Early induction of in vivo-in vitro hepatocyte replicative DNA synthesis(RDS) by nongenotoxic and genotoxic hepatocarcinogens in male F334 rats and B6C3F1 mice.

Abstract

In vivo-in vitro hepatocyte replicative DNA synthesis (RDS) tests using male F344 rats and B6C3F1 mice were conducted in the present study applying single treatments of 56 nongenotoxic (Ames-negative) hepatocarcinogens, 7 genotoxic (Ames-positive) hepatocarcinogens, 31 nongenotoxic and genotoxic noncarcinogens, and the correlation between early increased RDS events leading to cell proliferation and hepatocarcinogenesis was then reviewed. In the RDS test, 51 of the 63 nongenotoxic and genotoxic hepatocarcinogens clearly induced increased RDS events, whereas it was very rare for noncarcinogens to cause such increase. A good correlation between early RDS induction and hepatocarcinogenicity was thus achieved. The results suggest that nongenotoxic hepatocarcinogens always give equivocal DNA modifications which never lead to Ames-positive events, such as extremely low levels of oxidative DNA adducts and/or alteration of DNA methylation levels (hypomethylation). Genotoxic hepatocarcinogens might simultaneously act as tumor promoters in multistage carcinogenesis and genetic instability-inducing agents. That early disruption of cell cycle controls, resulting in induction of RDS events by nongenotoxic and genotoxic hepatocarcinogens, is postulated to contribute to carcinogenesis in line with a process of increasing genetic instability. In the present review, the current status of the correlation between cell proliferation and hepatocarcinogenesis is also discussed.