Abstract
Thiobenzamide (TB), a thiono-containing compound, was administered for 38 weeks to female Sprague-Dawley rats at a dose of 1 g/kg standard diet; the resulting liver pathology was followed up to 8 months after withdrawal of the compound from the diet. TB administration induced the appearance of biliary cirrhosis. In the first weeks of intoxication the progressive distortion of the liver architecture was mainly due to significant proliferation of the bile ductules. Later, the liver assumed a macronodular appearance. In addition to regenerative and degenerative changes of the hepatocytes, preneoplastic lesions were also detected, and some enzymic markers of the mixed-function monooxygenase system were decreased. Cholangiofibrotic areas were evident, and many biliary tubules within them showed mucous metaplasia. At the end of the intoxication period, as well as 4 months after drug suspension, large portions of the liver or entire lobes were substituted by connective tissue surrounding nests of bile ductules and atrophied hepatocellular nodules. Four months later, in the virtual absence of cirrhotic changes, each animal harboured one or more tumors (mainly cholangiomas).
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References
Bannasch P, Mayer D, Hacker HJ (1980) Hepatocellular glycogenosis and hepatocarcinogenesis. Biochim Biophys Acta 605: 217–245
Chieli E, Malvaldi G, Tongiani R (1979) Early biochemical liver changes following thiobenzamide poisoning. Toxicology 13: 101–114
Chieli E, Malvaldi G, Segnini D (1980) The hepatotoxicity of Thiobenzamide-S-oxide. Toxicol Lett 7: 175–180
deDuve C, Pressman BC, Gianetto R, Wattiaux R, Appelmans F (1955) Intracellular distribution patterns of enzymes in rat liver tissue. Biochem J 60: 604–613
Farber E, Cameron RG, Laishes B, Lin JC, Medline A, Ogawa K, Solt DB (1979) Physiological and molecular markers during carcinogenesis. In: Griffin AC, Shaw CR (eds) Carcinogens: identification and mechanisms of action, Raven, New York, p 319
Fukushima S, Shibata M, Hibino T, Yoshimura T, Hirose M, Ito N (1979) Intrahepatic bile duct proliferation induced by 4′4-diaminodiphenylmethane in rats. Toxicol Appl Pharmacol 48: 145–155
Goldfarb S (1973) A morphological and histochemical study of carcinogenesis of the liver in rats fed 3′methyl 4-dimethylaminoazobenzene. Cancer Res 33: 1119–1128
Gupta DN (1956) Nodular cirrhosis and metastatising tumors produced in the liver of rats by prolonged feeding with Thioacetamide. J Pathol Bacteriol 72: 415–425
Hanzlik RP, Vyas KP, Traiger JG (1978) Substituent effects on the hepatotoxicity of thiobenzamide derivatives in the rat. Toxicol Appl Pharmacol 46: 685–694
Hanzlik RP, Cashman JR, Traiger JG (1980) Relative hepatotoxicity of substituted thiobenzamides and thiobenzamide-S-oxides in the rat. Toxicol Appl Pharmacol 55: 260–272
Karnowski MJ, Roots LA (1964) A direct thiocoline method for cholinesterase. J Histochem Cytochem 12: 219–221
Lopez M, Mazzanti L (1955) Experimental investigations on alpha-naphthylisothiocyanate as hyperplastic agent on the biliary ducts in the rat. J Pathol Bacteriol 69: 243–250
Malvaldi G (1977) Liver changes following thiobenzamide poisoning. Experientia 83: 1200–1201
Malvaldi G (1978) Tumori epatici da tiobenzamide nel ratio. Boll. Soc It Biol Sper 54: 1027–1030
Malvaldi G, Chieli E, Pollera M (1982) Liver cell proliferation induced by a single administration of thiobenzamide. Toxicol Lett 10: 259–263
Malvaldi G, Pollera M (1982) Long term fate of the bile ducts cells proliferated during chronic thioacetamide poisoning. Int J Tissue Reac 4: 55–61
Malvaldi G, Saviozzi M (1982) Histochemical characterization of cholangiofibrotic areas. Basic Appl Histochem (suppl) 26: 103
McLean AEM, Day P (1974) New methods to measure the effect of diet and inducers of microsomal enzyme synthesis on cytochrome P-450 in liver homogenates and on metabolism of dimethylnitrosamine. Biochem Pharmacol 23: 1173–1178
Neal RA (1980) Microsomal metabolism of thiono-sulfur compounds: mechanisms and toxicological significance. In: Hodgson E, Bend JR, Philpot RM (eds) Reviews on biochemical toxicology vol II. Elsevier, North Holland, New York, Amsterdam, p 131
Nebert DW, Gelboin HV (1968) Substrate inducible microsomal arylhydrocarbon hydroxylase in mammalian cell culture. I: assay and properties of induced enzyme. J Biol Chem 243: 6242–6249
Ogawa K, Onoè T, Takeuchi M (1981) Spontaneous occurrence of γ-glutamyltranspeptidase positive hepatocitic foci in 105 week old Wistar and 72 week old Fischer 344 male rats. J Natl Cancer Inst 67: 407–412
Orrenius S (1965) On the mechanism of drug hydroxylation in rat liver microsomes. J Cell Biol 26: 713–723
Rutemburg AM, Kim H, Fischbein JW, Hanker JS, Wasserkrug HL, Seligman AM (1969) Histochemical demonstration of γ-glutamyltranspeptidase activity. J Histochem Cytochem 17: 517–526
Stenger RJ, Porway M, Johnson EA, Datta RK (1975) Effects of chlordane pretreatment on the hepatotoxicity of carbon tetrachloride. Exp Mol Pathol 23: 144–153
Tennekes HA, Wright AS, Dix KM, Koeman JH (1981) Effects of dieldrin diet and bedding on enzyme function and tumors incidence in livers of male CF-1 mice. Cancer Res 41: 3615–3620
Terao K, Nakano M (1974) Cholangiofibrosis induced by short term feeding of 3′methyl-4-dimethylaminoazobenzene. An electron microscopic observation. Gann 65: 249–260
Tsuda H, Lee G, Farber E (1980) Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens. Cancer Res 40: 1157–1164
Yokoyama S, Kaneko A, Dempo K, Chisaka N, Mori M, Onoè T (1982) Histochemical and cytochemical study of butyrylcholinesterase activity in rat hepatocellular carcinomas induced by 3′methyl-4-dimethylaminoazobenzene. Cancer Res 42: 4158–4163
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Malvaldi, G., Chieli, E. & Saviozzi, M. Biliary cirrhosis and tumors induced by chronic administration of thiobenzamide to rats. Arch Toxicol 55, 34–38 (1984). https://doi.org/10.1007/BF00316583
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DOI: https://doi.org/10.1007/BF00316583