Scientific Researches On:
Ellagic Acid (Raspberry/Pomegranate
Extract)
USA National Center for Biotechnology Information
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121:
Carcinogenesis. 1991
Dec;12(12):2227-32.
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Erratum in:
The crystal and molecular structure of
ellagic acid dihydrate: a dietary
anti-cancer agent.
Rossi M,
Erlebacher J,
Zacharias DE,
Carrell HL,
Iannucci B.
Department of Chemistry, Vassar College,
Poughkeepsie, NY 12601.
The crystal and molecular structure of
ellagic acid dihydrate has been determined
by X-ray diffraction techniques. This acid
inhibits the carcinogenic properties of a
variety of chemical compounds including
benzo[alpha]pyrene-7,8-diol-9,10-epoxide,
aflatoxin B1, N-methyl-N-nitrosourea,
3-methyl-cholanthrene and
7,12-dimethylbenz[alpha]anthracene. Ellagic
acid dihydrate forms triclinic crystals with
unit cell dimensions: a = 7.656(1) A, b =
9.563(1)A, c = 4.623(1) A, alpha = 97.88(1)
degrees, beta = 103.2(1) degrees, gamma =
102.22(1) degrees, V = 315.9 A3, space group
= P1. There is a center of symmetry in the
crystal coinciding with the center of the
molecule, so that there is only one molecule
in the unit cell. Ellagic acid is planar and
molecules are interconnected by hydrogen
bonds to water, giving rise to layers of
molecules throughout the crystal. Its
activity and anti-cancer properties are
compared with those of a similar naturally
occurring compound, quercetin.
Publication Types:
PMID: 1747921 [PubMed - indexed for MEDLINE]
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Chemoprevention of colon carcinogenesis
by dietary administration of piroxicam,
alpha-difluoromethylornithine, 16
alpha-fluoro-5-androsten-17-one, and ellagic
acid individually and in combination.
Rao CV,
Tokumo K,
Rigotty J,
Zang E,
Kelloff G,
Reddy BS.
Division of Nutritional Carcinogenesis,
American Health Foundation, Valhalla, New
York 10595.
The chemopreventive action of 40 and 80%
maximum tolerated dose (MTD) levels of
piroxicam, D,L-alpha-difluoromethylornithine
(DMFO), 16 alpha-fluoro-5-androsten-17-one (DHEA
analogue 8354), and ellagic acid (EA)
administered in diet individually and in
combination before and during initiation and
postinitiation phases of azoxymethane-induced
neoplasia of the intestine was studied in
male F344 rats. The MTD levels of piroxicam,
DFMO, DHEA analogue, and EA were determined
in male F344 rats and found to be 500,
5,000, 500, and 10,000 ppm, respectively, in
modified AIN-76A diet. When these agents
were fed in combination, the MTD levels
were: piroxicam plus DFMO, 250 and 2500 ppm;
piroxicam plus DHEA analogue, 250 and 250
ppm; piroxicam plus EA, 250 and 5000 ppm;
piroxicam plus DFMO plus DHEA analogue, 250,
2500, and 250 ppm; and piroxicam plus DFMO
plus EA, 250, 2500, and 5000 ppm. From these
MTD values, 40 and 80% MTD levels were
calculated and tested for their efficacy. At
5 weeks of age, animals were fed the
modified AIN-76A (control) diet and
experimental diets containing 40 and 80% MTD
levels of piroxicam, DFMO, DHEA analogue,
and EA individually and in combination. At 7
weeks of age, all animals except the
vehicle-treated groups were administrated
s.c. injections of azoxymethane (15 mg/kg
body weight/week for 2 weeks). Animals
intended for vehicle treatment received s.c.
injections of an equal volume of normal
saline. Fifty-two weeks after azoxymethane
and saline treatment all the animals were
necropsied, and colon and small intestinal
tumor incidence (percentage of animals with
tumors) and multiplicity (tumors/animal)
were compared among various dietary groups.
