The results of an electron microscopic study of the changes in hepatocytes induced by chronic intoxication with thioacetamide are reported. During the poisoning aspecific toxic changes are intermingled with progressive, preneoplastic ones. The main cell sub-populations identified are: 1) large hepatocytes with smooth endoplasmic reticulum (SER) hypertrophy, with or without rough endoplasmic reticulum (RER) neoformation and glycogen storage, which is starvation resistant; 2) smaller hepatocytes, where RER hypertrophy and ribosome accumulation are the prominent features. Such a pattern persists for months. After the withdrawal of the drug most of the cell changes disappear. However, during this time a simplification of the liver structure and cell composition takes place, allowing a sequence of cell events which seem relevant for establishment of neoplastic progression. The SER-hypertrophied cell appears first and gives rise, via several intermediate stages, to the RER-hypertrophied one, which is believed to play a key role as the ultimate precursor of cancer cells.
Get full access to this article
View all access options for this article.
References
1.
ApfelC.A.: The endoplasmic reticulum membrane system and malignant neoplasia. Prog. Exp. Tumor Res., 22: 317–362, 1978.
2.
BannaschP.: Die Cytologie der Hepatocarcinogenese. In: Handbuch der Allgemeinen Pathologic BdVI/7, pp. 123–176, Springer Verlag, Berlin-Heidelberg-New York, 1975.
3.
BannaschP., HesseJ., AngererH.: Hepatocelluläre Glykogenose und die Genese sogenannter hyperplastischer Knoten in der Thioacetamid-vergifteten Rattenleber. Virchows Arch. B. Cell Path., 17: 29–50, 1974.
4.
BruniC.: Distinctive cells similar to fetal hepatocytes associated with liver carcinogenesis by diethylnitrosamine. Electron microscopic study. J. Nat. Cancer Inst., 50: 1513–1528, 1973.
5.
DaoustR., MolnarF.: Cellular populations and mitotic activity in rat liver parenchyma during azo dye carcinogenesis. Cancer Res., 24: 1898–1909, 1964.
6.
DaoustR., CalamaiR.: Hyperbasophilic foci as sites of neoplastic transformation in hepatic parenchyma. Cancer Res., 31: 1290–1296, 1971.
7.
DemlE., OesterleD.: Histochemical demonstration of enhanced glutathione content in enzyme altered islands induced by carcinogens in rat liver. Cancer Res., 40: 490–491, 1980.
EpsteinS., ItoN., MerkowL., FarberE.: Cellular analysis of liver carcinogenesis. The induction of large hyperplastic nodules in the liver with 2-fluorenylacetamide or ethionine and some aspects of their morphology and glycogen metabolism. Cancer Res., 27: 1702–1711, 1967.
10.
FarberE.: Hyperplastic liver nodules. In: Methods in Cancer Research. Vol. 7, pp. 345–376, BuschH. (ed.), Academic Press, New York, 1974.
11.
FarberE.: The pathology of experimental liver cancer. In: Liver Cell Cancer. pp. 243–277, CameronH.M., LinsellD.A., and WarwickG.P. (eds.), Elsevier, Amsterdam, 1976.
12.
GilletteJ.R., JollowD.J.: Drug metabolism in liver. In: The Liver, Normal and Abnormal Functions, BeckerF. (ed.), Dekker, New York, 1974.
13.
GothoskarS.V., TalwalkarG.V., BhideS.V.: Tumorigenic effect of thioacetamide in Swiss strain mice. Br. J. Cancer, 24: 498–503, 1970.
14.
GuptaD.N.: Nodular cirrhosis and metastasizing tumors produced in the liver of rats by prolonged feeding with thioacetamide. J. Pathol. Bact., 72: 415–422, 1956.
KitagawaT.: Responsiveness of hyperplastic lesions and hepatomas to partial hepatectomy. Gann, 62: 217–224, 1971.
17.
KitagawaT., PitotH.C., MillerE.C., MillerJ.A.: Promotion by dietary phenobarbital of hepatocarcinogenesis by 2-methyl-N,N-dimethylaminoazobenzene in the rat. Cancer Res., 39: 112–115, 1979.
18.
MillerE.C.: Some current perspectives on chemical carcinogenesis on humans and experimental animals. Cancer Res., 38: 1479–1496, 1978.
19.
NoviA.M.: Liver carcinogenesis in rats after aflatoxin B1 administration. Curr. Top. Pathol., 65: 115–163, 1977.
20.
PerainoC., Michael FryR.J., GrubeD.D.: Drug induced enhancement of hepatic tumorigenesis. In: Carcinogenesis: Mechanisms of Tumor promotion and Cocarcinogenesis. Vol. 2, pp. 421–432, SlagaT.J., SivakA., BoutwellR.K. (eds.), Raven Press, New York, 1978.
21.
PorterW.R., NealR.A.: Metabolism of thioacetamide and thioacetamide-S-oxide by rat liver microsomes. Drug Metab. Dispos., 6: 379–388, 1978.
22.
PughT.D., GoldfarbS.: Quantitative histochemical and autoradiographic studies of hepatocarcinogenesis in rats fed 2-aceytlaminofluorene followed by phenobarbital. Cancer Res., 38: 4450–4457, 1978.
23.
ReddyJ., ChigaM., SvobodaD.: Initiation of the division cycle of rat hepatocyte following a single injection of TAA. Lab. Invest., 20: 405–411, 1969.
24.
ReesK.R., RowlandG.F., VarcoeJ.S.: The metabolism of tritiated thioacetamide in the rat. Int. J. Cancer, 1: 197–206, 1966.
25.
SchererE., EmmelotP.: Kinetics of induction and growth of precancerous liver cell foci and liver tumor formation by diethylnitrosamine in the rat. Eur. J. Cancer, 11: 689–696, 1975.
26.
ShettyT.K., NarurkarL.M., NarurkarM.V.: Cytoplasmic changes during thioacetamide induced hepatocarcinogenesis in rats. Br. J. Cancer, 25: 109–120, 1971.
27.
SoltB.D., MedlineA., FarberE.: Rapid emergence of carcinogen induced hyperplastic lesions in a new model for the sequential analysis of liver carcinogenesis. Am. J. Pathol., 88: 595–618, 1977.
28.
SquireR.A., LevittM.A.: Report of a workshop on classification of specific hepatocellular lesions in rats. Cancer Res., 35: 3214–3223, 1975.
29.
SvobodaD., HigginsonJ.: A comparison of ultrastructural changes in rat liver due to chemical carcinogens. Cancer Res., 28: 1703–1733, 1968.
30.
Symposium: Early lesions and the development of epithelial cancer. Cancer Res., 36: 2532–2588, 1976.
31.
TaperH.S., BannaschP.: Histochemical differences between so-called megalocytosis and preneoplastic or neoplastic liver lesions induced by N-nitrosomorpholine. Eur J. Cancer, 15: 189–197, 1979.
32.
TongianiR., MalvaldiG., LopezM., PuccinelliE.: Hepatocyte population dynamics during hvdrocortisone and thioacetamide treatment, Histochemistry, 47: 1–21, 1976.
33.
WansonJ.C., DrochmansP., MayC., PenasseW., PopowskiA.: Isolation of centrolobular and perilobular hepatocytes after phenobarbital treatment. J. Cell Biol., 66: 23–41, 1975.
34.
ZedekM.S., SterbergS.S.: Megalocytosis and other abnormalities expressed during proliferation in regenerating liver of rats treated with methylazoxymethanol acetate prior to partial hepatectomy. Cancer Res., 35: 2117–2122, 1975.
