Different responses other than the formation of DNA-adducts between the livers of carcinogen-resistant rats (DRH) and carcinogen-sensitive rats (Donryu) to 3'-methyl-4-dimethylaminoazobenzene administration.

Abstract

Carcinogen‐resistant inbred DRH rats developed from the Donryu strain showed a remarkably low incidence of liver tumors when they were fed diets containing hepatocarcinogens such as 3′‐methyl‐4‐dimethylaminoazobenzene (3′‐Me‐DAB). In this work, we examined various characteristics of male DRH and Donryu rats during 3′‐Me‐DAB administration for 8 weeks. 32P‐Postlabeling analysis showed that essentially similar levels of DNA‐adducts were generated by the metabolites of 3′‐Me‐DAB in the livers of these two strains of rats at several time points. However, both GADD45 (growth arrest and DNA damage‐inducible) and O6‐methylguanine methyltransferase (putatively DNA damage‐inducible) mRNA levels were increased significantly in Donryu rat livers, but were increased to a lesser extent in DRH rats. [3H]Thymidine incorporation into hepatic DNA began to increase around 10 to 20 days after the start of 3′‐Me‐DAB administration in Donryu rats probably due to DNA repair, while no significant change occurred in DRH rats under the same conditions. Furthermore, inductions of heme oxygenase (due to degradation of heme‐proteins) and hepatocyte growth factor (HGF; cell death and regeneration of hepatocytes) mRNAs were greater in Donryu rat livers than those of DRH, suggesting that the former were more sensitive to cytotoxic effects of 3′‐Me‐DAB than the latter. Another remarkable difference observed between these two strains was the significant induction of cytochrome P‐450 2E1 mRNA in Donryu rat livers; this may contribute to the generation of reactive oxygen intermediates. Finally, increases of glutathione S‐transferase (P‐form) and γ‐glutamyltranspeptidase mRNAs as marker enzymes of preneoplastic changes of hepatocytes were clearly seen only in Donryu rat livers at 6 to 8 weeks after the start of 3′‐Me‐DAB administration. These results indicate that the different susceptibility to hepatocarcinogenesis between these two strains of rats may arise from events other than the DNA adduct formation.