The results indicate that 40 and 80% MTD
levels of dietary piroxicam and DFMO
significantly (P less than 0.001) inhibited
colon and small intestinal tumor incidence
and multiplicity. DHEA analogue at 40% MTD
level significantly decreased the small
intestinal and colon tumor incidences (P
less than 0.05), whereas 80% MTD of DHEA
analogue inhibited only small intestinal
tumor incidence. EA at 40 and 80% MTDs had
no significant effect on colon tumor
incidence (P greater than 0.05), but 80% MTD
of EA showed a significant inhibitory effect
on the incidence of small intestinal
adenocarcinomas (P less than 0.01). In the
combination study, 40 and 80% MTD levels of
piroxicam plus DFMO significantly (P less
than 0.001) inhibited colon adenocarcinoma
incidence (8.3%) and multiplicity (0.08 +/-
0.04) (SE) when compared to colon
adenocarcinoma incidence (72.2%) and
multiplicity (1.14 +/- 0.18) in control
diet-fed animals.(ABSTRACT TRUNCATED AT 400
WORDS)
Publication Types:
PMID: 1831401 [PubMed - indexed for MEDLINE]
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Inhibition of tumor promoter-induced
ornithine decarboxylase activity by tannic
acid and other polyphenols in mouse
epidermis in vivo.
Gali HU,
Perchellet EM,
Perchellet JP.
Anti-Cancer Drug Laboratory, Kansas State
University, Manhattan 66506.
Naturally occurring plant phenols with
antimutagenic and anticarcinogenic
activities were tested for their abilities
to inhibit the ornithine decarboxylase (ODC)
response linked to skin tumor promotion by
12-O-tetradecanoylphorbol-13-acetate (TPA).
Topical applications of tannic acid (TA)
inhibit remarkably and in a dose-dependent
manner TPA-induced ODC activity in mouse
epidermis in vivo. This inhibitory effect of
TA is dependent on the time of its
administration relative to TPA. The
induction of epidermal ODC activity by 8.5
nmol of TPA is inhibited maximally when 20
mumol of TA are applied topically to the
skin 20 min before the tumor promoter.
Gallic acid and several of its derivatives
inhibit the ODC response to TPA to a lesser
degree than TA. Ellagic acid is the least
effective inhibitor tested. TA also inhibits
the ODC-inducing activities of several
structurally different tumor promoters and
the greater ODC responses produced by
repeated TPA treatments. The ability of TA
to inhibit by 85% the ODC marker of skin
tumor promotion suggests that TA and other
polyphenols may be effective not only
against tumor initiation and complete
carcinogenesis but also against the
promotion phase of tumorigenesis.
Publication Types:
PMID: 2032222 [PubMed - indexed for MEDLINE]
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Lung tumorigenicity of NNK given orally
to A/J mice: its application to
chemopreventive efficacy studies.
Castonguay A,
Pepin P,
Stoner GD.
Laboratory of Cancer Etiology and
Chemoprevention, School of Pharmacy, Laval
University, Quebec City, Canada.
The ability of five chemopreventive agents
to inhibit
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK)-induced lung tumors in A/J mice was
determined. The carcinogen was administered
in the drinking water during 7 weeks (at
doses of 9.2 to 3.1 mg/mouse). Three
chemopreventive agents: (dose, g/kg diet)
ellagic acid (4.0), 2(3)-BHA (5.0), and
sulindac (0.13) inhibited the multiplicity
of lung adenomas by 52, 88, and 52%,
respectively, when compared to NNK controls.
beta-Carotene + retinol (2.14 + 0.009), in
combination, and selenium (0.0022) were
ineffective. NNK was absorbed more rapidly
from the duodenum than from the stomach and
was metabolized in both tissues. The
activation of NNK by alpha-carbon
hydroxylation and its deactivation by
pyridine N-oxidation was more extensive in
the duodenum than in the stomach. Carbonyl
reduction of NNK was 10 times higher in the
duodenum. Liver microsomes were more active
than lung microsomes in the alpha-carbon
hydroxylation of NNK, suggesting that some
liver isozymes of cytochrome P-450 have a
high affinity for NNK. Pyridine N-oxidation
was five times more extensive in lung
microsomes than in liver microsomes.
