The Hepatocarcinogenicity of Tannic Acid
B. KORP.g-ssY
(Department of PathologicalAnatomy and Pathohistology, University Medical School, Szeged, tlungary)
In the group of chemical hepatocarcinogenic
agents, the number of which has steadily increased
in recent years (:$7), tannic acid deserves attention.
Owing to its astringent effect, this compound was
formerly used widely in therapy. The local treat-
m e n t of thermal burns with tannic acid was sug-
gested by Davidson (1935), and his procedure
was generally employed in Hungary during World
War II. It was in the course of this war that
the hepatotoxic action of tannic acid was recog-
nized (1, 3, 4, 7, 36). Since the results of Anglo-
Saxon scientific investigations were, on account
of the war, unknown in Central Europe, nobody
in Hungary was informed about the hepatotoxic
effect of tannic acid before 1946.
Liver damage and cirrhosis.--On the basis of
comparative histologic examinations of the liver
of individuals who had died of burns which were
treated with tannic acid and/or untreated, we
suspected the hepatotoxic effect of this substance
as early as 1943-43. This suspicion was fully
confirmed by animal experiments, but our results
could not, because of the war, be presented before
1946, and the experiments had to be repeated,
because our files had been lost for the same reason.
I t was shown in those experiments that tannic
acid is a selective poison of liver parenchyma,
the effect of which manifests itself, depending
on the dose and the route of administration, in
acinocentral necrosis of varying extent. The dis-
appearance of glycogen from the cytoplasm of
liver cells is an early phenomenon, but it is not
followed by fatty degeneration (12).
Next, we demonstrated the cirrhogenous effect
~f tannic acid. White rats were given repeatedly,
a t intervals of several days, subcutaneous injec-
tions of tannic acid as a 1 per cent watery solution
for the first ten doses, and thereafter as a 3
per cent solution, in graded doses of 10-70 mg/rat.
This treatment resulted in a gradual transforma-
tion of liver architecture (Fig. 1). In the early stages
(up to the 40th day) breakdown and subsequent
regeneration of the liver cells were the most strik-
ing features, with a frequent acinocentral collapse
of the argentophilic fibrous meshwork. Another
Received for publication December 5, 1958.
501
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Research.
early phenomenon was the swelling and increase
of the cells constituting the retieulo-histiocyte
system. In the 8d month of treatment, the diffuse
proliferation of connective tissue was rather con-
spicuous. Pseudolobuli appeared, and the prolif-
eration of small bile duets could frequently be
observed. The liver of the rats that survived
beyond the 100th day of treatment was shrunken,
and it surface was coarsely granular. Thus, the
liver changes induced by tannic acid treatment
were very similar to the so-called postnecrotie
or posthepatitic cirrhosis (16).
Stressor effect of tannic acid.--The parenteral
administration of tannic acid also resulted in a n
intensive systemic stress (35, 37). In the course
of protracted administration of tannic acid, the
cytologic evidence of increased neurosecretory ac-
tivity was found in the anterior hypothalamic
nuclei (36). Further, male rats were found to be
more susceptible than females to the lethal doses
of tannic acid. In acute experiments twice as
many males as females died before the 60th hour,
whereas with chronic treatment 61 per cent of
females, but only 33 per cent of the males, were
alive on the 300th day. A high casein (30 per cent)
diet gave some protection against the lethal and
hepatotoxic action of tannic acid: of the rats
kept on a low casein (1 per cent) diet, exactly
twice as many died, before the 103th hour, as
of those kept on a high casein diet (18). I t should
be mentioned that acute poisoning with tannic
acid may often be attended by gastric erosion
(17); in the course of protracted treatment, u]cers
are found in nearly 70 per cent of the rats at
the pyloric region (33).
Absorption of tannic acid from the gastrointestinal
tract.--The question whether tannic acid adminis-
tered orally is absorbed from the alimentary tract
was also studied. Handler and Baker (10) claimed
t h a t the gastrointestinal mucosa was, in their
experiments on rats, impermeable to tannic acid.
We administered to rabbits and dogs aqueous
solutions of tannic acid in several concentrations
(3.5, 5, and 10 per cent), tea, and claret by
stomach tube. We then examined blood samples,
taken at various times, by a photometric micro-
 502 Cancer Research
method based on the reduction of arsenotungstic
acid. The ingestion of the compounds was soon
