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 inducti on of mammary adenocarcinomas, but their susceptibility to hepatocarci nogenesis is virtually unknown, Rat liver is a well-characterized and easily manipulated tissue in which to study carcinogenesis, Therefore, if Cop rats are resistant to hepatocarcinogenesis, studies into resis tance mechanisms may be feasible, Male Cop and F344 rats, 7-8 weeks ol d, were initiated using either N-nitrosodiethylamine (DEN) (200 mg/kg, i.p.) or a two-thirds partial hepatectomy (PH) followed by N-methyl-N -nitrosourea (MNU) (60 mg/kg, i.p.). The rats were then promoted using a modified resistant hepatocyte (RH) protocol (a combination of four doses of 2-acetylaminofluorene (2-AAF) and a single dose of CCl4 that provides a selective mitotic stimulus for initiated cells), Six weeks after initiation the rats were killed and liver sections were stained for glutathione S-transferase 7-7 (GST 7-7), a marker for putative pre neoplastic hepatocytes, Cop rats were found to be highly resistant, ha ving a similar to 9- and similar to 27-fold smaller percentage of live r area occupied by GST 7-7-positive foci than susceptible F344 rats fo llowing initiation by DEN and MNU respectively, Furthermore, gross liv er nodules did not form in any of the Cop rats, whereas all F344 rat l ivers contained nodules, Hepatic necrosis caused by DEN during initiat ion, and CCl4 during promotion is necessary to stimulate compensatory hepatocyte division, We demonstrated that these agents do indeed incre ase serum transaminase levels and produce histologic evidence of necro sis in Cop rats. In order for liver foci to grow rapidly in the RH pro tocol, the surrounding normal hepatocytes must be mito-inhibited by 2- AAF. We found that the degree of mito-inhibition of normal hepatocytes by 2-AAF is the same in Cop and F344 rats. These results show that th e Cop rat is highly resistant to the chemical induction of putative pr eneoplastic liver foci and nodules.