Collectively, these results demonstrate that
NNK given orally to A/J mice provides a
suitable model from which to assess the
relative activity and mechanisms of action
of chemopreventive agents in pulmonary
carcinogenesis.
Publication Types:
PMID: 2050045 [PubMed - indexed for MEDLINE]
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The effects of ellagic acid and
13-cis-retinoic acid on N-nitrosobenzylmethylamine-induced
esophageal tumorigenesis in rats.
Daniel EM,
Stoner GD.
Department of Pathology, Medical College of
Ohio, Toledo 43699.
Ellagic acid (EA) and 13-cis-retinoic acid (CRA),
both alone and in combination, were tested
for their ability to inhibit N-nitrosobenzylmethylamine-induced
tumors in the rat esophagus. Groups of male
rats were fed AIN-76A diet containing EA (4
g/kg), CRA (240 mg/kg), or a combination of
EA and CRA (4 g/kg and 240 mg/kg),
respectively, for 25 weeks. Two weeks after
initiation of the diets, NBMA (0.5 mg/kg per
injection) was administered s.c. once weekly
for 15 weeks. After 25 weeks on the diets,
the animals were necropsied. The incidence
of esophageal tumors was 97-100% in all NBMA-treated
groups. The multiplicity of tumors in NBMA-treated
groups was reduced significantly by EA
(60%), but not by CRA, or by EA + CRA. These
results demonstrate that EA and CRA do not
act synergistically to inhibit NBMA-induced
esophageal tumorigenesis.
Publication Types:
PMID: 1998940 [PubMed - indexed for MEDLINE]
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Combination of blocking agents and
suppressing agents in cancer prevention.
Ip C,
Ganther HE.
Department of Breast Surgery, Roswell Park
Cancer Institute, Buffalo, NY 14263.
The design of the present study was based on
the premise that if blocking agents and
suppressing agents are targeted at different
phases of chemical carcinogenesis, a greater
chemopreventive effect would be achieved by
using the combination treatment compared to
the single-agent treatment. The
dimethylbenz[a]anthracene (DMBA)-induced
mammary tumor model in rats was used to test
this hypothesis, with the blocking agent
given before DMBA only and the blocking
agent given after DMBA until the end of the
experiment. A total of three sets of
combination treatment were carried out;
diallyl sulfide/Se-methylselenocysteine,
ellagic acid/selenomethionine, and diallyl
sulfide/quercetin. In all three cases, the
combination regimen was much more effective
than the single-agent treatment in tumor
suppression. It should be noted that only
naturally occurring inhibitors were selected
for these experiments. The impact of minor
dietary anutrients in cancer chemoprevention
is also discussed.
Publication Types:
PMID: 1899813 [PubMed - indexed for MEDLINE]
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Inhibitory effect of ellagic acid on
genotoxicity induced by aflatoxins B1 and
G1.
Górski T,
Górska E,
Odlanicki J,
Sikora M.
Department for Cancer Prophylaxis and
Education, Sanitary Epidemiological Station,
Lodz, Poland.
PMID: 1906839 [PubMed - indexed for MEDLINE]
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The effect of retinoids, carotenoids and
phenolics on chromosomal instability of
bovine papillomavirus DNA-carrying cells.
Stich HF,
Tsang SS,
Palcic B.
Environmental Carcinogenesis Unit, British
Columbia Cancer Research Centre, Vancouver,
Canada.
Antioxidants were found to protect against
the genotoxic effects of chemical and
physical mutagenic and clastogenic agents.
This study focused on the capacity of
antioxidants to reduce an intrinsic and
persistent chromosome instability. As a
model system, strains of C127 cells, which
were transformed by bovine papillomavirus (BPV)
DNA and which carry BPV DNA varying from 20
to 160 copies, were used. Transformed cells
of 10 different strains showed a
persistently high incidence of mitotic
irregularities detectable at anaphase and
telophase (27.3-58.9%), an elevated
frequency of cells with micronuclei
(6.6-34.7%), and a broad spectrum of nuclear
sizes, as measured by image analysis. A
3-day exposure to retinoic acid, retinol,
beta-carotene, canthaxanthin, ascorbic acid
and ellagic acid greatly reduced the degree
of chromosome instability, whereas catechin,
eugenol and pyrogallol showed a smaller
inhibitory effect, and curcumin had no
detectable effect on the frequency of
mitotic irregularities. After withdrawal of
retinoic acid treatment, the high levels of
chromosome instability reappeared. The
possibility that the protective effect of
the retinoids and carotenoids examined in
the model system points to their beneficial
administration to human cells with an
intrinsic or acquired chromosome instability
is discussed.
