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

Carcinogen-resistant inbred DRH rats developed from the Donryu strain showed a remarkably low incidence of liver tumors when they were fed d iets containing hepatocarcinogens such as 3'-methyl 3'-methyl-4-dimeth ylaminoazobenzene (3'-Me-DAB). In this work, we examined various chara cteristics of male DRH and Donryu rats during 3'-Me-DAB administration for 8 weeks. P-32-Postlabeling analysis showed that essentially simil ar levels of DNA-adducts were generated by the metabolites of 3'-Me-DA B in the livers of these two strains of rats at several time points. H owever, both GADD45 (growth arrest and DNA damage-inducible) and O-6-m ethylguanine methyltransferase (putatively DNA damage-inducible) mRNA levels were increased significantly in Donryu rat livers, but were inc reased to a lesser extent in DRH rats. [H-3]Thymidine incorporation in to 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 condi tions. Furthermore, inductions of heme oxygenase (due to degradation o f heme-proteins) and hepatocyte growth factor (HGF; cell death and reg eneration of hepatocytes) mRNAs were greater in Donryu rat livers than those of DRH, suggesting that the former were more sensitive to cytot oxic effects of 3'-Me-DAB than the latter. Another remarkable differen ce observed between these two strains was the significant induction of cytochrome P-450 2E1 mRNA in Donryu rat livers; this may contribute t o the generation of reactive oxygen intermediates. Finally, increases of glutathione S-transferase CP-form) and gamma-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 differen t susceptibility to hepatocarcinogenesis between these two strains of rats may arise from events other than the DNA adduct formation.