Isothiocyanates, indoles and brassica vegetables have been shown to modulate
phase 1 and phase 2 enzyme activities. The induction of phase 1 enzymes can result
in inhibition of activation of compounds, but also in bioactivation of compounds.
When phase 2 enzymes are induced besides phase 1 enzymes, the activated
compounds can be detoxified.
Yu et al. [197] suggest that c-Jun N-terminal kinase 1 (JNKI) is involved in the
regulation of phase 2 detoxifying enzyme gene expression. When added to human
ovarian HeLa cells in vitro, PEITC caused a sustained activation of JNKl. Phenyl
isothiocyanate, phenylmethyl isothiocyanate,
Sphenylpentyl
isothiocyanate and
6-phenylhexyl isothiocyanate were weak inducers of JNKl activity, whereas 3phenylpropyl isothiocyanate and 4-phenylbutyl isothiocyanate stimulated transient
activation [ 1971.
Indoles, unlike isothiocyanates, induce the phase I enzyme estradioi 2-hydroxylase. This leads to the biotransformation of estradiol to 2-hydroxyestrone which has
a minimal estrogenic activity [61]. Liu et al. 1781showed that induction of estradiol
meta~lism was not required for the antiestro~nic activity of 13C and indoIq3,2blcarbazole (ICZ). In this study ICZ was also found to be a weak estrogen which
binds to the estrogen receptor. Jongen et al. [97] have found that modulating effects
of indoles are not directly related to induction of phase 1 enzymes, but to a shift in
the balance between phase 1 and phase 2 enzymes in favour of phase 2 enzymes.
The anticarcinogenic actions of the glucosinolate hydrolysis products and brassicas depend on the experimental conditions. Of importance are among others the
test system and the target tissue. It was shown that different test systems produced
different results and the modulation of enzyme activities, mutagenicity and carcinogenicity of compounds differed among tissues. Also of importance is the kind of
carcinogenic/mutagenic
agent that is used. Isothiocyanates were inhibitors of the
activation and DNA-binding of ~-nitrosamines, but seemed to have no effect on
the formation of ~nzo(a)pyrene-DNA
adducts.
The time interval between uptake of the anticarcinogenic compound and carcinogen exposure is also of importance for inhibition of tumor formation. Inhibition
would only occur when this time interval is short [122,123,144,156]. Preinitiation
exposure to indoles seems to reduce the carcinogen challenge, but postinitiation
exposure seems to enhance the effect of carcinogens f167,168].
Furthe~ore,
the anticarcinogenic action depends on the kind of anticarcinogenic
compound. In a recent study of Jiao et al. [106], it was found that the isothiocyanate functional group is essential for the inhibitory effects of isothiocyanates in
11841
U851
t2-Hydroxy-estrone:estriol
ratio
1 Levels of I-oxodG (oxidative DNA
damage)
1 Plasma GST-a levels
1 Plasma half-life of antipyrine,
t metabolic clearance rate of antipyrine
1 phenacetin plasma concentration,
+ plasma half-life of phenacetin
7 Plasma GST-a levels in males,
+ plasma GST-n levels
+ GST activity,
r rectal GST-a and -x levels
t 2-Hydroxyestrone/l6a-hydroxyestrone
ratio
+ 6-hydroxychlorzoxazone: chlorzoxazoneratio (P450 2El not affected);
7 caffeine metabolic ratio (P450 IA2 affected); f2-hydroxyestrone/l6a-hydroxyestrone ratio
t P450 IA2 activity, + IV-acetyltransferase
and xanthine oxidase activity
Males
Males &
females
Males &
females
Males &
females
Females
Males &
females
Males &
females
300 g per day for 3 weeks

300 g and 200 g respectively per
day for 7 days
300 g per day for 7 days
380-400 g per day for 5 days
500 g per day for IO days
Brussels sprouts
Brussels sprouts & cabbage
Brussels sprouts
Brussels sprouts
Mix of Brussels sprouts, cabbage,

broccoli and cauliflower
Broccoli
Broccoli
13C, indole-3-carbinol.
bT, increased; 1. decreased; + , no effect; GST. Glutathione-S-transferase;
I3C
Brussels sprouts
R-oxodG, 8-oxo-7,8-dihydro-2-deoxyguanosine.
[I831
t Estradiol 2-hydroxylation
Males &
females
Females
Males
[192,193]
u911
u901
11891
[1881
[1861
[If371
11821
r Estradiol 2-hydroxylation
Males
500 mg (6-7 mg/kg) per day for