Publication Types:
PMID: 2165562 [PubMed - indexed for MEDLINE]
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Inhibition of transformation in cultured
rat tracheal epithelial cells by potential
chemopreventive agents.
Steele VE,
Kelloff GJ,
Wilkinson BP,
Arnold JT.
Environmental Sciences Division, NSI
Technology Services Corporation, Research
Triangle Park, North Carolina 27709.
Twenty-eight compounds were screened for
chemopreventive activity by using a rat
tracheal epithelial cell transformation
inhibition assay. In this new assay,
chemicals were tested for their ability to
inhibit the formation of transformed rat
tracheal epithelial cell colonies which
arise following exposure to the carcinogen
benzo(a)pyrene. The 15 positive compounds
were N-acetylcysteine, bismuththiol, calcium
glucarate, (+/-) catechin, diallyl
disulfide, glycaric acid,
D-glucaro-1,4-lactone,
N-(4-hydroxyphenyl)retinamide, D-limonene,
mesna, retinoic acid, rutin, quercetin,
silymarin, and taurine. In examining the
nature of compounds that inhibited rat
tracheal epithelial cell transformation,
several possible chemopreventive mechanisms
appeared to be predominant: compounds that
were positive (a) increased glutathione
levels or enhanced conjugation; (b)
increased cytochrome P-450 activity; (c)
displayed nucleophilic activity; or (d)
induced differentiation. Thirteen compounds
were negative in the rat tracheal epithelial
transformation inhibition assay: crocetin,
difluoromethylornithine, ellagic acid,
esculetin, enoxalone, ibuprofen, levamisole,
nordihydroguaiaretic acid,
L-2-oxothiazolidine-4-carboxylate, piroxicam,
sodium butyrate, D-alpha-tocopherol acetate,
and polyethylene glycol 400. It was evident
from these results that this assay would not
detect compounds that were (a)
anti-promoting in nature; (b) glutathione
inhibitors; (c) differentiation inhibitors;
(d) O6-methylguanine inhibitors; (e) organ
specific; or (f) inactive. The rat tracheal
epithelial cell transformation inhibition
assay appeared to identify chemopreventive
compounds that act at early stages of the
carcinogenic process.
Publication Types:
PMID: 2138505 [PubMed - indexed for MEDLINE]
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Inhibition of N-nitrosobenzylmethylamine-induced
esophageal tumorigenesis in rats by ellagic
acid.
Mandal S,
Stoner GD.
Department of Pathology, Medical College of
Ohio, Toledo 43699.
In this report, we describe the ability of
ellagic acid (EA), a phenolic compound
present in a number of fruits and nuts, to
inhibit N-nitrosobenzylmethylamine (NBMA)
tumorigenesis in the rat esophagus. When
administered in a semi-purified diet at
concentrations of 0.4 and 4 g/kg, EA
produced a significant (21-55%) decrease in
the average number of NBMA-induced
esophageal tumors after 20 and 27 weeks of
the bioassay. EA exhibited inhibitory
effects toward preneoplastic lesions as well
as neoplastic lesions. Tumors were not
observed in vehicle-control rats or in rats
that received EA alone.
Publication Types:
PMID: 2295128 [PubMed - indexed for MEDLINE]
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Erratum in:
Metabolism of
4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
by hamster respiratory tissues cultured with
ellagic acid.
Castonguay A,
Allaire L,
Charest M,
Rossignol G,
Boutet M.
Laboratory of Cancer Etiology and
Chemoprevention, School of Pharmacy, Laval
University, Quebec City, Canada.
