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University of Minnesota Cancer Center, Minneapolis, MN 55455
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONChemoprevention of NNK-induced...Effects of watercress on...Approaches to chemoprevention of...CONCLUSIONSREFERENCES |
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KEY WORDS: • chemoprevention • phenethyl isothiocyanate • 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone • isothiocyanates • watercress
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONChemoprevention of NNK-induced...Effects of watercress on...Approaches to chemoprevention of...CONCLUSIONSREFERENCES |
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). When the vegetable is
chewed or otherwise damaged, the enzyme myrosinase is released from a
separate cellular compartment and hydrolyzes the
glucosinolate-producing isothiocyanates, as well as other products.
Substantial amounts of glucosinolates occur in a wide variety of
vegetables, and their occurrence has been extensively reviewed (Fenwick et al. 1989
, Tookey et al. 1980
). Consumption of average portions of
appropriate vegetables can result in the release of tens of milligrams
of isothiocyanates. For example, a minimum of ~12 mg of phenethyl
isothiocyanate
(PEITC)3
is released when 2 oz (56.8 g) of watercress is consumed (Chung et al. 1992
, Hecht et al. 1995
). The remarkable ability of some isothiocyanates to prevent cancer in laboratory animals treated with carcinogens stems from their favorable effects on carcinogen metabolism. Virtually all dietary or environmental carcinogens to which humans are exposed require enzymatic transformation to exert their carcinogenic effects. The most common enzymatic process is through the addition of oxygen, catalyzed by cytochrome P450 enzymes. This generally makes the molecule more polar and consequently more readily excreted. This type of transformation is referred to as Phase 1 metabolism. Some of the intermediates formed in this process may be electrophiles, which can react with nucleophilic sites in critical macromolecules such as DNA, RNA and protein. Reaction with these macromolecules results in covalent binding products called adducts. DNA adducts that persist unrepaired can cause miscoding and thus produce mutations in critical genes such as oncogenes and tumor suppressor genes. The conversion of a carcinogen to a macromolecular adduct via metabolism is termed metabolic activation. Competing with metabolic activation is detoxification. Some of the Phase 1 metabolites are detoxified because the addition of oxygen renders them less reactive toward macromolecules than the parent carcinogen. A second group of enzymes known as Phase 2 enzymes and typified by glutathione-S-transferases, UDP-glucuronosyl transferases and sulfotransferases adds polar moieties to the oxygenated carcinogen, generally producing highly polar molecules that are readily excreted.
Blocking carcinogen metabolic activation and enhancing carcinogen
detoxification are two ways to decrease carcinogenicity. Many
isothiocyanates have one type of activity or the other, and some have
both. A large amount of data is available and no attempt will be made
to review it here; some of these data have been discussed in reviews
(Smith and Yang 1994
, Yang et al. 1994
, Zhang and Talalay 1994
). In
summary, some isothiocyanates are reasonably selective inhibitors of
specific cytochrome P450 enzymes in rodent tissues, depending on the
conditions employed. Numerous isothiocyanates are also potent inducers
of Phase 2 detoxification enzymes such as glutathione-S-transferases
and NAD(P)H:(quinone acceptor) oxidoreductase. The specific effects of
a particular isothiocyanate on the metabolism of a given carcinogen
must be determined individually. This will be discussed further, with
PEITC and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) as
examples. A large body of data is available, which clearly demonstrates
that isothiocyanates are effective inhibitors of carcinogenesis. Some
data on inhibition of carcinogenesis by isothiocyanates are summarized
in Table 1
.