followed by a rapid increase in the level of tannic
acid in the blood. Peak effects were observed
at 3 hours (55-110 gg/cu cm plasma); the con-
centration then gradually diminished, and by the
end of 24 hours the blood contained no tannic
acid (14). Histological examination revealed t h a t
the hepatotoxic effect after oral administration
was similar to that observed after parenteral treat-
ment (15). Long-lasting treatment (over 180 days)
of rats per os also resulted in cirrhosis, if the dose
given per os exceeded by several times the usual
parenteral dose (a total amount of 10-15 gin.
tannic acid given in 90-120 doses was effective)
(11).
Induction of liver t u m o r s . - - O n e drawback of
subcutaneous administration is that the toxic ef-
fect of tannic acid is great and t h a t the skin
undergoes necrosis and subsequent ulceration at
the place of injections. For this reason the majority
of the animals died early in the experiment. (The
lethal effect is influenced by dose, method of
administration, age, sex, and diet.) Nevertheless,
when 150-200 m g / k g body weight was injected
subcutaneously every 5th day in a 1.5 or ~ per
cent aqueous solution, 30-50 per cent of the ani-
mals survived for ~00, and 5-15 per cent for
300, days. Of the animals that survived the 100th
day of treatment, hepatomas and/or cholangiomas
developed in about 56 per cent. Liver tumors
induced by this approach were always multiple
and mostly benign, although invasion of the liver
veins and an atypical pattern seen in some eases
suggest that the possibility of low-grade malig-
nancy should be considered (13, 19, ~0).
The hepatocarcinogenic effect was inhibited by
a high casein-low fat diet (25 per cent casein,
5 per cent oil) and promoted by a diet containing
little casein and much fat (3 per cent casein,
~0 per cent sunflower oil). On the other hand,
the cirrhogenous effect of tannic acid could not
be influenced by the casein and fat content of
the food. Although the survival of the rats main-
tained on a high casein-low fat diet was somewhat
longer than that of the animals fed a low casein-
high fat diet, liver tumors occurred in the latter
group twice as frequently (67.5 per cent) as in
the former (29.7 per cent). The diet containing
little casein and much fat exerted, by itself, no
carcinogenic or cirrhogenous effect (21, 22). Vita-
min B12 (Berubigen, Upjohn), 1 ~g/100 gm twice
weekly given intramuscularly, exerted no influence
on the hepatocarcinogenic effect of tannic acid. 1
Although subdermal application of tannic acid
i Korphssy and Mosonyi, unpublished experiments.
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Vol. 19, J u n e , 1959
gave rise to ulceration of the skin, these ulcers
rapidly and completely healed if the treatment
was stopped temporarily or if the injections were
given at another site. In no case did a tumor arise
from the margin of an ulcer or from the healed
scars. Local carcinogenic effects were not observed
even when the skin ulcers of rats produced by
thermocauterization were painted with tannic acid
for 1 year (19). Local carcinogenic effects were
not observed with white mice either, when their
skin was treated with a tannic acid solution for
a longer time. These mice showed no hepatic
tumors. 2
The simultaneous administration of tannic acid
and ~-acetvlaminofluorene (tannic acid oarenteral-
ly, AAF in the food) showed t h a t tannic acid
greatly enhanced the hepatocarcinogenic action
of ~-acet:vlaminofluorene. On the lS0th day of
the experiment, 9~ per cent of the rats treated
with both substances, but onlv ~8 per cent of
the rats treated only with AAF. developed liver
tumors, aside from the fact that in the first group
metastases were also present. The incidence in
rats treated with tannic acid alone was about
50 per cent. Among the animals treated with both
compounds, advanced liver c;rrhosis frequently
occurred, in contrast to the mild hepatic changes
found in the animals treated only with AAF.
These experiments suggest that liver cirrhosis is
an important promoting factor in liver carcino-
genesis (29).
In the liver of rats treated with tannic acid
per o8 or parenterally for a long time, the appear-
ance of small loci of myeloid metaplasia was a
common phenomenon. At the same time, hyper-
cellular bone marrow was found. In a few animals
treated for a long time, leukemic myelosis de-
veloped, as seen from the tremendous enlargement
of the spleen and the disappearance of its normal
pattern, as well as the myeloid infiltration in
various organs. The high grade of anaplasia and
the mass of mitotic nuclei indicated stem-cell
leukemia.
Massive deposition of a yellowish-brown, iron-
containing pigment, especially in the spleen, may