Previous studies have shown that the
nicotine-derived
N-nitrosamine-4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) induces tracheal papillomas and lung
carcinomas in Syrian golden hamsters. In
this study, we showed that hamster tracheal
and lung explants metabolize NNK by
alpha-carbon hydroxylation, pyridine
N-oxidation and carbonyl reduction. alpha-Methylene
hydroxylation and methyl hydroxylation yield
methylating and pyridyloxobutylating
intermediates, respectively. Levels of
binding of the pyridyloxobutyl moiety to
explant proteins was 200 times lower than
the total amount of metabolites formed by
alpha-carbon hydroxylation and released in
the culture medium. Viable and heat-treated
lung explants were cultured with [CH3-3H]NNK
or [5-3H]NNK. In viable explants, the rate
of binding of the methyl group was 2-fold
higher than the rate of binding of the
pyridyloxobutyl moiety of NNK. Heat
treatment reduced 54-fold the binding of
[CH3-3H] NNK but only 5-fold the binding
[5-3H]NNK. Tracheal explants were cultured
with [5-3H]NNK (5.6 microM) and ellagic acid
(EA, 10 microM), a naturally-occurring plant
phenol. EA did not inhibit any of the three
metabolic pathways nor the binding of the
pyridyloxobutyl moiety to explant proteins.
Lung explants were cultured with NNK (3.7
microM) and with or without EA (100 microM).
EA inhibits alpha-carbon hydroxylation by
19% and the overall metabolism of NNK by 6%.
Formation of 7-methylguanine and
O6-methylguanine was observed in lung
explants and the levels of both adducts were
reduced by EA (100 microM). These results
suggest that high concentrations of EA
modulate the metabolism of NNK and that NNK
does not necessarily require enzymatic
activation to bind to protein.
Publication Types:
PMID: 2752387 [PubMed - indexed for MEDLINE]
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Ellagic acid effects on the
carcinogenicity, DNA-binding and metabolism
of 7,12-dimethylbenz(a)anthracene (DMBA).
Singletary K,
Liao CH.
Division of Foods and Nutrition, School of
Human Resources and Family Studies,
University of Illinois, Urbana 61801.
Naturally-occurring components of the human
food supply have recently received attention
as possible agents for cancer
chemoprevention. The plant phenol ellagic
acid has been reported to be an effective
inhibitor of carcinogen metabolism and
certain chemically-induced tumors.
Therefore, we evaluated the efficacy of
ellagic acid in inhibiting DMBA metabolism,
DNA-binding and the initiation of DMBA-induced
carcinogenesis in rat mammary tissue.
Mammary epithelial cell aggregates were
isolated from rats fed control and ellagic
acid (0.4 and 0.8%) containing diets. When
incubated with DMBA, aggregates from ellagic
acid-fed rats exhibited a significant but
modest inhibition of DMBA metabolism and
DNA-binding. An inhibition of DMBA-DNA
binding and DMBA metabolism in secondary
cultures of mammary epithelial cells also
was detected only when ellagic acid was
added at 150 molar excess compared to DMBA.
The feeding of ellagic acid (0.8%) to rats
for 28 days prior to the administration of
DMBA resulted in a 21% reduction in mammary
tumor incidence at 21 weeks which was,
however, not statistically significant.
Together, these results indicate that, in
contrast to its effects with other
carcinogens in other tissues, ellagic acid
is not a potent inhibitor of DMBA
metabolism, DNA-binding and carcinogenicity
with rat mammary tissue.
PMID: 2519851 [PubMed - indexed for MEDLINE]
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Dietary ellagic acid reduces the
esophageal microsomal metabolism of
methylbenzylnitrosamine.
Barch DH,
Fox CC.
Department of Medicine, University of
Illinois, Chicago 60612.
Dietary ellagic acid has been shown to
reduce the incidence of
methylbenzylnitrosamine-induced esophageal
carcinoma in the rat.
Methylbenzylnitrosamine (MBN) is a naturally
occurring carcinogen which requires
cytochrome P-450 dependent activation to be
mutagenic. We examined whether the reduction
in tumor incidence observed with dietary
ellagic acid was associated with alterations
in the cytochrome P-450 dependent microsomal
metabolism of MBN. Dietary ellagic acid was
shown to significantly reduce total
esophageal and hepatic microsomal cytochrome
P-450 (P less than 0.05) and significantly
reduce the esophageal microsomal metabolism
of MBN (P less than 0.05). The addition of
ellagic acid in vitro also resulted in a
significant inhibition (P less than 0.05) of
the esophageal microsomal metabolism of MBN.