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are effective inhibitors
of carcinogenesis, although there are some cases for which no effect or
even enhancement is observed. Some of the effective compounds are
remarkably potent. For example, single doses of 0.1 µmol
6-phenylhexyl isothiocyanate (PHITC) and some related lipophilic
isothiocyanates inhibit lung tumorigenesis in the A/J mouse induced by
a subsequent single dose of 10 µmol NNK (Jiao et al. 1994
). As
illustrated in Table 1
, both naturally occurring isothiocyanates such
as benzyl isothiocyanate (BITC), PEITC and sulforaphane
[CH3S(O)(CH2)4N=C=S] and
synthetic compounds have shown good activity. Although some
isothiocyanates such as 
-naphthyl isothiocyanate would clearly be
precluded as chemopreventive agents because of their toxicity, many,
such as PEITC, show outstanding chemopreventive activity without any
apparent toxicity in rodents. Most isothiocyanates tested to date
inhibit cancer when administered before or during carcinogen treatment,
but not when given subsequent to carcinogen treatment. One exception is
BITC, which inhibits mammary tumorigenesis in rats when given
subsequent to 7,12-dimethylbenz[a]anthracene (DMBA). In
one case, PHITC enhanced colon tumorigenesis induced by azoxymethane,
when given during and subsequent to carcinogen treatment (Rao et al. 1995
). The effects of isothiocyanates as chemopreventive agents can be
remarkably specific. For example, BITC inhibits lung tumor induction by
benzo[a]pyrene (BaP) in A/J mice, but PEITC has no effect
when tested in the same protocol (Lin et al. 1993
, Wattenberg 1987
). In
contrast PEITC, but not BITC, is a strong inhibitor of lung
tumorigenesis in the A/J mouse induced by NNK and of esophageal
tumorigenesis in rats induced by N-nitrosobenzylmethylamine
(NBMA) (Morse et al. 1989a, 1989b, 1991 and 1992
, Wilkinson et al. 1995
). PHITC is a strong inhibitor of lung tumorigenesis in NNK-treated
A/J mice as noted above, but enhances esophageal tumorigenesis in
NBMA-treated rats (Jiao et al. 1994
, Morse et al. 1991
, Stoner et al. 1995
). These specific effects are most likely due to interactions of
the isothiocyanates with specific enzymes involved in carcinogen
activation and detoxification. In general, however, the inhibitory
activities of isothiocyanates administered before or during carcinogen
treatment can be attributed to the favorable effects on carcinogen
metabolism noted above. |
Chemoprevention of NNK-induced lung tumorigenesis by PEITC. |
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TOPABSTRACTINTRODUCTIONChemoprevention of NNK-induced...Effects of watercress on...Approaches to chemoprevention of...CONCLUSIONSREFERENCES |
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).
Approximately 87% of lung cancer deaths are attributable to cigarette
smoking (American Cancer Society 1996
). Thus, smoking cessation is the
best way to prevent lung cancer. However, smoking cessation has not
been uniformly successful, and there are ~48,000,000 smokers in the
United States, many of whom may be addicted to nicotine. For the
addicted smoker who cannot quit, even after having tried smoking
cessation programs using nicotine replacement therapy, chemoprevention
may be a feasible way to lengthen life and avoid lung cancer. Our
approach to chemoprevention of lung cancer is based on an understanding
of the carcinogens present in tobacco smoke. Currently, available
evidence strongly favors NNK and polynuclear aromatic hydrocarbons
(PAH), typified by BaP, as the major lung carcinogens in tobacco smoke
(Hecht 1996a
, Hoffmann and Hecht 1990
). This is based on the presence
of these compounds in tobacco smoke, their potent pulmonary
carcinogenicities in rodents, on biochemical studies that demonstrate
that they can be metabolically activated by human tissues, on the
detection of their DNA adducts in human lung and on mutations in
ras and p53 genes isolated from lung tumors. Although other
agents in tobacco smoke such as free radicals, nitrogen oxides and
aldehydes may also damage pulmonary DNA in smokers, the evidence that
relevant doses of such compounds can cause lung cancer in rodents is
weak. Our strategy for chemoprevention of lung cancer can be summarized
in Figure 1
.The metabolic activation of NNK and PAH leads to DNA adducts that can
cause miscoding when they persist unrepaired. The resultant mutations
in critical genes such as ras and p53 are critical in the
induction of lung cancer. It is now believed that multiple critical
mutations are required to convert a normal cell to a cancer cell. These
multiple mutations can be caused by metabolically activated tobacco
smoke carcinogens to which smokers are exposed on a daily basis. Thus,
by blocking the metabolic activation process or enhancing
detoxification at any point during the induction of these multiple
changes, the process can be slowed or halted. We are investigating the
use of isothiocyanates and other agents to block the metabolic
activation process. Inhibition of NNK metabolic activation and
tumorigenesis by PEITC will be described as an example of this
strategy.
