The Hepatocarcinogenicity of Tannic Acid · The Hepatocarcinogenicity of Tannic Acid B. KORP.g-ssY...
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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- ment 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. It 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, at 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. 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 an 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). It 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 that 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- 501 Research. on May 13, 2020. © 1959 American Association for Cancer cancerres.aacrjournals.org Downloaded from
Transcript of The Hepatocarcinogenicity of Tannic Acid · The Hepatocarcinogenicity of Tannic Acid B. KORP.g-ssY...
The Hepatocarcinogenicity of Tannic Acid
B. KORP.g-ssY
(Department of Pathological Anatomy 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- ment of thermal burns with tannic acid was sug- gested by Davidson (1935), and his procedure was generally employed in Hungary during World War II. I t 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 fat ty 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/ra t . 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.
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 t reatment was shrunken, and it surface was coarsely granular. Thus, the liver changes induced by tannic acid t reatment 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 an 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 t reatment 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 tha 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-
501
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502 Cancer Research Vol. 19, June , 1959
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 tha 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).
Induct ion of liver tumors . - -One drawback of subcutaneous administration is that the toxic ef- fect of tannic acid is great and tha 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 mg/kg 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.
gave rise to ulceration of the skin, these ulcers rapidly and completely healed if the t rea tment 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 tha 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 tha t the leukemoid reaction elicited by long-lasting tannic acid t reatment may, in exceptional cases, result in a true leukemia (24). I t should be noted tha t in the strain of ra t which we have used for 10 years spontaneous tumors rarely occurred; those observed were of
Korp~ssy and Bart6k, unpublished experiments.
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KoRPXSsY--Hepatocarcinogenicity of Tannic Acid 503
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 re 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
(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.
REFERENCES 1. BAKER, R. D., and HANDLER, P. Animal Experiments
with Tannic Acid. Ann. Surg., 118:417-26, 1943. 2. CAMERON, G. R.; MILTON, R. F.; and ALLEN, J. W.
Toxicity of Tannic Acid. An Experimental Investigation. The Lancet, 2:179-86, 1943.
a Obtained through Johnson & Sons, Ltd., Hendon, London, N.W.4.
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504 Cancer Research Vol. 19, June, 1959
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: $66- 73, 1949.
17. - - . Haemorrhagic Gastric Erosions and Duodenum Pigmentation in Rats Following Parenteral Administration of Solutions of Tannic Acid. Acta physiol. Hung., 1:125- 30, 1950.
18. Komes B.; Kovs K ; and SZTANOJEV~TS, A. Influ- ence of Sex and Dietary Casein Content upon Lethal and Liver Injurious Effect of Tannic Acid. Acta Physiol. Hung., 3:233-41, 195~.
19. KORP~SSY, B., and MosoNrI, M. The Carcinogenic Activ- ity of Tannic Acid. Liver Turnouts Induced in Rats by Prolonged Subcutaneous Administration of Tannic Acid Solutions. Brit. J. Cancer, 4:411-20, 1950.
~0. ~ . The Carcinogenic Action of Tannic Acid. Effect of Casein on the Development of Liver Tumours. Acta Morph. Hung., 1:87-54, 1951.
21. ~ . Influence of Dietetic Factors on Carcinogenic Ac- tivity of Tannic Acid. Lancet, 1:1416, 1951.
22. - - . Infuence of Dietary Protein on the Carcinogenic Activity of Tannic Acid. Acta Morph. Hung., 3:853-62, 1953.
23. KORPkSSu B.; MOSONYI, M.; SZTAI~OJEVITS, A.; and TRAUB, A. Chronic Local Irritation and Acetylamino- fluorene Carcinogenesis. Ceskoslovenska Oncologia, 2: 308-16, 1955.
.~4. KORP.~.SSY, B.; SZTANOJEVITS, A. ; and KOLTAY, N. A Pre- liminary Study on Haemoblastoses Produced in Rats by Tannic Acid. Acta Morph. Hung., 4:91-102, 1954.
~5. KORP~SSr, B.; T(iRSK, J.; and Kovkcs, K. Endokrine Ver~nderungen bei experimenteller akuter Gerbs~urever- giftung mit besonderer RUcksicht auf die Nebennieren- rinde. Acta Physiol. Hung., 1:113-24, 1950.
~6. KOV.~CS, K.; BACHRACH, D.; JACOBOVITS, A.; HORV~TH, ]~. ; SZTANOJEVITS, A. ; and KoaP$.ssr, B. Histomorphologi- cal Changes following Aspecific Damage in the Anterior 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 Alarm Reaction. Acta Physiol. Hung., 3: 243-53, 195~.
28. MARTINEK, R. G., and WOLMAN, W. Xanthines, Tannins, and Sodium in Coffee, Tea and Cocoa. J.A.M.A., 158: 1030-31, 1955.
s MosoNYI, M., and KORP~SSr, B. Rapid Production of Malignant Hepatomas by Simultaneous Administration of Tannic Acid and 2-Acetylaminofluorene. Nature, 171: 791, 1953.
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- aminoazobenzene. Cancer Research, 11:398-403, 1951.