In contrast, dietary ellagic acid and the
addition of ellagic acid in vitro did not
alter the hepatic microsomal metabolism of
MBN. The reduced rate of MBN metabolism by
the esophageal microsomes from the ellagic
acid fed rats may contribute to the
decreased incidence of esophageal carcinoma
observed in these animals.
Publication Types:
PMID: 2917341 [PubMed - indexed for MEDLINE]
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Selective inhibition of
methylbenzylnitrosamine-induced formation of
esophageal O6-methylguanine by dietary
ellagic acid in rats.
Barch DH,
Fox CC.
Department of Medicine, University of
Illinois, Chicago 60612.
Ellagic acid is a naturally occurring plant
phenol which has been shown to reduce the
incidence of a number of carcinogen-induced
tumors including methylbenzylnitrosamine (MBN)-induced
esophageal carcinoma in the rat. The
postulated mechanism of MBN-induced
esophageal carcinogenesis is through
oxidation of MBN to form benzaldehyde and an
activated metabolite which methylates DNA
forming a variety of methylated DNA adducts
including O6-methylguanine (O6-mGua) and
7-methylguanine (m7Gua). O6-mGua adducts
have been shown to induce DNA mutations
which can lead to cancer, while m7Gua
adducts do not appear to be related to tumor
induction. In this study, we examined
whether the decreased incidence of MBN-induced
esophageal carcinoma observed with dietary
ellagic acid was associated with a decrease
in the in vivo and in vitro formation of MBN-induced
DNA adducts and whether this reduction was
specific to O6-mGua or due to a reduction in
total methylation. Weanling male Sprague-Dawley
rats were fed a nutritionally complete diet
with and without the addition of 0.4 g of
ellagic acid per kg of diet. This dose of
dietary ellagic acid has previously been
shown to reduce the incidence of MBN-induced
esophageal carcinoma by 30 to 50%. After 3
wk on the diets, rats were given injections
of a single dose of MBN (2.0 mg/kg of body
weight i.p.) and sacrificed 1 h after
injection. Dietary ellagic acid
significantly reduced the MBN-induced in
vivo formation of esophageal O6-mGua,
without significantly reducing the formation
of esophageal m7Gua. Examination of this
effect in an in vitro methylation assay
demonstrated that dietary ellagic acid did
not reduce the ability of esophageal
microsomes to methylate purified calf thymus
DNA; however, pretreatment of the calf
thymus DNA with ellagic acid selectively
reduced the MBN-induced formation of O6-mGua
by microsomes from both ellagic acid-fed and
control animals without altering the in
vitro formation of m7Gua. These results
suggest that ellagic acid bound to DNA
selectively blocks methylation of the
O6-position of guanine without inhibiting
the activation of MBN or the ability of MBN
to methylate DNA.
Publication Types:
PMID: 3191485 [PubMed - indexed for MEDLINE]
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Dietary inhibitors of mutagenesis and
carcinogenesis.
Hayatsu H,
Arimoto S,
Negishi T.
Faculty of Pharmaceutical Sciences, Okayama
University, Japan.
Dietary inhibitors of mutagenesis and
carcinogenesis are of particular interest
because they may be useful for human cancer
prevention. Several mutagenesis inhibitors
have been demonstrated to be carcinogenesis
inhibitors also, e.g., ellagic acid,
palmitoleic acid, and N-acetylcysteine. This
means that the search for mutagenesis
inhibitors may be useful for discovering
anticarcinogenic agents. Many mutagenesis
inhibitors have been discovered by the use
of short-term assays, particularly the Ames
Salmonella test. This simple in vitro system
has provided opportunities to elucidate the
mechanisms of inhibition. The elucidation of
the mechanism may allow us to infer the
possible anticarcinogenic activity of the
reagent. In this chapter, inhibitors of
mutagenesis and carcinogenesis that can
arise as components of diet have been
reviewed. Most of the inhibitors have been
demonstrated to be effective against a
specific class of mutagens or carcinogens.