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(Hecht 1996b
). In rodents and humans, NNK is extensively converted
to its carbonyl reduction product 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), which is a potent
pulmonary carcinogen in rats and mice. NNAL in turn can undergo
glucuronidation to two diastereomers of NNAL-Gluc that are excreted in
rodent and human urine and are believed to be detoxification products
of NNK. NNK and NNAL also undergo pyridine-N-oxidation,
another detoxification pathway. The metabolic activation of NNK and
NNAL proceeds by hydroxylation of the carbons next to the nitroso group
(-hydroxylation). This gives rise to diazohydroxide intermediates
(4 and 5 in Fig. 2
), which bind to DNA. The
resulting adducts are mutagenic and cause G-A and G-T mutations.
|
). PEITC was selected
as a potential inhibitor of NNK carcinogenesis. Studies in rats and
mice (summarized in Table 1
) have clearly demonstrated that PEITC is an
effective inhibitor of lung tumorigenesis induced by NNK. In a recent
study conducted in rats (Hecht et al. 1996b
), complete inhibition of
NNK-induced lung adenomas and adenocarcinomas was observed when PEITC
was added to the diet for 112 wk at a dose of 3 µmol/g diet (489 ppm)
in conjunction with NNK in the drinking water for 111 wk at a dose of 2
ppm. No toxic effects of PEITC were noted. At intervals during this
study, blood samples from NNK-treated rats were analyzed for hemoglobin
adducts, a biomarker of the metabolic activation of NNK. A consistent
inhibition of NNK metabolic activation by the pathway involving
intermediate 5 of Figure 2
was observed. Moreover, analysis
of the urine of these rats at intervals during the bioassay
demonstrated that there was a four- to sixfold increase in levels of
excreted NNAL plus NNAL-Gluc, consistent with inhibition of the
metabolic activation pathway (Hecht et al. 1996b
). In other studies, we
have shown that PEITC inhibits the metabolic activation of NNK in the
rat lung and inhibits oxidative metabolism in several other tissues,
under the conditions employed for inhibition of tumorigenesis by NNK
(Staretz and Hecht 1995
). We have demonstrated that the inhibition of
NNK-induced lung tumorigenesis does not result from a redistribution of
NNK and its metabolites. These results are consistent with other data
that demonstrate that administration of PEITC causes a persistent
inhibition of NNK metabolic activation in the rat lung and in vitro
data that demonstrate that PEITC is a selective inhibitor of certain
P450 enzymes in rat liver and lung, acting by a competitive mechanism
as well as by covalent inactivation (Guo et al. 1992 and 1993
).
IC50 values for PEITC in rat lung are in the range of
120–210 nmol/L for NNK oxidation, and its concentrations in the lung
have been estimated to be in the micromolar range under conditions used
for examining its ability to inhibit P450 activities (Guo et al. 1992
).
PEITC has limited effects on Phase 2 enzymes in rats (Guo et al. 1992
).
Collectively, the available data strongly indicate that PEITC inhibits
NNK-induced lung carcinogenesis in rats by inhibiting the metabolic
activation of NNK via pulmonary cytochrome P450 enzyme(s), although the
specific P450 enzyme(s) responsible has not been fully defined. |
Effects of watercress on NNK metabolism in smokers. |
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TOPABSTRACTINTRODUCTIONChemoprevention of NNK-induced...Effects of watercress on...Approaches to chemoprevention of...CONCLUSIONSREFERENCES |
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).