I week
500 mg (6-7 mg/kg) per day for
1 week
400 mg per day for 3 months
300 g per day for 3 weeks
I3C
I3C
Refs
Effectb
Subjects
Dose and duration
Compound/vegetable
Table 8
Effects of indoles and brassicd vegetables given to humans
NNK-induced lung tumori~enes~s. In experiments using various arylalkyl isothiocyanates, i.e. isothio~yanates with an aromatic side chain like PEITC, it was found
that the inhibitory activity of these isothiocyanates against tumorigenesis was
increased with alkyl chain length [53,109--113,146). It is suggested that isothiocyanates can bind to the active sites of certain phase 1 enzymes which is governed
largely by lipophilicity and results in competitive inhibition or covalent inactivation
of these enzymes [145]. Although the difference in inhibitory activity is accurate
with respect to NNK car~inogenesis in A/J mouse lung, it is not found for NMBA
car~inogenesis in the rat esophagus. PEXTC was found to be a potent inhibitor of
NMBA ~~c~nogenesis in the rat esophagus ]120,121], but the longer chain isothiocyanate, 4-phe~ylbu~yl isothio~yanate (PB~TC~, was found to be less effective than
PEITC [132], and 4-phe~ylhexyl isot~oc~anate (PHITC) actually enhanced NMBA
t~origenesis
in the rat esophagus [164]. In addition, PHITC enhanced
a~oxymethane carcinogenesis in the rat colon ]52].
Most studies on indoles examined the anticarcinogenic effect of 13C. Some
studies also examined the effect of synthetic indole compounds or acid condensation products of 13C. It is concluded that synthetic indole compounds seem to have
a greater potential as chemoprotective agents than 13C, because of an observed
dose-dependent intrinsic toxicity of 13C [34,35]. Besides, the in vivo effects of 13C
may be attributed to indole acid condensation products, such as DIM and XCZ, but
not to 13C itself [62,64,71,75,76,141,198]. The formation of acid ~~densation
products in the stomach is a likely prerequisite for I3C anticarcinogen~is.
ICZ is
also the most important product of ascorbigen ~ransfo~ation
in gastric juice.
Some of the cancer-modulating activities of ascorbigen may be due to IGZ 1191.
In comparison to the number of studies using indoles and isothio~yanates the
number of studies using whole brassica vegetables is small. The anticarcinogenic
effects of the individual compounds may be different from the effect of brassicas,
because of possible interactions between compounds of the vegetables. The animal
studies on brassicas were carried out with freeze-dried or cooked vegetables.
Human studies were carried out with lightly steamed or cooked vegetables. Processing vegetables leads to a certain degree of glucosinolate hydrolysis by myrosinase
hydrolysis or other chemical reactions. By cooking the vegetables myrosi~se is
inactivated and loss of intact glu~sinolates occurs because of thermal degradation
and wash out 1181, In studies using whole bras&a vegetables, it was found that
these vegetables affected phase I and phase 2 enzyme activities, decreased AFBlDNA binding and decreased tumor formation.
Most evidence concerning anticar~inogenic effects of glucosinolate hydrolysis
products and brassica vegetables results from in vivo studies in animals. In animal
studies differences between species are found which makes it difficult to extrapolate
the results to humans. Schulze et al. [199] found differences between species in both
the extent of total metabolism of NNK (hamsters > mice > rats) and the metabolite
composition. The dose of both the anticarcinogenic and the carcinogenic compound
used in animal studies is usually much higher than those to which man is exposed
via a normal diet. In a study of Kore et al. f32] no signi~~~t induction of phase
I and phase 2 enzymes were detected when 3-metb~lsul~~ylpropyl isothiocy~ate
was tested at doses approximate to those found in human diet. However, isothiocyanates, indoles and brassicas may have beneficial effects. At high but realistic
consumption levels, indoles and brassicas did show positive effects on health in
human studies [182- 1911. This seems to be in accordance with epidemiological
studies that showed a negative association between consumption of brassica vegetables and cancer risk [200].
5. Adverse effects of glucosinolate hydrolysis products and brassicas

