Resistance to the promotion of glutathione S-transferase 7-7-positive liver lesions in Copenhagen rats

Previously, we have shown that Copenhagen (Cop) rats are highly resistant t o the induction of putative preneoplastic, glutathione S-transferase 7-7 (G ST 7-7)-positive liver lesions following treatment with a modified resistan t hepatocyte protocol, The objective of the current study was to establish the time course for the development of resistance and examine potential res istance mechanisms in Cop rats using F344 rats as susceptible controls. Mal e Cop and F344 rats (n = 25), 7-8 weeks of age, were initiated with diethyl nitrosamine (200 mg/kg) and promoted 3 weeks later with four doses of 2-ace tylaminofluorene (20 mg/kg) and a 2/3 partial hepatectomy (PH). Groups of r ats from each strain were killed on days 2, 4, 7, 14 and 21 post-PH, 2 h af ter receiving bromodeoxyuridine. Cop livers contained similar numbers of GS T 7-7-positive lesions to F344 livers on days 2 and 4 post-PH. The percent volume of liver occupied by these lesions did not differ between the strain s on days 2, 4 and 7 post-PH. On day 14, however, similar to 29% of the liv er volume in F344 rats was occupied by lesions, whereas in Cop rats this wa s significantly less (similar to 9%, P < 0.001). On day 21, lesions occupie d similar to 58% of F344 rat livers and only similar to 6% of Cop livers. D espite these differences, the labeling index of hepatocytes was not signifi cantly different between the strains at any time point, either within lesio ns or within surrounding normal liver. Furthermore, the apoptotic indices w ere not different between the strains at any time. However, differences wer e found in the extent of lesion remodeling (redifferentiation) and in the p attern of oval cell response following PH in Cop livers. By day 14 post-PH, similar to 76% of Cop liver lesions showed evidence of remodeling, compare d with only similar to 14% of F344 lesions. The oval cell response to PH wa s equivalent in the two strains up to day 4 post-PH but by day 7, in F344 l ivers there was extensive migration of these cells into the liver parenchym a, whereas in Cop livers, the response remained localized to the portal reg ions. These results suggest that Cop resistance occurs at the promotion sta ge and not the initiation stage of carcinogenesis. Resistance appears not t o be due to a lower proliferation rate nor to a higher apoptotic rate withi n Cop lesions, Precocious remodeling and/or a diminished oval cell response , however, may contribute to the resistance of Cop rats to the growth of GS T 7-7-positive hepatic lesions.