Therefore, it may be argued that these
inhibitors are antagonistic only to those
particular agents. Here again, understanding
of the mechanisms of these inhibitions is
necessary for the assessment. Dietary
inhibitors reviewed in this article include:
(1) as inhibitors of mutagenesis:
porphyllins, fatty acids, vitamins,
polyphenols, and sulfhydryl compounds, (2)
as inhibitors of carcinogenesis: vitamins A,
E and C, ellagic acid, sulfhydryl compounds,
fats, selenium, calcium, and fiber. Further
studies in this area of science appear to
help establish the recipe of a healthy diet.
Publication Types:
PMID: 3057372 [PubMed - indexed for MEDLINE]
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Inhibitory effect of ellagic acid on
N-2-fluorenylacetamide-induced liver
carcinogenesis in male ACI/N rats.
Tanaka T,
Iwata H,
Niwa K,
Mori Y,
Mori H.
First Department of Pathology, Gifu
University School of Medicine.
The effect of ellagic acid (EA) on the
hepatocarcinogenesis induced by
N-2-fluorenylacetamide (FAA) was
investigated in male ACI/N rats. Rats were
fed diet containing 200 ppm FAA and 400 ppm
EA for 16 weeks, and diet containing 400 ppm
EA alone was fed to the animals for one week
before FAA exposure and one week after the
carcinogen treatment. Animals were killed at
intervals up to 20 weeks after cessation of
the carcinogen. Liver altered foci and
neoplasms were quantified using gamma-glutamyl
transpeptidase reaction as well as
conventional staining for identification.
Exposure to FAA alone induced a substantial
number of altered foci and at the end of
experiment (week 36), the incidence of
hepatocellular neoplasms was 100%. In the
group receiving EA together with FAA, the
number of altered foci was decreased at all
time points and at termination, the final
incidence of hepatocellular neoplasms (30%)
was also reduced. Thus, EA inhibited the
hepatocarcinogenesis induced by FAA when it
was administered concurrently with the
carcinogen.
PMID: 2906931 [PubMed - indexed for MEDLINE]
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Mechanism of inhibition of N-methyl-N-nitrosourea-induced
mutagenicity and DNA binding by ellagic
acid.
Dixit R,
Gold B.
Eppley Institute for Research in Cancer and
Allied Diseases, University of Nebraska
Medical Center, Omaha 68105.
Ellagic acid (EA) is a dilactone derivative
of shikimic acid, which is found in a
variety of soft fruits and vegetables. EA
inhibits mutagenesis and carcinogenesis
induced by benzo[a]pyrene and its bay-region
dihydrodiol epoxide derivative by preventing
their covalent binding to DNA. EA at
concentrations of 100, 250, 500 and 1000
nmol/plate inhibited the mutagenicity of
N-methyl-N-nitrosourea (MNU) (400 nmol/plate)
in Salmonella typhimurium TA100 by 3, 13, 45
and 60%, respectively. A study of inhibition
of 3H-MNU-mediated DNA methylation by EA
showed that it inhibited only the formation
of O6-methylguanine, while attack at the N7
and N3 positions of guanine and adenine,
respectively, was not altered. This
inhibition was observed only in
double-stranded DNA. Ultraviolet and
equilibrium dialysis studies show that EA
has a definite affinity for DNA, but that an
intercalating process is not involved.
Publication Types:
PMID: 2445674 [PubMed - indexed for MEDLINE]
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Effect of ellagic acid and
3-O-decylellagic acid on the formation of
benzo[a]pyrene-derived DNA adducts in vivo
and on the tumorigenicity of
3-methylcholanthrene in mice.
Smart RC,
Huang MT,
Chang RL,
Sayer JM,
Jerina DM,
Wood AW,
Conney AH.
