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 Wilson's disease, have a susceptibility gene(s) to hepatocarcinogenesis in addition to the causative gene, Atp7b, we established a new congenic strain, WKAH.C-Atp7b rats, in which the Atp7b gene of the LEG 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 incidence being slightly lower than that in LEG rats. Incidences of spontaneous liver tumors in LEG, WKAH.C-Atp7b and WKAH rats correlated with hepatic copper and iron concentrations. Medium-term liver bioassay showed that LEG rats were more susceptible to the induction of glutathione S-transferase placental form-positive preneoplastic foci than WKAH.C-Atp7b rats, and WKAH.C-Atp7b rats were more susceptible than WKAH rats. In an N-diethylnitrosamine (DEN)-induced long-term carcinogenicity study, 1) LEC rats were similarly or rather less susceptible to hepatocellular tumors than WKAH.C-Atp7b and WKAH rats, indicating that the progression of the preneoplastic foci to liver cancer in LEG rats was worse than that in WKAH.C-Atp7b and WKAH rats, 2) the incidences of kidney tumors in LEG and WKAH.C-Atp7b rats were higher than that in WKAH rats and high copper concentrations in the kidneys were observed in LEG and WKAH.C-Atp7b rats, 3) LEC rats were resistant to lung carcinogenesis. These data indicate that the susceptibility of LEG rats to liver and kidney carcinogenesis could be explained by Atp7b gene mutation and that the susceptibility to lung carcinogenesis is controlled by gene(s) other than Atp7b.