3~. RICHARDSON, H. L.; O'NEAL, M. A.; ROBERTSON, C. H.; and GRIFFIN, A. C. The Role of Hormones in Azo-Dye In- duction of Liver Cancer and the Adrenal-lipoid Response 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.
34. THUNBERG, T. Tannin und Dehydrogenasen. Ein Beitrag zu Frage der biologischen Wirkungen der Gerbstoffe. Skand. Arch. Physiol., 73:199-210, 1936.
35. TRUHAUT, R. Les dangers de canc~risation, r~sultant de la presence de substances ~trangeres dans les aliments. Arz- helm. Forsch., 5:613-24, 1955.
36. WELLS, D. B.; HUMPHREY, H. D.; and COLL, J. J. The Relation of Tannic Acid to the Liver Necrosis Occurring in Burns. New England J. Med., 226:629-35, 1942.
37. Conference on Experimental Hepatomas. J. Nat. Cancer Inst. (SuppI 'lmti: 1417-1650, 1955.
38. Ministry of ~'ood Bulletin, 13 June, 1953; Nr. 705; Station- ery Office, London.
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 ml . )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.
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.
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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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504 Cancer Research Vol. 19, June, 1959
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: $66- 73, 1949.
17. - - . Haemorrhagic Gastric Erosions and Duodenum Pigmentation in Rats Following Parenteral Administration of Solutions of Tannic Acid. Acta physiol. Hung., 1:125- 30, 1950.
18. Komes B.; Kovs K ; and SZTANOJEV~TS, A. Influ- ence of Sex and Dietary Casein Content upon Lethal and Liver Injurious Effect of Tannic Acid. Acta Physiol. Hung., 3:233-41, 195~.
19. KORP~SSY, B., and MosoNrI, M. The Carcinogenic Activ- ity of Tannic Acid. Liver Turnouts Induced in Rats by Prolonged Subcutaneous Administration of Tannic Acid Solutions. Brit. J. Cancer, 4:411-20, 1950.
~0. ~ . The Carcinogenic Action of Tannic Acid. Effect of Casein on the Development of Liver Tumours. Acta Morph. Hung., 1:87-54, 1951.
21. ~ . Influence of Dietetic Factors on Carcinogenic Ac- tivity of Tannic Acid. Lancet, 1:1416, 1951.
22. - - . Infuence of Dietary Protein on the Carcinogenic Activity of Tannic Acid. Acta Morph. Hung., 3:853-62, 1953.
23. KORPkSSu B.; MOSONYI, M.; SZTAI~OJEVITS, A.; and TRAUB, A. Chronic Local Irritation and Acetylamino- fluorene Carcinogenesis. Ceskoslovenska Oncologia, 2: 308-16, 1955.
.~4. KORP.~.SSY, B.; SZTANOJEVITS, A. ; and KOLTAY, N. A Pre- liminary Study on Haemoblastoses Produced in Rats by Tannic Acid. Acta Morph. Hung., 4:91-102, 1954.
~5. KORP~SSr, B.; T(iRSK, J.; and Kovkcs, K. Endokrine Ver~nderungen bei experimenteller akuter Gerbs~urever- giftung mit besonderer RUcksicht auf die Nebennieren- rinde. Acta Physiol. Hung., 1:113-24, 1950.
~6. KOV.~CS, K.; BACHRACH, D.; JACOBOVITS, A.; HORV~TH, ]~. ; SZTANOJEVITS, A. ; and KoaP$.ssr, B. Histomorphologi- cal Changes following Aspecific Damage in the Anterior 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 Alarm Reaction. Acta Physiol. Hung., 3: 243-53, 195~.
28. MARTINEK, R. G., and WOLMAN, W. Xanthines, Tannins, and Sodium in Coffee, Tea and Cocoa. J.A.M.A., 158: 1030-31, 1955.
s MosoNYI, M., and KORP~SSr, B. Rapid Production of Malignant Hepatomas by Simultaneous Administration of Tannic Acid and 2-Acetylaminofluorene. Nature, 171: 791, 1953.
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- aminoazobenzene. Cancer Research, 11:398-403, 1951.
3~. RICHARDSON, H. L.; O'NEAL, M. A.; ROBERTSON, C. H.; and GRIFFIN, A. C. The Role of Hormones in Azo-Dye In- duction of Liver Cancer and the Adrenal-lipoid Response 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.
34. THUNBERG, T. Tannin und Dehydrogenasen. Ein Beitrag zu Frage der biologischen Wirkungen der Gerbstoffe. Skand. Arch. Physiol., 73:199-210, 1936.
35. TRUHAUT, R. Les dangers de canc~risation, r~sultant de la presence de substances ~trangeres dans les aliments. Arz- helm. Forsch., 5:613-24, 1955.
36. WELLS, D. B.; HUMPHREY, H. D.; and COLL, J. J. The Relation of Tannic Acid to the Liver Necrosis Occurring in Burns. New England J. Med., 226:629-35, 1942.
37. Conference on Experimental Hepatomas. J. Nat. Cancer Inst. (SuppI 'lmti: 1417-1650, 1955.
38. Ministry of ~'ood Bulletin, 13 June, 1953; Nr. 705; Station- ery Office, London.
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 ml . )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.
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.
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