Studies on molecular mechanisms underlying endogenous carcinogenesis using transgenic reporter genes as internal probes

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In order to cast light on carcinogen-specific molecular mechanisms underlying experimental hepatocarcinogenesis in rats, in vivo mutagenicity and mutation spectra of known genotoxic rat hepatocarcinogens N-nitrosopyrrolidine (NPYR) and 2-amino-3-methylimidazo[4,5-f]quinoline (IQ), as well as the non-genotoxic hepatocarcinogen di(2-ethylhexyl)phthalate (DEHP) and the non-carcinogen acetaminophen (AAP), were investigated in gpt delta transgenic rats, a recently developed animal model for genotoxicity analysis. After 13-weeks treatment, GST-P positive liver cell foci were significantly increased in NPYR-treated and IQ-treated rats. In the DEHP-treated rats, marked hepatomegaly with centrilobular hypertrophy of hepatocytes occurred although GST-P staining was consistently negative. Positive mutagenicity was detected in IQ-and NPYR-treated rats. Mutant frequencies (MFs) in the liver DNA were 188.0x10^<-6> and 56.5x10^<-6>, approximately 35-and 10-fold higher, respectively, than that of non-treatment control rats (5.5x10^<-6>). There were no increases in MFs in the DEHP-or AAP-treated rats as compared to the non-treatment control value. IQ mainly induced base substitutions leading to G : C to T : A transversions (56.9%) and deletions of G : C base pairs. In contrast, NPYR primarily caused specific A : T to G : C transitions (49.3%), which are very rare in the other groups. These data provide support for the conclusion that IQ and NPYR hepatocarcinogenesis depends on genotoxic processes and specific DNA adduct formation while DEHP exerts its influence via a non-genotoxic promotional pathway. Our data also indicate that analysis of specific in vivo mutational responses using transgenic animal models can provide crucial information for understanding the molecular mechanisms underlying chemical carcinogenesis.