The putative beneficial properties of glucosinolate hydrolysis products and
brassicas are the main focus of this review. Beside beneficial effects, brassicas,
glucosinolates and their hydrolysis products have also shown some adverse effects.
Therefore, their possible mutagenicity, carcinogenicity, toxicity and goitrogenicity
are described in short.
5.1. Possible mutagenicity and carcinogenicity
Besides anticarcinogenic properties a few isothiocyanates and indoles showed

mutagenic and carcinogenic properties in some studies (Table 9). According to
McDanell et al. [17] a possible hazard from indoles is an ability to react with
nitrites to form carcinogenic 1V-nitroso compounds. Tiedink et al. 12061found that
brassica vegetables contain precursors of N-nitroso compounds, but that glucosinolates and indole compounds should not be considered as important precursors of
directly mutagenic N-nitroso compounds in brassicas [212,213]. 13A, when tested
pure, formed directly mutagenic N-nitroso compounds upon nitrite treatment,
while in green cabbage it contributed only marginally to the total mutagenicity of
the nitrite treated cabbage [212].
5.2. Toxicity
In various studies the toxicity of glucosinolates and their hydrolysis products are
described. In a study of Morse et al. PEITC and benzyl isothiocya~te
(BITC)
decreased food consumption and body weight gain in mice [14X]. In rats, BITC
caused a decrease in food consumption and body weight gain, an increase in serum
cholesterol level, renal dysfunction and changes in weights of various organs [214].
In mice, 5, IO-dihydroindenol[ l,Zb]indole (a synthetic indole) produced no observable 24 h acute toxicity, but I3C elicited hepatotoxicity, demonstrated by increases
in plasma alanine aminotransferase and ornithine transcarbamylase activities, and
13C produced increases in neurological impairment [35]. In a study of Nishie and
Daxenbichler [215] the toxicological effects of epiprogoitrin, sinigrin and sinalbin
(cruciferous glucosinolates) and nine of their derivatives (isothiocyanates, nitriles,
R-Svinyl-2-oxazolidinethione)
were examined in the rat. None of the compounds
proved teratogenic, but ally1 isothiocyanate, 3-methylsulfinylpropyl isothiocyanate
and 1-cyano-3,4-epithiobutane
were embryotoxic. High intake of rapeseed glucosi-
vitro
Ascorbigen
I-~ethyI~rbigen
Cauliflower, Brussels sprouts, cabbage,
broccoli, kohlrabi, Swede
TAlOO
TAlOO
TAIOO
TA98, TAlOO
TAIOO
TA98, TAlOO,
AITC, BITC, sinigrin

AITC, BITC, MITC, PEITC
AITC
AITC
Sulforaphane
I3C, 13A, 13-acetamide, 13-acetic acid,
3-methyhndole,
13-akdehyde, 13-carboxyhc acid, indole
WP2 uvrA/pKMlOi &
treated with nitrite at
PH 3
TA98, TAlOO
TA98, TAlOO
TAlOO
Strain?
indoles, and cruciferae
Substratea
Gene mutations in bacteria (Ames test)
1. In
Table 9
Mutagenicity and carcinogenicity of isothiocyanates,
-act
Results
-+
+
-+
3
+d
-+
+ act
PO51
PW
PO61
~1241
PO21
12031
WI
w41
PO11
Ref
uvrB/recA, uvr+/rec+
AITC, BITC, MITC, PEITC
AITC
Substrate
-..-~-
Chinese hamster epithelial cells

Human fibroblasts
Test system
----
. _.. .._
.._--_-... .
Chinese hamster ovary cells

Chinese hamster epithelial cells
Indian muntjac cells
Human hepatma cells
Sinigrin, gluconasturtin
BITC
AITC
AITC, BITC, PEITC, PITC
AITC, EITC, PEITC, MITC
Ascorbigen
I-methylascorbigen
._
AITC, PEITC
Neoplastic transformation of cultured mammalian cells
-_^_I_____~
Test systems
AITC, BITC, PEITC
Substratea
Chromosome mutations in cultured mammalian cells
Strainsb
Substratea
DNA repair in bacteria
by AITC
SCEs
SCEs, nor
SCEs, not
--~-
. ._~
Neoplastic transformation
No neoplastic transformation
Results, -cat
-+ CA and SCEs
-+ CA, t SCEs at highly
cytotoxic doses
1 CA and
by AITC
f CA and
by AITC
t CA
t CA and
T CA
7 CA, not
-act
-act
_-
TMN
T CA
+ act
+ act
[IlO]
WfI
P-051
w41
w91
Wgl
12031
w71
12071
11241
Ref
~1241
Ref
_--.-.
--
T Transitional-cell papillomas of the

urinary bladder in male rats only
No tumor induction
1 Mammary tumor incidence and
multiplicity
I Incidence of endometrial and uterine adenocarcinoma, I Incidence of
mammary fibroadenoma, 1
Frequency of preneoplastic endometrial lesions
2 year assay, rat