Eleven smokers maintained constant smoking habits and avoided
cruciferous vegetables and other sources of isothiocyanates throughout
the study. The subjects donated 24-h urine samples on three consecutive
days (baseline period);1–3 d later, they consumed 2 oz (56.8 g) of
watercress at each meal for 3 d and gave 24-h urine samples on
each of these days (watercress consumption period). One and two weeks
later they again gave 24-h urine samples on two to three consecutive
days (follow-up periods). The samples were analyzed for two metabolites
of NNK; NNAL and NNAL-Gluc, as well as PEITC-NAC, a metabolite of
PEITC. Minimum exposure to PEITC during the watercress consumption
period averaged 19–38 mg/d. Seven of the 11 subjects had increased
levels of urinary NNAL plus NNAL-Gluc on d 2 and 3 of the watercress
consumption period compared with the baseline period. Overall, the
increase in urinary NNAL plus NNAL-Gluc in this period was significant
[mean ± SD, 0.924 ± 1.12 nmol/24 h (33.5%),
P < 0.01] (Fig. 3
).Urinary levels of NNAL plus NNAL-Gluc returned to near baseline levels
in the follow-up periods. The percentage of increase in urinary NNAL
plus NNAL-Gluc during d 2 and 3 of the watercress consumption period
correlated with intake of PEITC during this period as measured by total
urinary PEITC-NAC (r = 0.62, P = 0.04).
The results of this study support our hypothesis that PEITC inhibits
the oxidative metabolism of NNK in humans, as seen in rodents, and
support further development of PEITC as a chemopreventive agent against
lung cancer.
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Approaches to chemoprevention of lung cancer. |
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TOPABSTRACTINTRODUCTIONChemoprevention of NNK-induced...Effects of watercress on...Approaches to chemoprevention of...CONCLUSIONSREFERENCES |
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, PAH must also be
considered in this strategy. In studies conducted to date, PEITC has
little effect on lung tumorigenesis induced by BaP, one of the most
important PAH in cigarette smoke. In contrast, BITC is an effective
inhibitor of BaP-induced lung tumorigenesis in mice, and the effects of
combinations of BITC and PEITC on lung tumorigenesis by BaP and NNK are
now being investigated. It is very likely that properly constructed
mixtures of chemopreventive agents will be necessary to prevent lung
cancer in smokers. There are a number of compounds already available in
addition to BITC that are known to inhibit lung tumorigenesis by BaP.
These include butylated hydroxyanisole, sodium cyanate and diallyl
sulfide (Hecht 1997
). Other important constituents of a mixture of
chemopreventive agents could be antioxidants and suppressing agents,
which presumably could stop or reverse some of the biological damage
that has already occurred in the lung. Unfortunately, few suppressing
agents for lung cancer are presently known, based on bioassays for lung
tumorigenesis using BaP or NNK as the carcinogen. ß-Carotene was
widely discussed in this regard, but human trials have been
disappointing (The -Tocopherol ß Carotene Cancer Prevention Study
Group 1994
, Hennekens et al 1996
, Omenn et al 1996
). It is worth
noting, however, that there are no data in the literature that indicate
that ß-carotene can inhibit lung tumorigenesis in laboratory animals
(Beems 1987
, Moon et al. 1992
, Murakoshi et al. 1992
). |
CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONChemoprevention of NNK-induced...Effects of watercress on...Approaches to chemoprevention of...CONCLUSIONSREFERENCES |
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FOOTNOTES |
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2 Supported by grant CA-46535 from the National
Cancer Institute.
3 Abbreviations used: BaP,
benzo[a]pyrene; BITC, benzyl isothiocyanate; DMBA,
7,12-dimethylbenz[a]anthracene; NBMA,
N-nitrosobenzylmethylamine; NNAL,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; NNK,
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PAH, polynuclear
aromatic hydrocarbons; PEITC, phenethyl isothiocyanate; PHITC,
6-phenylhexyl isothiocyanate.
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TOPABSTRACTINTRODUCTIONChemoprevention of NNK-induced...Effects of watercress on...Approaches to chemoprevention of...CONCLUSIONSREFERENCES |
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