Resistance of Copenhagen rats to chemical induction of glutathione S- transferase 7-7-positive liver foci

Copenhagen (Cop) rats are completely resistant to the chemical induction ofmammary adenocarcinomas, but their susceptibility to hepatocarcinogenesisis virtually unknown. Rat liver is a well- characterized and easilymanipulated tissue in which to study carcinogenesis. Therefore, if Cop ratsare resistant to hepatocarcinogenesis, studies into resistance mechanismsmay be feasible. Male Cop and F344 rats, 7-8 weeks old, were initiatedusing either N-nitrosodiethylamine (DEN) (200 mg/kg, i.p.) or a two-thirdspartial hepatectomy (PH) followed by N-methyl-N-nitrosourea (MNU) (60mg/kg, i.p.). The rats were then promoted using a modified resistanthepatocyte (RH) protocol (a combination of four doses of 2-acetylaminofluorene (2-AAF) and a single dose of CCl4 that provides aselective mitotic stimulus for initiated cells). Six weeks after initiationthe rats were killed and liver sections were stained for glutathioneS-transferase 7-7 (GST 7-7), a marker for putative preneoplastichepatocytes. Cop rats were found to be highly resistant, having aapproximately 9- and approximately 27-fold smaller percentage of liver areaoccupied by GST 7-7-positive foci than susceptible F344 rats followinginitiation by DEN and MNU respectively. Furthermore, gross liver nodulesdid not form in any of the Cop rats, whereas all F344 rat livers containednodules. Hepatic necrosis caused by DEN during initiation, and CCl4 duringpromotion is necessary to stimulate compensatory hepatocyte division. Wedemonstrated that these agents do indeed increase serum transaminase levelsand produce histologic evidence of necrosis in Cop rats. In order for liverfoci to grow rapidly in the RH protocol, the surrounding normal hepatocytesmust be mito-inhibited by 2-AAF. We found that the degree ofmito-inhibition of normal hepatocytes by 2-AAF is the same in Cop and F344rats. These results show that the Cop rat is highly resistant to thechemical induction of putative preneoplastic liver foci and nodules.