2 year assay, mouse
8 months assay, mouse
660 days assay, rat
AITC
13C
13c
Ref
AITC, ally1 isothiocyanate; BITC, benzyl isothiocyanate; 13-, indole-3-; 13A, indole-3-acetonitrile; I3C, indole-3-carbinol; MITC, methyl isothiocyanate;
PEITC, phenetbyl isothiocyanate; PITC, phenyl isothiocyanate.
bSaimonella typ~~murium strains TA98, TABOO;Es~herichja coli WP2 uvrA/pKMlOl, uvrB/recA, uvr+jrec+.
-act, without metabolic activation; fact, with metabolic activation; + , positive; -, negative, -+, no effect; 1, increased; 1, decreased.
dhigh concentration of metabofising system suppressed mutagenicity.
addition of metabohsing system reduced effect.
after treatment with nitrite under acid conditions.
GA, chromosome aberrations; SCEs, sister chromatid exchanges; MN, micronucleus.
ResuhsC
.--.
Test system
vivo
Substratea
2. In
Table 9 (continued)
nolates or their hydrolysis products resulted in growth decrease [216] and liver
enlargement 12171 in animals. When a rapeseed glucosinolate~rich diet was fed to
growing rats liver and kidneys weights increased, and feed intake and growth curve
depleted [ZIS]. When rats were fed diets with a high content of Brussels sprouts,
growth depression and decreased food intake, decreased haemoglobin levels, increased prothrombin times, and an increase in relative kidney and liver weight
occurred [l-5]. No toxic effects were found when humans were given a diet with a
high but realistic content of Brussels sprouts 12193.
From these studies it can be concluded that consumption of glucosinoIates and
their hydrolysis products can result in toxic effects. However, no toxic effects on
humans have been identified so far and the doses used in the animal studies exceed
the normal human daily consumption by far.
5.3. Goitrogenicity
Brassica vegetables have a goitrogenic potential [7,17]. The goitrogenic effects
have been ascribed to hydrolysis products of glucosinolates, in particular thiocyanate ion and 5-vinyloxazolidine-2~thione
(goitrin). The mechanism of goitrogenicity seems to be different between thiocyanate ion and goitrin. The thiocyanate
ion would compete with iodine for uptake by the thyroid gland. Thus, its goitrogenicity depends upon the iodine content of the diet. Coitrin would interfere with
thyroid hormone synthesis and would therefore be goitrogenic irrespective of the
iodine status.
In several studies goitrogenicity of rapeseed glucosinolates was examined [2 171. In
animals, inhibition of thyroid hormone synthesis, thyroid hy~rtrophy
and goitre
occurred, depending upon the dose of rapeseed glucosinolates tested and the
animals used. In swine, reacting strongly to the goitrogenic activity of rapeseed
glucosinolates [217], this is particularly a problem since rapeseed contributes largely
to their food intake. Feeding a diet with a high content of Brussels sprouts to rats
resulted in decreased levels of circulating thyroxin and in an increase of morphological thyroid activation [15]. In human, no effect of a high but realistic intake of
Brussels sprouts on the thyroid function was found [219,220].
There is now much evidence to suggest that brassica vegetables possess anticarcinogenic properties. Components of brassicas possibly responsible for these properties are glucosinolates. Myrosinase-catalysed
transfo~ation
of glucosinolates
seems necessary for the anticarcinogenic effects, thereby releasing isothiocyanates
or indoles as the active principles. Isothiocyanates and indoles influence several
processes related to chemical carcinogenesis, e.g. the activity of phase 1 and phase
2 biotransformation
enzymes, and the metabolism, DNA-binding and mutagenic
activity of promutagens. Hence, a possible inhibitory activity of isothiocyanates and
indoles against tumo~genesis appears to stem mainly from their ability to influence
118
D.T.H.
Verhoeven et al. / Chemico-Biological Interactions IO3 (1997) 79-129
phase 1 and phase 2 biotransformation enzyme activities. It should be emphasized