be considered a sign of intravascular hemolysis.
Thus, the occurrence of extramedullary hemo-
poietic loci may be regarded as a compensatory
process. I t is supposed t h a t the leukemoid reaction
elicited by long-lasting tannic acid treatment may,
in exceptional cases, result in a true leukemia
(24). I t should be noted t h a t in the strain of
r a t which we have used for 10 years spontaneous
tumors rarely occurred; those observed were of
Korp~ssy and Bart6k, unpublished experiments.
 KoRPXSsY--Hepatocarcinogenicity of Tannic Acid
mesenchymal origin, but no spontaneous leukemia
was observed in untreated animals.
Histogenesis.--It seems that tumor formation
induced by tannic acid treatment in the liver
is related to the regenerative liver cell and bile
duct hyperplasia occurring as a sequel of repeated
breakdown of the parenchyma. The cholangio-
fibrosis observed, in the presence of the reparative
epithelial proliferation after the 100th day of
the experiment, is, in our view, a preneoplastic
change. The intense reticuloendothelial hyper-
plasia of the early phase later became less con-
spicuous. In our opinion cirrhosis is an important
promoting factor in hepatocarcinogenesis; tumor
formation, however, is not a necessary sequel
to this process.
When the action of tannic acid on liver is
compared with that of substances of quite dif-
ferent chemical composition (dimethylaminoazo-
benzene, ~-acetylaminofluorene, ethionine, carbon
tetrachloride, alkaloids of Senecio jacobaea, etc.),
one may be greatly impressed by the resemblance
in the sequence of pathologic changes. From this
point of view, the statement of Farber (5) deserves
to be quoted: "It therefore appears that many
different chemical compounds, capable of produc-
ing liver tumors in rats and mice, induce a similar
sequence of histological changes in which oval
cell hyperplasia, presumably of bile duct epithelial
origin, is prominent." We arrived, earlier, at the
same conclusion, with the difference that we be-
lieved the "oval ceils" to be of reticuloendothelial
origin (16, 19). I t is noteworthy that myeloid
metaplasia was also found in the liver in the
course of carcinogenesis by p-dimethylaminoazo-
benzene (31). This phenomenon is, in the opinion
of W. Fischer (6), rather characteristic.
Mechanism of action.--The metabolic changes
associated with tannic acid carcinogenesis are not
known. Thunberg (34) showed in 1936 that lan-
nic acid inhibited the hydrogenase activities in
certain crude seed and animal tissue extracts.
In an examination of endocrinologic relationships
tannic acid exhibited a strong s t r e t ~ r effect, mani-
festing itself in the activation of the adrenocortical
function of the pituitary and in the hypertrophy
of the zona fasciculata in the adrenal cortex.
Other authors (9, 3~) believe that a pituitary-
adrenal interrelationship may be a prerequisite
for liver cancer formation.
Source and chemistry.--A variety of tannic acids
is found in nature. These acids are polymers of
various hydroxybenzoic acids. The acid commonly
referred to as tannic acid is gallotannic acid. I t
is usually obtained from nutgall, an excrescence
on the young twigs of various species of Quercus
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Research.
503
(Goodman and Gilman, 1955). Even purified phar-
maceutical preparations of gallotannic acid con-
tain, however, in addition, pentadigaUoylglucose
and several other known or partly known organic
substances in small quantities, for example, ellagic
acid, quercitol, and quercic acid.
Oenotannic acid (contained in red wine) and
gallotannic acid (obtained from nutgall) are not
identical, the former belonging to the group of
condensated tannic acids or pyrocatechins, the
latter to the tannic acids having an ester binding.
To our knowledge, oenotannin is not available
commercially.
The tannic acid used in all our experiments
was Acid. tannic. U.S.P. 3
Human-pathologic relationships.--Since tannic
acid is no longer applied locally to thermal burns,
the substance is now ingested only with food.
As is known, certain beverages (tea, coffee, cocoa,
claret) contain varying amounts of tannic acid:
there are 94--475 mg. in a cup of tea, ~15-371
mg. in a cup of cocoa, and 90-187 mg. in a
cup of coffee (~8). "Light" clarets contain 0.1-1.15
per cent, "heavy" ones 0.~-0.3 per cent, those
obtained from Southern Europe 0.5 per cent or
more (30). Thus, at least 1-~ gm. tannic acid
is ingested with 1 liter claret. I t is not known
whether the tannic acid of red wine and that
obtained from nutgall act on the liver in the same
manner.
Among the so-called antioxidants used for the
preservation of fruits, vegetables, etc., there are
also derivatives of gallic acid. The British Com-
