Biliary cirrhosis and tumors induced by chronic administration of thiobenzamide to rats

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).