that their protective action seems to depend upon many factors, such as the test
system, the target tissue, the type of carcinogen challenge and anticarcinogenic
compound, the doses, as well as the timing of the treatment. In contrast to their
presumed protective action, some isothiocyanates showed mutagenic potential in
mammalian cells and bacteria.
Most evidence concerning anticarcinogenic effects of glucosinolate hydrolysis
products and brassica vegetables has come from studies in animals. Because of
inter-species differences, and since the dose of both the anticarcinogenic and the
carcinogenic compound used in animal studies often greatly exceeds the estimated
level of the compound in a normal human diet, it is difficult to extrapolate results
from animal studies to humans. Therefore, more studies are required in which
normal consumption levels are used to find out whether the glucosinolate hydrolysis
products and brassica vegetables also exert their protective effects in humans.
Besides examining the effects of the individual compounds, studies should examine
the effects of glucosinolates and their hydrolysis products in their normal matrix,
because of possible interactions between vegetable compounds.
Acknowledgements
The authors thank J. Bogaards for his comments on this manuscript.
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Chemico-Biological Interactions Volume 103 Issue 2 1997 (Doi 10.1016/s0009-2797 (96) 03745-3) Dorette T.H. Verhoeven Hans Verhagen R.alexandra Goldbohm Pie - A Review of Mechanisms Underlying

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Chemico-Biological Interactions Volume 103 Issue 2 1997 (Doi 10.1016/s0009-2797 (96) 03745-3) Dorette T.H. Verhoeven Hans Verhagen R.alexandra Goldbohm Pie - A Review of Mechanisms Underlying

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ELSEVIER

A review of mechanisms underlying

Brassica vegetables; Glucosinolates;

* Corresponding author. Tel.: + 31 30 6944755: fax: -i- 31 30 6957952.

Verhoeven et al. 1 Chemico-Biological Interactions 103 (1997) 79-129

2. Occurrence and intake of glucosinolates

turnip. Detailed information on the consumption of brass&as is not readily

3. Chemistry of gluc~inolates and their hy~olysis products

138-2083 [13], 530-1140 [16], 122 [14]

597-2542 114, 1628 [IS]

Level of total glucosinolates in cooked

392-1657 [13], 260 [lo]

669 [13], 410-1090 [IO]

Level of total glucosinolates in unprocessed

Verhoeven et al. / Ch~~i~~-%~o~o~i~alInteru~ti~tls IO.? [i997] 19-i-79

Glucosinolate hydrolysis products make a significant contribution to the typical

qf glucosinoiate composition und content

The analysis methods for determining glucosinolate composition and content

Myrosinase hydrolysis products

Reproduced with permission from De Vos and Blijleven [18].

Side chain (R) =

Verhoeuw et al. / ~hemico-Biol~gi~ul I~ter~~ti~~ 103 (1997) 79-129

these compounds. rsothiocyanates and nitriles can be analyzed by GLC. HPLC

4. Putative beneficial properties of glucosinolate hydrolysis products and brassicas

I3C, I3A, DIM, ascorbigen,

BylITC, BITC, ButITC, PPITC

indoles and brassica vegetables

t Small intestine (Brussels sprouts>

] Liver, when compounds were given p.o.

+ Liver, + small intestine

Brussels sprouts, cabbage,

1 Liver, 1 nasal mucosa, --$ lung

t Liver, but only weak and transient

t Liver, only by 13C (given p.o. z

1 Small intestine, not by 13A

Brussels sprouts, cabbage,

Sin&in, progoitrin, glucobrassicin, glu~otropaeolin

t Small intestine, only by ~lucobr~sici~,

In vitro, Hepa lclc7

13C, NI3C, NCHO, DIM,

13C, I3A, DIM, 13CHO

In vivo. rainbow trout

13C, 13A, DIM, ascorbigen

I3C, I3-ethanol, 13-aldehyde,

In vitro, human P450 IA2

P450 IAI, I450 IA2

1 Liver, -+ lung, $ nasal mucosd

1 Small intestine, -+ large intestine,

__t (Small intestine z large intestine > liver)

P450 3A2, P450 4Al

T Liver, T small intestine

I Liver, 1 small intestine, t

BITC, PEITC, PBITC,

indoles and brassica vegetables

T Liver, -+ lung, -+ nasal mucosa

BITC, PEITC, PBITC,

1 Liver & intestine only by Brussels

t Liver, t small intestine

AITC, goitrin, Brussels

In vitro, Hepa lcIc7 murine

In vitro, Hepa lclc7 murine

Erucin: I (smati intestine > Iiver >

t Liver, 7 forestomach, t gIanduIar

Verhoeven et al. / Chi-%~o~o~i~alInteru~ti~tls IO.? [i997] 19-i-79

Verhoeuw et al. / ~hemico-Biol~gi~ul I~terti 103 (1997) 79-129