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 a putative causal event in chemical carcinogenesis. It has been shown that one cellular response to DNA damage that leads to DNA repair is poly(ADP-ribosyl)ation of nuclear proteins. To examine the possible existence of an altered poly(ADP-ribosyl)ation response to 2-AAF-mediated damage of rat liver DNA, tissue ADP-ribose polymer levels were determined during various stages of 2-AAF-mediated carcinogenesis. 2-AAF was administered to rats in a discontinuous feeding regimen comprised of five consecutive cycles, each cycle consisting of 3 weeks on 2-AAF diet followed by 1 week of recovery on a control diet without 2-AAF. During cycle one of 2-AAF administration, rat liver ADP-ribose polymer levels increased 3-fold over that found in livers of rats fed only the control diet. In contrast, when rats were administered the non-genotoxic liver mitogen 4-AAF for one cycle, no significant elevation occurred in ADP-ribose polymer levels. Elevated ADP-ribose polymer production was also observed 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 for hepatocarcinogenesis, an altered pattern of ADP-ribose polymer production occurred in rat livers. ADP-ribose polymer levels in these rat livers remained low, similar to levels found in control rat livers, despite the administration of 2-AAF. When the livers from rats fed either one or five cycles of 2-AAF were analyzed for possible decreases in the levels of tissue NAD+, the substrate for poly(ADP-ribose) polymerase, no changes in relative abundance were found. In addition, analysis of poly(ADP-ribose) polymerase activity showed no decrease at five cycles of 2-AAF administration. These results indicated that at late stages of 2-AAF-induced hepatocarcinogenesis, 2-AAF does not induce an expected increase in ADP-ribose polymer levels, and suggested that significant changes in DNA repair may occur at a time just preceding an increased risk for developing liver cancer.
Kiehlbauch
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Samuel Roberts Noble Foundation, Inc., Biochemical Pharmacology Section, Ardmore, OK 73402.
Kosanke
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Ringer
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D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D004249:DNA Damage; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011108:Polymers; D051381:Rats; D017207:Rats, Sprague-Dawley
D002273:Carcinogens; D011108:Polymers; D000246:Adenosine Diphosphate Ribose; D015073:2-Acetylaminofluorene; D011065:Poly(ADP-ribose) Polymerases