Hepatocarcinogen 4-methylquinoline induced G:C to C:G transversions in the cII gene in the liver of lambda/lacZ transgenic mice (Muta™Mouse)

Abstract

We have previously reported that quinoline increased the mutation frequency of the cII gene in the liver of lambda/lacZ transgenic mice (Muta™Mouse), and G:C to C:G transversions were the molecular signature of quinoline-induced mutations. 4-Methylquinoline (4-MeQ) has the highest mutagenicity among quinoline and isomeric methylquinolines according to the Ames test using Salmonella typhimurium TA 100, in the presence of rat liver microsomal enzymes. In this report, we examined the effect of 4-MeQ on mutagenesis in the lambda cII gene in the liver of the Muta™Mouse, and we analyzed the sequences of the mutated genes. The mutation frequency of the liver cII gene was seven times higher in 4-MeQ-treated mice than in control mice. Sequence analysis revealed that 4-MeQ primarily induced G:C to C:G transversions (37 of 45). The specificities of 4-MeQ for target organ and mutation pattern were very consistent with those of quinoline. Thus, we showed that 4-MeQ was also genotoxic in the liver of the Muta™Mouse, and as with quinoline, the G:C to C:G transversion was the molecular signature of the 4-MeQ-induced mutations.