Absence of H-ras point mutation at codon 12 in N-methyl-N-nitrosourea-induced hepatocellular neoplasms in the rat.

In order to assess the possibility that activated ras-associated hepatic carcinomas might be much rarer in rats than mice because of the more frequent or rapid occurrence of powerful carcinogenic event(s) other than ras point mutations in the former animals, precancerous lesions and hepatocellular carcinomas induced by a weak hepatocarcinogen N-methyl-N-nitrosourea (MNU) in the rat liver were analyzed for the presence or absence of ras point mutations. MNU was chosen because it is well known that MNU-induced rat mammary carcinomas contain activated H-ras at very high frequency. Male Fisher rats were treated with a single dose of MNU after partial hepatectomy, and then administered dietary phenobarbital or repeated s.c. injections of carbon tetrachloride as promoting procedures. Analyses by oligonucleotide hybridization, MnlI-restriction-fragment-length polymorphism and NIH3T3 cell transfection assays revealed neither H-ras point mutations nor transforming ability of the DNA from 36 MNU-induced rat hepatic neoplasms. The results were in agreement with previous results for rat hepatocellular carcinomas induced by other potent liver carcinogens and did not support our hypothesis that the frequency of finding ras activation might be dependent on the strength of the carcinogen.