mittee for Alimentary Standards suggested as
an upper limit 0.01 per cent for pyrogallate and
0.0~ per cent for butylhydroxyanisole (35, 38).
In our opinion, the possibility that the excessive
consumption of tea, coffee, cocoa, or claret, as-
sociated with the absorption of their tannic acid
content may, especially if certain favorable dietetic
factors be present, result in hepatic damage should
become a subject of deliberation.
In considering the carcinogenicity of tannic
acid, the following properties are of particular
interest: (a) it is water-soluble; (b) it is weakly
carcinogenic and acts at a site distant from its
application; (c) its action on the liver is influenced
by dietetic and endocrinologic factors; and (d) it
enters the human organism via the food.
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504 Cancer Research
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Administered Tannic Acid. Science, 99:398, 1944.
11. KOLTAY,N., and KORPkSSr, B. Esperimenti per provocare
cirrosi epatica in ratti mediante soluzione di acido tannico
somministrato per via orale durante un periodo prolungato.
Arch. "de Vecchi," 17:307-28, 1951.
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13. - - . H~patomes et cholangiomes provoqu~s chez le rat
par administration sous-cutan~e d'acide tannique. Bull. du
Cancer, 37: 52-56, 1950.
14. KORPASsr, B.; HORVAI, R.; and KOLTAr, N. On the Ab-
sorption of Tannic Acid from the Gastro-intestinal Tract.
Arch. Internat. Pharmacodyn., 88: 368-77, 1951.
15. KoRP~,SSY, B.; KOLTAr, N.; and HORVAY, R. Toxizitiit
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ministration of Tannic Acid. Brit. J. Exper. Path., 30: $66-
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17. - - . Haemorrhagic Gastric Erosions and Duodenum
Pigmentation in Rats Following Parenteral Administration
of Solutions of Tannic Acid. Acta physiol. Hung., 1:125-
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18. Komes B.; Kovs K ; and SZTANOJEV~TS,A. Influ-
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21. ~ . Influence of Dietetic Factors on Carcinogenic Ac-
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FIG. 1.--Numerous mitoses in the regenerating liver paren-
chyma of a 105-gin. rat, treated 4 times with 2.5 per cent
aqueous tannic acid solution (3 m l . ) a t 2-hour intervals by
stomach tube. The rat was killed after 50 hours. Hematoxylin
& eosin. X400.
FIG. ~.--Proliferation of reticnloendotheliat (oval) cells in
the liver of a 120-gm. rat treated with 4 ml./5 per cent/tannic
acid solution by stomach tube once daily for 8 days. The
rat was killed on the 7th day. Hematoxylin and eosin. X400.
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Vol. 19, June, 1959
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Ver~nderungen bei experimenteller akuter Gerbs~urever-
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]~. ; SZTANOJEVITS,A. ; and KoaP$.ssr, B. Histomorphologi-
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Hypothalamic Nuclei of Rats. Acta Morph. Hung. 4:409-
416, 1954.
27. Kov~.cs, K., and KORPASSY,B. Effect of Dietary Protein
Content on the Hypophyseal Adrenocortical System and
the Lymphatic Organs of Normal Rats and of Rats in
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28. MARTINEK, R. G., and WOLMAN,W. Xanthines, Tannins,
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30. PETTENKOFFER,S. A bor~szat k~zlk(inyve. (A Textbook of
Oenology.) Budapest: Pallas, 1922.
31. RICHARnSON, H. L., and BOI~OS-NACHTNEBEI~ E. Study
of Liver Tumor Development and Histologic Changes in
Other Organs in Rats Fed Azo-Dye SP-Methyl-4-dimethyl-
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in Hypophysectomized Rats. Cancer, 7:1044-47, 1954.
33. SZTANOJEVITS, A.; M6NUS, B. Z.; and KORP~SsY, B. Ex-
perimentally Induced Gastric Ulcer in Rats. Problems of
the Pathogenesis. Acta med. Hung., 5:~51-65, 1954.
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zu Frage der biologischen Wirkungen der Gerbstoffe.
Skand. Arch. Physiol., 73:199-210, 1936.
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36. WELLS, D. B.; HUMPHREY, H. D.; and COLL, J. J. The
Relation of Tannic Acid to the Liver Necrosis Occurring in
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FIG. 8.--Completely transformed archilecture of the liver,
with the formation of pseudo-lobules. The rat, weighing 187
gm., was treated with 750 mg. tannic acid administered
subcutaneously in 28 doses. The rat was killed on the 141st
day. GCim~ri's reticuIum stain. X 100.
FiG. 4.--Coarse nodular cirrhosis. The rat was treated with
9,700 mg. tannic acid/kg body weight, administered subcu-
taneously in 48 injections, and died on the 278th day.
 q

