Role of Atp7b Gene in Spontaneous and N‐Diethylnitrosamine‐induced Carcinogenesis in a New Congenic Strain, WKAH.C‐Atp7b Rats

Abstract

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 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 incidence being slightly lower than that in LEC rats. Incidences of spontaneous liver tumors in LEC, WKAH.CAtp7b 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 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 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 observed in LEC and WKAH.C-Atp7b rats, 3) LEC rats were resistant to lung carcinogenesis. These data indicate that the susceptibility of LEC 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.Key words: LEC rat -Atp7b -Congenic -N-Diethylnitrosamine -Copper LEC rats were established as a mutant strain in which hepatitis (hepatocellular necrosis) with severe jaundice and liver tumors develop spontaneously.1-3) About 10-20% of male, and 40-50% of female rats die of fulminant hepatitis.2-4) Their hepatitis is controlled by a single recessive gene designated as Wnd (Atp7b), which is a coppertransporting ATPase gene homologous to the Wilson's disease gene, and LEC rats have a partial deletion of the Atp7b gene.5) The Atp7b gene was originally named the hts gene, and mapped on chromosome 16. 6) These rats also show arrest of maturation from CD4 + 8 + to CD4 + 8 − cells in the thymus, which is not linked to hepatitis genetically and the T-helper immunodeficiency (thid) gene is mapped on chromosome 1. 7,8) In LEC rats, hepatocellular and renal cell tumors develop due to excess copper and/or hemolysis-induced iron accumulation in the organs.9-11) An in vivo short-term assay study suggested that LEC rats are a DENsusceptible strain 12) and the susceptibility of this strain to hepatocarcinogens is genetically independent of copper accumulation in the liver. 13) We have been employing genetic linkage analysis to determine hepatocarcinogen susceptibility loci using a total of 139 DEN-treated (F344×LEC)F2 and (LEC×F344)F2 rats, but we have not yet found susceptibility loci (unpublis...

Low susceptibility to N-ethyl-N-nitrosourea-induced transplacental carcinogenesis in Long-Evans Cinnamon (LEC) rats

“…our studies (6,7). Prenatal and neonatal administrations of N -ethyl-N -nitrosourea (ENU) induce brain and trigeminal nerve tumors (8).…”