Scientific Researches On:
Ellagic Acid (Raspberry/Pomegranate
Extract)
USA National Center for Biotechnology Information
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141:
Cancer Lett. 1986
Feb;30(2):169-74.
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Combined effects of butylated
hydroxyanisole and other
antioxidants in induction of
forestomach lesions in rats.
Hirose M,
Hagiwara A,
Masui T,
Inoue K,
Ito N.
The possibility that changes in the
forestomach of rats induced by
butylated hydroxyanisole (BHA) are
caused by inductions of free
radicals and their reactions with
macromolecules was examined. Groups
of five male F344 rats were
pretreated with 1% alpha-tocopherol,
1% ellagic acid, 1% propyl gallate,
0.25% ethoxyquin, 0.5% glutathione,
1% sodium L-ascorbate or 1%
3,3'-thiodipropionic acid for 1
week, then treated with the same
antioxidant plus 1% BHA for 1 week,
and then killed. Histological
examination showed that BHA induced
epithelial hyperplasia of the
forestomach. This induction of
hyperplasia was not inhibited, but
increased by the antioxidants,
particularly propyl gallate and
ethoxyquin. Thus the induction of
hyperplasia by BHA may not be
related to a free radical reaction.
Publication Types:
PMID: 3955538 [PubMed - indexed for
MEDLINE]
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Description and evaluation of a
new chromogenic substrate assay kit
for the determination of
prekallikrein in human plasma.
Friberger P,
Gallimore MJ.
Because of an increasing interest in
the determination of prekallikrein a
kit was made for the determination
of this plasma proenzyme. The kit
consists of 1) a prekallikrein
activator of the cephalin-ellagic
acid type containing Factor XII and
HMW-kininogen to ensure a total
activation of the prekallikrein even
in pathological plasmas, 2) a buffer
which is optimal for both activation
and substrate hydrolysis and 3) the
chromogenic substrate S-2302. A
control plasma is also included.
This kit was evaluated by thirteen
research groups as well as by
ourselves. Both normal and patient
plasmas were analyzed. Good
correlations were obtained for
prekallikrein levels in plasma
samples between the kit method and
two other methods (immunochemical
and functional). As well as in
deficiency states the prekallikrein
level was low in pancreatitis (n =
20), cancer (n = 16), early
pregnancy with gestosis (n = 15),
cirrhosis (n = 9) and cases with
thromboembolic disorders (n = 5).
The prekallikrein level was high in
late pregnancy (n = 4).
PMID: 3643742 [PubMed - indexed for
MEDLINE]
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Effect of ellagic acid and
hydroxylated flavonoids on the
tumorigenicity of benzo[a]pyrene and
(+/-)-7 beta, 8 alpha-dihydroxy-9
alpha, 10
alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene
on mouse skin and in the newborn
mouse.
Chang RL,
Huang MT,
Wood AW,
Wong CQ,
Newmark HL,
Yagi H,
Sayer JM,
Jerina DM,
Conney AH.
Ellagic acid, quercetin and
robinetin were tested for their
ability to antagonize the
tumor-initiating activity of
benzo[a]pyrene (B[a]P) and (+/-)-7
beta, 8 alpha-dihydroxy-9 alpha, 10
alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene
(B[a]P 7,8-diol-9,10-epoxide-2), the
ultimate carcinogenic metabolite of
benzo[a]-pyrene. Ellagic acid,
robinetin or quercetin (2500 nmol)
had no tumor-initiating activity on
mouse skin, but the topical
application of 2500 nmol of ellagic
acid 5 min before a tumor-initiating
dose of 200 nmol of B[a]P
7,8-diol-9,10-epoxide-2 caused a
59-66% inhibition in the number of
skin tumors per mouse that were
observed after 15-20 weeks of
promotion with
12-O-tetradecanoylphorbol-13-acetate.
Similar treatment with 2500 nmol of
robinetin or quercetin caused a
statistically insignificant 16-24%
inhibition in the tumor-initiating
activity of 200 nmol of B[a]P
7,8-diol-9,10-epoxide-2 applied 5
min later. Treatment of mice with
2500 nmol of ellagic acid 5 min
before the application of 50 nmol of
B[a]P inhibited the mean number of
skin tumors per mouse by 28-33%
after 15-20 weeks of promotion, but
these decreases were not
statistically significant. Robinetin
and quercetin had little or no
effect on the tumor-initiating
activity of B[a]P on mouse skin.