The effect of ellagic acid and its more
lipophilic derivative, 3-O-decylellagic
acid, on the amount of DNA-bound adducts in
the epidermis or lung of CD-1 mice treated
with [3H]benzo-[a]pyrene ([3H]B[a]P) was
evaluated using several different treatment
protocols. The i.v. administration of 50
mumol/kg of ellagic acid or 3-O-decylellagic
acid either together with or 5 min before a
0.2 mumol/kg i.v. dose of [3H]B[a]P did not
inhibit the formation of pulmonary DNA-bound
adducts. Feeding mice a diet that contained
1% ellagic acid for 10 days or the i.p.
administration of 120 mumol/kg of ellagic
acid 30 min before the i.v. administration
of 0.2 mumol/kg of [3H]B[a]P did not inhibit
the formation of DNA-bound adducts in the
lung. The application of 2,500 nmol of
ellagic acid or 3-O-decylellagic acid to
mouse skin 5 min before the application of
2, 10 or 50 nmol of [3H]B[a]P had little or
no effect on the covalent binding of
[3H]B[a]P metabolites to epidermal DNA.
Feeding mice a diet containing 1% ellagic
acid for 10 days did not inhibit the
formation of epidermal DNA-bound adducts
after a topical dose of 2 nmol of [3H]B[a]P.
Similarly, the topical application of 2,500
nmol of ellagic acid at 2 h, 1 h and 5 min
before and at 10 min after the application
of 2 nmol of [3H]B[a]P did not inhibit the
formation of DNA-bound adducts, but the same
dosing regimen of 3-O-decylellagic acid
(total dose of 10,000 nmol) resulted in a
modest inhibition in the formation of
DNA-bound adducts. The topical application
of 1,500 nmol of ellagic acid 1 h before the
application of 1,500 nmol of
3-methylcholanthrene (3-MC) to CD-1 or BALB/c
mice twice weekly did not inhibit the
development of skin tumors. Our results
indicate that ellagic acid and
3-O-decylellagic acid are not effective in
inhibiting [3H]B[a]P DNA adduct formation in
mouse skin and lung and that ellagic acid
does not inhibit 3-MC-induced skin
tumorigenesis in BALB/c or CD-1 mice.
PMID: 3757169 [PubMed - indexed for MEDLINE]
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Pharmacological modification of epidermal
detoxification systems.
Bickers DR,
Das M,
Mukhtar H.
The skin is a major interface between the
body and the environment and possesses
membrane-bound cytochrome P-450-dependent
enzyme activity that is capable of both
detoxifying endogenous and exogenous
substrates and enhancing the toxic effects
of selected substances. The use of chemical
inhibitors of enzyme activation by
P-450-dependent enzymes represents one
possible approach to controlling toxic
responses in target tissue such as the skin.
Our data indicate that certain polyphenols
and imidazoles are potent inhibitors of
epidermal carcinogen metabolism, and of the
DNA binding and the carcinogenicity of PAHs
such as BP. The use of such agents may offer
a novel approach to the prevention of
environmentally induced cancer.
Publication Types:
PMID: 3741806 [PubMed - indexed for MEDLINE]
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Inhibition of
3-methylcholanthrene-induced skin
tumorigenicity in BALB/c mice by chronic
oral feeding of trace amounts of ellagic
acid in drinking water.
Mukhtar H,
Das M,
Bickers DR.
Chronic p.o. feeding of small amounts of
ellagic acid, a naturally occurring dietary
plant phenol, to BALB/c mice in drinking
water afforded significant protection
against skin tumorigenesis induced by
3-methylcholanthrene, a polycyclic aromatic
hydrocarbon carcinogen. A significant
increase in the latent period for the
development of skin tumors by
3-methylcholanthrene was observed in the
ellagic acid-fed group of mice (9 wk on
test) as compared to the control group of
animals (6 wk on test). The observed
protection against tumor induction in the
ellagic acid-fed group of animals may be due
to the inhibition of the metabolic
activation of the polycyclic aromatic
hydrocarbon since epidermal aryl hydrocarbon
hydroxylase activity was found to be
significantly inhibited. Our results suggest
that dietary supplementation with small
amounts of ellagic acid may prove useful in
reducing the risk of skin carcinogenesis
induced by environmental chemicals.
Publication Types:
PMID: 3486036 [PubMed - indexed for MEDLINE]
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