Changes in levels of ADP-ribose polymers in rat liver during 2-acetylaminofluorene-induced hepatocarcinogenesis

The exposure of rats to the carcinogen 2-acetylaminofluorene(2-AAF) results in the accumulation of DNA-damaging adducts.The inability of cells to repair such damage adequately is aputative causal event in chemical carcinogenesis. It has beenshown that one cellular response to DNA damage that leads toDNA repair is poly(ADP-ribosyl)ation of nuclear proteins. Toexamine the possible existence of an altered poly(ADP-ribosyl)ationresponse to 2-AAF-mediated damage of rat liver DNA, tissue ADP-ribosepolymer levels were determined during various stages of 2-AAF-mediatedcarcinogenesis. 2-AAF was administered to rats in a discontinuousfeeding regimen comprised of five consecutive cycles, each cycleconsisting of 3 weeks on 2-AAF diet followed by 1 week of recoveryon a control diet without 2-AAF. During cycle one of 2-AAF administration,rat liver ADP-ribose polymer levels increased 3-fold over thatfound in livers of rats fed only the control diet. In contrast,when rats were administered the non-genotoxic liver mitogen4-AAF for one cycle, no significant elevation occurred in ADP-ribosepolymer levels. Elevated ADP-ribose polymer production was alsoobserved during cycles two and three of 2-AAF administration.However, during cycles four and five of 2-AAF administration,a period when rats administered 2-AAF acquire a high risk forhepatocarcinogenesis, an altered pattern of ADP-ribose polymerproduction occurred in rat livers. ADP-ribose polymer levelsin these rat livers remained low, similar to levels found incontrol rat livers, despite the administration of 2-AAF. Whenthe livers from rats fed either one or five cycles of 2-AAFwere analyzed for possible decreases in the levels of tissueNAD+, the substrate for poly(ADP-ribose) polymerase, no changesin relative abundance were found. In addition, analysis of poly(ADP-ribose)polymerase activity showed no decrease at five cycles of 2-AAFadministration. These results indicated that at late stagesof 2-AAF-induced hepatocarcinogenesis, 2-AAF does not inducean expected increase in ADP-ribose polymer levels, and suggestedthat significant changes in DNA repair may occur at a time justpreceding an increased risk for developing liver cancer.