Treatment of preweanling mice with
1/7, 2/7 and 4/7 of the total dose
of ellagic acid (300 nmol),
robinetin (1400 nmol), myricetin
(1400 nmol) or quercetin (1400 nmol)
i.p. on their first, eighth and
fifteenth day of life, respectively,
did not cause the formation of
tumors in animals that were killed
9-11 months later. Similar treatment
of preweanling mice with the above
doses of the phenolic compounds 10
min before the i.p. injection of a
total dose of 30 nmol of B[a]P
7,8-diol-9,10-epoxide-2 during the
animal's first 15 days of life
caused a 44-75% inhibition in the
number of diol-epoxide-induced
pulmonary tumors per mouse. Similar
treatment with these plant phenols
had little or no effect on B[a]P-induced
pulmonary tumors.
PMID: 3926336 [PubMed - indexed for
MEDLINE]
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Inhibition of benzo(a)pyrene and
benzo(a)pyrene-trans-7,8-diol
metabolism and DNA binding in mouse
lung explants by ellagic acid.
Dixit R,
Teel RW,
Daniel FB,
Stoner GD.
The effect of ellagic acid, a
naturally occurring plant phenol, on
the binding to DNA and metabolism of
benzo(a)pyrene (BP) and
trans-7,8-dihydro-7,8-dihydroxybenzo(a)pyrene
(BP 7,8-DHD) in cultured explants of
strain A mouse lung was
investigated. The explants were
cultured in a rocking organ culture
chamber for 16 h in the presence or
absence of 10, 25, 50, and 100
microM ellagic acid. These
concentrations of ellagic acid were
nontoxic as determined by
biochemical and histological
methods. The ellagic acid was then
removed from the cultures, and the
explants were incubated with either
1 microM [3H]BP or [3H]BP 7,8-DHD
for 24 h. Explant DNA was isolated
using hydroxylapatite
chromatography, and the BP
metabolites in the medium were
analyzed by high-pressure liquid
chromatography. Ellagic acid (50
microM) inhibited the binding of BP
and BP 7,8-DHD to lung DNA by 46 to
50% and 60 to 70%, respectively.
High-pressure liquid chromatography
analysis showed that ellagic acid
(100 microM) inhibited the
metabolism of BP by 20 to 40% and of
BP 7,8-DHD by 20%, as indicated by
the increased amounts of
unmetabolized substrates and
decreased amounts of metabolites in
the medium. The major BP:DNA adduct
in the explants was 7R-N2-[10
beta-[7 beta, 8 beta, 9
alpha-trihydroxy-7,8,9,10-tetrahydrobenzo(a)pyrene]yl:
deoxyguanosine, and its formation
was reduced by 60 to 65% in the
presence of 100 microM ellagic acid.
These data suggest that the
reduction of BP and BP 7,8-DHD
metabolite binding to DNA by ellagic
acid may have been due to inhibition
of the formation and/or removal of
BP 7,8-diol-9,10-epoxide prior to
its binding to DNA.
Publication Types:
PMID: 4039974 [PubMed - indexed for
MEDLINE]
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Ellagic acid: a potent naturally
occurring inhibitor of
benzo[a]pyrene metabolism and its
subsequent glucuronidation,
sulfation and covalent binding to
DNA in cultured BALB/C mouse
keratinocytes.
Mukhtar H,
Del Tito BJ Jr,
Marcelo CL,
Das M,
Bickers DR.
The metabolism of [3H]benzo[a]pyrene
(BP) by cultured primary
keratinocytes prepared from BALB/C
mouse epidermis was found to be
largely inhibited by the dietary
plant phenol, ellagic acid. Varying
concentrations of ellagic acid added
to the keratinocyte cultures
resulted in a dose-dependent
inhibition of the cytochrome
P-450-dependent monooxygenases aryl
hydrocarbon hydroxylase (AHH) and
7-ethoxycoumarin-O-deethylase (ECD).