.i

.j
q.

.i

9.

91

,u

Downloaded from cancerres.aacrjournals.org on October 6, 2019. © 1959 American Association for Cancer
Research.
 I~G. 5.--Polymorphism of the liver cells with an enormous
binucleale cell and proliferated oval cells. The rat was given
sixteen subcutareous injections, or a total of 320 mg. tannic
acid ; it was killed on the 71st day. Hematoxylin & eosin. X400.
FIG. 6.--Invasion of a large blood vessel in the liver.
The rat was treated with 4,~50 mg/kg body weight tannic
acid, administered in ~ doses,and died on the l ~ d day. )<3~0.
FIG. 7.--Atypical pattern in cholangioma simulating
low-grade adex~ocarcinoma. The rat was given a total of 9950
mg. tannic acid/kg body weight in 49 injections, and died
on the ~294th day. Hematoxylin & eosin. )<$60.
FIG. 8.--Cholangiocarcinema invading hepatic tissue of
rat (~':ee Fig. 6). Hernatoxylin & eosin. X400.

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Research.
504 Cancer Research
8. DAvxnsoN, E. C. Tannic Acid in the Treatment of Burns.
Surg. Gynec. & Obst., 41:~02, 1925.
4. ERB, I. H.; MORGAN, E. M.; and FAR~ER, A. W. The
Pathology of Burns. Ann. Surg., 117:~34-55, 1943.
5. FARBER,E. Similarities in the Sequence of Early Histologi-
cal Changes Induced in the Liver of the Rat by Ethionine,
~-Acetylaminofluorene, and $'-Methyl-4odimethylamino-
azobenzene. Cancer Research, 16:14~-48, 1956.
6. FISCHER, W. Durch Buttergelb erzeugte Tumoren. Arch.
Geschwalstforsch., 7: 301-~0, 1954.
7. FORBES, J. C., and EVANS, E. I. Tannic Acid and Liver
Necrosis. Surg. Gynec. & Obst., 76:61~-13, 1943.
8. GOODMAN, L. S., and GILMAN, A. The Pharmacological
Basis of Therapeutica. New York: MacMillan Co., 1955.
9. GRIFFIN, A. C.; RINFRET, A. P.; and CORSIGI~A, V, F.
The Inhibition of Liver Carcinogenesis with 8~-Methyl-4-
dimethylaminoazobenzene in Hypophysectomized Rats.
Cancer Research, 13: 77-79, 1953.
10. HANDLER, P., and BAKER, R. D. The Toxicity of Orally
Administered Tannic Acid. Science, 99:398, 1944.
11. KOLTAY,N., and KORPkSSr, B. Esperimenti per provocare
cirrosi epatica in ratti mediante soluzione di acido tannico
somministrato per via orale durante un periodo prolungato.
Arch. "de Vecchi," 17:307-28, 1951.
12. KoRPkssY, B. Leberschiidigung durch Gerbs~iure. Schweiz.
Ztschr. Path. u. Bakt., 12:13-23, 1949.
13. - - . H~patomes et cholangiomes provoqu~s chez le rat
par administration sous-cutan~e d'acide tannique. Bull. du
Cancer, 37: 52-56, 1950.
14. KORPASsr, B.; HORVAI, R.; and KOLTAr, N. On the Ab-
sorption of Tannic Acid from the Gastro-intestinal Tract.
Arch. Internat. Pharmacodyn., 88: 368-77, 1951.
15. KoRP~,SSY, B.; KOLTAr, N.; and HORVAY, R. Toxizitiit
peroral verabreichter Gerbsiiure. Wien. ]din. Wnsehr.,
62:270-71, 1950.
16. KoRPkSSr, B., and KovAcs, K. Experimental Liver Cir-
rhosis in Rats Produced by Prolonged Subcutaneous Ad-
ministration of Tannic Acid. Brit. J. Exper. Path., 30: $66-
73, 1949.
17. - - . Haemorrhagic Gastric Erosions and Duodenum
Pigmentation in Rats Following Parenteral Administration
of Solutions of Tannic Acid. Acta physiol. Hung., 1:125-
30, 1950.
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FIG. ~.--Proliferation of reticnloendotheliat (oval) cells in
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acid solution by stomach tube once daily for 8 days. The
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Research.
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FIG. 8.--Completely transformed archilecture of the liver,
with the formation of pseudo-lobules. The rat, weighing 187
gm., was treated with 750 mg. tannic acid administered
subcutaneously in 28 doses. The rat was killed on the 141st
day. GCim~ri's reticuIum stain. X 100.
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taneously in 48 injections, and died on the 278th day.
The Hepatocarcinogenicity of Tannic Acid
B. Korpássy

Cancer Res 1959;19:501.

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