Role of Atp7b gene in spontaneous and N-diethylnitrosamine-induced carcinogenesis in a new congenic strain, WKAH.C-Atp7b rats

To examine whether Long-Evans Cinnamon (LEC) rats, a mutant rat model of Wi lson's disease, have a susceptibility gene(s) to hepatocarcinogenesis in ad dition to the causative gene, Atp7b, we established a new congenic strain, WKAH.C-Atp7b rats, in which the Atp7b gene of the LEC rats is inserted into the normal Wistar-King Aptekman Hokkaido (WKAH) background. Hepatocellular tumors developed spontaneously in both sexes of WKAH.C-Atp7b rats, their i ncidence being slightly lower than that in LEC rats. Incidences of spontane ous liver tumors in LEC, WKAH.C-Atp7b and WKAH rats correlated with hepatic copper and iron concentrations. Medium-term liver bioassay showed that LEC rats were more susceptible to the induction of glutathione S-transferase p lacental form-positive preneoplastic foci than WKAH.C-Atp7b rats, and WKAH. C-Atp7b rats were more susceptible than WKAH rats. In an N-diethylnitrosami ne (DEN)-induced long-term carcinogenicity study, 1) LEC rats were similarl y or rather less susceptible to hepatocellular tumors than WKAH.C-Atp7b and WKAH rats, indicating that the progression of the preneoplastic foci to li ver cancer in LEC rats was worse than that in WKAH.C-Atp7b and WKAH rats, 2 ) the incidences of kidney tumors in LEC and WKAH.C-Atp7b rats were higher than that in WKAH rats and high copper concentrations in the kidneys were o bserved in LEC and WKAH.C-Atp7b rats, 3) LEC rats were resistant to lung ca rcinogenesis. These data indicate that the susceptibility of LEC rats to li ver and kidney carcinogenesis could be explained by Atp7b gene mutation and that the susceptibility to lung carcinogenesis is controlled by gene(s) ot her than Atp7b.