The major organic
solvent-extractable metabolites
found intracellularly in the
cultured cells were
trans-7,8-dihydro-7,8-dihydroxybenzo[a]-pyrene
(BP-7,8-diol) and
3-hydroxybenzo[a]pyrene (3-OH-BP),
although small amounts of
9-hydroxybenzo[a]pyrene, quinones
and
trans-9,10-dihydro-9,10-dihydroxybenzo[a]-pyrene
(BP-9,10-diol) were also present.
The major organic
solvent-extractable metabolites
found in the extracellular culture
medium were BP-7,8-diol and
BP-9,10-diol, with smaller
quantities of unconjugated phenols
and quinones. The major
intracellular and extracellular
water-soluble metabolites of BP were
conjugated with glucuronide
(primarily 3-OH-BP and several BP-quinones),
and to a lesser extent with sulfate
(primarily BP-7,8-diol). Both
intracellular and extracellular
metabolism of organic
solvent-extractable and
water-soluble conjugates was
significantly inhibited by ellagic
acid in a dose-dependent manner. The
intracellular enzyme-mediated
binding of BP to mouse keratinocyte
DNA was also largely inhibited in a
dose-dependent fashion by ellagic
acid. Our results indicate that
cultured primary mouse keratinocytes
offer a useful model system for
studying factors affecting the
metabolic activation and
detoxification of polycyclic
aromatic hydrocarbon carcinogens in
the epidermis, and that polyphenolic
compounds such as ellagic acid may
prove useful in modulating the risk
of cutaneous cancer that results
from exposure to these environmental
chemicals.
Publication Types:
PMID: 6333937 [PubMed - indexed for
MEDLINE]
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Protection against
3-methylcholanthrene-induced skin
tumorigenesis in Balb/C mice by
ellagic acid.
Mukhtar H,
Das M,
Del Tito BJ Jr,
Bickers DR.
Topical application of ellagic acid,
a naturally occurring dietary plant
phenol, to Balb/C mice resulted in
significant protection against
3-methylcholanthrene (MCA)-induced
skin tumorigenesis. Ellagic acid was
found to be an effective inhibitor
of tumor formation whether the tumor
data are considered as percent mice
with tumors, cumulative number of
tumors, tumors per mouse or tumors
per tumor bearing animal as a
function of the number of weeks on
test. By 8, 10, 12, 14, and 16 weeks
of testing, the number of tumors per
mouse in the group receiving MCA
alone was 2.0, 3.4, 4.0, 4.9 and
5.3, respectively, whereas the
corresponding numbers in the group
receiving MCA plus 2 mumol ellagic
acid were 0, 0.3, 0.4, 0.6 and 1.2,
respectively. At the termination of
the experiment (16 weeks) aryl
hydrocarbon hydroxylase (AHH)
activity in skin and liver and the
extent of 3H-BP-binding to skin,
liver and lung DNA were determined
and both of these parameters were
found to be significantly inhibited
in the animals treated with ellagic
acid. These results indicate that
ellagic acid can inhibit the
metabolism of polyaromatic
hydrocarbons and modulate skin
carcinogenesis induced by these
chemicals.
Publication Types:
PMID: 6324772 [PubMed - indexed for
MEDLINE]
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Protective effects of ellagic
acid and other plant phenols on
benzo[a]pyrene-induced neoplasia in
mice.
Lesca P.
The inhibitory effects of three
phenolic compounds (ferulic,
chlorogenic and ellagic acids) on
benzo[a]pyrene- and
7,12-dimethylbenz[a]anthracene-induced
neoplasia have been investigated in
mice. Ellagic acid was the most
potent antagonist of tumorigenesis
since this compound is active, by
i.p. administration or added in the
diet, on benzo[a]pyrene-induced
pulmonary adenoma formation in A/J
mice and, after topical application,
on
7,12-dimethylbenz[a]anthracene-induced
skin tumorigenesis in NMRI Swiss
mice. If ellagic acid has little or
no effect on the number of tumor
bearing animals, the incidence of
pulmonary tumors per animal is
decreased by greater than 50%.
