Characterization of the promoting activity of thiobenzamide on liver carcinogenesis

To characterize the promoting activity of thiobenzamide (TB), a thiono-sulfur-containing xenobiotic, rats of both sexes were treated with the compound for 4 or 8 weeks after an initiating dose of diethyl-nitrosamine. The number, area (volume), and phenotypic complexity of the enzyme-altered hepatocyte foci were studied in serial sections stained with hematoxylin/eosin and reacted for glycogen, iron, and gamma-glutamyltranspeptidase activity. The TB-induced changes on the drug metabolizing systems were also investigated. The main findings were: When fed in a dose range of 500-2,000 mg/kg of diet, TB induced a number of foci greater than controls, especially in female rats. Benzamide, a major TB metabolite, was ineffective. The appearance of hepatocyte foci upon TB feeding was nearly synchronized. An increase of the phenotypic complexity of the hepatocyte foci occurred only during the first 4 weeks of TB administration; it correlated with an increase in size. The liver microsome content of cytochrome P-450 as well as the activity of many monooxygenases was decreased, some of the phase II reactions being increased. In conclusion TB behaves as an efficient promoter of liver carcinogenesis, possibly as a consequence of an induced adaptive response.