Reduction of DNA repair efficiency during the initial phase of rat liver carcinogenesis.

Chemically induced DNA fragmentation and unscheduled DNA synthesis (UDS) were determined in hepatocyte primary cultures (HPC) obtained from the entire liver during the development of hyperplastic lesions induced in rats by the following treatment: 200 mg/kg i.p. of N-nitrosodiethylamine (DEN) on day 0; 2 ml/kg i.g. of CCl4 on day 21; dietary administration of 0.02% 2-acetylaminofluorene (2-AAF) during the 3rd and the 4th week, and of 0.05% phenobarbital (PB) from the 6th week. At 4, 5, 6, and 7 weeks after DEN injection, the level of DNA fragmentation elicited by either the activation-independent carcinogen methyl methanesulfonate (MMS) or the activation-dependent carcinogen N-nitrosodimethylamine (DMN) was significantly lower than that in HPC from age-matched normal rats. In the same HPC, a statistically significant decrease was observed in the capability of repairing DNA damage induced by MMS, while the reduction of the DNA repair efficiency did not reach the level of significance after exposure to DMN.