Ferulic acid and chlorogenic acid (5
X 100 mg/kg, by i.p. route) were
also active, but less than ellagic
acid, against the lung
carcinogenesis by benzo[a]-pyrene
(100 mg/kg, i.p.) but were totally
ineffective against the formation of
skin tumors by
7,12-dimethylbenz[a]anthracene.
These results remarkably paralleled
the in vitro antimutagenic effects
of these compounds shown by Wood et
al. on benzo[a]pyrene. It must be
noted that ellagic acid only
exerted, by i.p. route, a severe
toxicity after four injections of
100 mg/kg, in oil suspension,
whereas the oral administration in
the diet (a daily dose of 100 mg/kg
during 15 days) did not cause any
toxicity.
Publication Types:
PMID: 6317220 [PubMed - indexed for
MEDLINE]
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Inhibition of epidermal
metabolism and DNA-binding of
benzo[a]pyrene by ellagic acid.
Del Tito BJ Jr,
Mukhtar H,
Bickers DR.
Ellagic acid, a common plant phenol,
was shown to be a potent inhibitor
of epidermal microsomal aryl
hydrocarbon hydroxylase (AHH)
activity in vitro, and of
benzo[a]pyrene (BP)-binding to both
calf thymus DNA in vitro and to
epidermal DNA in vivo. The in vitro
addition of ellagic acid (0.25-2.0
microM) resulted in a dose-dependent
inhibition of AHH activity in
epidermal microsomes prepared from
control or carcinogen-treated
animals. The I50 of ellagic acid for
epidermal AHH was 1.0 microM making
it the most potent inhibitor of
epidermal AHH yet identified. In
vitro addition of ellagic acid to
microsomal suspensions prepared from
control or coal tar-treated animals
resulted in 90% inhibition of
BP-binding to calf thymus DNA.
Application of ellagic acid to the
skin (0.5-10.0 mumol/10 gm body wt)
caused a dose-dependent inhibition
of BP-binding to epidermal DNA. Our
results suggest that phenolic
compounds such as ellagic acid may
prove useful in modulating the risk
of cutaneous cancer from
environmental chemicals.
Publication Types:
PMID: 6309171 [PubMed - indexed for
MEDLINE]
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Plasma prekallikrein (Fletcher
factor) deficiency in a patient with
chronic lymphocytic leukemia.
Waddell CC,
Brown JA,
Udden MM.
We have described the first patient
to be reported in whom plasma
prekallikrein (Fletcher factor)
deficiency and chronic lymphocytic
leukemia were both present. This
most likely represents a
coincidental occurrence, but the
markedly elevated peripheral blood
lymphocyte count and the detection
of the defect using ellagic acid are
unique for Fletcher factor
deficiency.
Publication Types:
PMID: 6905267 [PubMed - indexed for
MEDLINE]
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Enhancement of pulmonary
metastases following the intravenous
infusion of a suspension of ellagic
acid in traumatized rats.
Agostino D,
Agostino N.
A significant shortening of the
silicone and glass clotting times
and a reduction of oozing from the
exposed femoral veins was observed
following the infusion of EA.
Ellagic acid significantly enhanced
metastases formation; and in
traumatized animals its effect was
more pronounced. No definite
explanation on the combined effect
of trauma and EA can be offered at
this time; however several
possibilities are discussed. There
was no obvious untoward side effect
of EA in any of the animals studied.
Publication Types:
PMID: 7445109 [PubMed - indexed for
MEDLINE]
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[Influence of ellagic acid and
heparin on coagulation, fibrinolysis
and metastasis in traumatized
animals (author's transl)]
[Article in Spanish]
Agostino D,
Agostino N.
Publication Types:
PMID: 7221832 [PubMed - indexed for
MEDLINE]
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Induction of acute cholecystitis
by activation of factor XII.
Becker CG,
Dubin T,
Glenn F.
Acute, acalculous cholecystitis is
seen among patients suffering with
bacterial sepsis, burns, trauma, or
cancer; clinical conditions that
could lead to activation of factor
XII-dependent pathways and result in
inflammation of the gall bladder. To
test this hypothesis, dogs were
injected intravenously with ellagic
acid or rutin, known polyphenol
activators of factor XII, or with
Escherichia coli endotoxin, also
known to activate factor XII, and
monkeys were injected intravenously
with ellagic acid. In both species,
in vivo activation of factor
XII-dependent pathways with
polyphenol activator resulted in
rapid and selective development of
acute vasculitis in the serosa and
muscularis of the gallbladder and
margination of polymorphonuclear
neutrophils in pulmonary blood
vessels. Intravenous injection of E.
coli endotoxin in dogs resulted in
necrosis and thrombosis of vessels
that were especially severe in the
serosa and muscularis of the
gallbladder but also present in
vessels of many other organs. These
observations indicate that blood
vessels of the gall bladder and, to
a lesser degree, the lung are
especially sensitive to injury
consequent to in vivo activation of
factor XII-dependent pathways and,
in view of the common ingestion of
plant polyphenols, may provide
important insight into the
pathogenesis of cholecystitis in
man.
Publication Types:
PMID: 6765972 [PubMed - indexed for
MEDLINE]
PMCID:
PMC2185753
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[The influence of ellagic acid on
the oncolytic effect of clostridium
M55 (author's transl)]
[Article in German]
Möse JR,
Fischer G.
Publication Types:
PMID: 4370579 [PubMed - indexed for
MEDLINE]
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Experimental hypercalcaemia and
whole blood clotting.
Hilgard P.
Experimental hypercalcaemia was
induced in rats by (1)
transplantation of the solid Walker
256 tumour, and (2) intraperitoneal
injections of calcium gluconate.
Whole blood clotting was studied by
means of thromboelastography and
whole blood clotting times in
polystyrene and glass test tubes. At
serum calcium levels between 10.3
and 11.5 m-equiv/l a slight delay in
clot formation was found which was
reversible by the addition of EDTA
to whole blood. Acute, calcium-gluconate-induced
hypercalcaemia, however, leads to a
significant shortening of the
clotting time in the polystyrene
tube and to a lesser degree in the
glass tube. Maximal factor XII
activation in vitro with ellagic
acid levels the difference of
clotting times again. From these
experiments it is concluded that
acute hypercalcaemia induces a
hypercoagulable state, possibly by
partial contact activation, and thus
may favour thrombus formation in
vivo.
PMID: 4200324 [PubMed - indexed for
MEDLINE]
PMCID:
PMC477835
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Enhancement of pulmonary
metastases following the intravenous
infusion of a suspension of ellagic
acid.
Agostino D.
PMID: 5422227 [PubMed - indexed for
MEDLINE]
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[Ellagic acid and hemostasis]
[Article in Italian]
Girolami A.
PMID: 5317297 [PubMed - indexed for
MEDLINE]
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Endotoxin, epinephrine, and
ellagic acid effects on the
radiation-sensitized walker 256 rat
carcinosarcoma.
Contreras MD,
Bale WF.
Department of Radiation Biology and
Biophysics, University of Rochester
School of Medicine and Dentistry,
Rochester, New York, USA.
A radiation exposure of 1500 R to
the Walker 256 rat tumor was found
to sensitize this tumor to the
effect of a sublethal dose of
endotoxin (Sarratia marcescens
lipopolysaccharide) given 2 days
later so that complete or almost
complete destruction of the tumor
resulted. Histological. study showed
rapidly developing massive necrosis
of tumor tissue. Tracer experiments
with 131I-labeled antibody to rat
fibrin indicated an absence of blood
circulation in the treated tumor.
These results suggest that the
lesion may be secondary to blood
coagulation occurring in the
vascular bed of the tumor.
Apparently identical lesions were
also produced by epinephrine and
ellagic acid, alone or in
combination. It is known that even
untreated tumors are often the site
of fibrin deposition. Presumably
radiation, by injury to tumor cells,
enhances the release of
coagulation-producing substances
into the vascular bed. It is
postulated that the effect of
subsequent treatment with the drugs
listed above is produced by
circulatory stasis induced in the
tumor. This may be associated with
Hageman factor activation or release
of platelet factor 3.
Publication Types:
PMID: 17387937 [PubMed - indexed for
MEDLINE]
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[Effect of ellagic acid on the
latency and the development of I.R.E.
solid reticulosarcoma]
[Article in Italian]
Fumarola D,
Marcuccio L,
Restuccia P.
PMID: 4988236 [PubMed - indexed for
MEDLINE]
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