Mutagenicity and DNA damage induced by arylamines in the Salmonella/hepatocyte system.
Coincubation of isolated, intact rat hepatocytes with Salmonella typhimurium tester strain TA 98 (Salmonella/hepatocyte system) has been employed to determine both bacterial mutagenicity and DNA damage in rat hepatocytes following treatment with 2-acetylaminofluorene (AAF) and its derivatives. In vivo pretreatment of rats with either 2,3,7,8-tetrachlorodibenzodioxin or 3-methylcholanthrene markedly increased both DNA damage and bacterial mutation frequency upon incubation of AAF or 2-aminofluorene (AF) in this system. The increase in damage to the hepatocyte DNA was more pronounced after AAF treatment than following AF exposure, while the increase in bacterial mutation frequency was greater after AF treatment. Treatment of hepatocytes with paraoxon prior to exposure to N-hydroxy-2-acetylaminofluorene (N-OH-AAF) or N-acetoxy-2-acetylaminofluorene (N-OAc-AAF) partially inhibited both DNA damage and the bacterial mutagenicity caused by these agents. Treatment of primary rat hepatocytes with 2-hydroxy-2-aminofluorene (N-OH-AF) causes a low level of DNA breaks. Substitution of primary rat hepatocytes with highly differentiated rat hepatoma cells (Reuber H4-II-E) revealed a low level of DNA breakage after exposure to N-OH-AAF whereas treatment with either N-OAc-AAF or N-OH-AF induced a dose dependent increase in DNA breaks. Pretreatment of the Reuber cells with paraoxon inhibited the DNA damage caused by N-OAc-AAF whereas the DNA damage induced by N-OH-AF was increased after paraoxon treatment. Employing host cells with differing metabolic capacity, such as Reuber vs. primary hepatocytes, in the Salmonella/hepatocyte system, may allow a determination of the relative importance of different metabolic pathways in mutagenicity and/or genotoxicity of arylamines.
D015073:2-Acetylaminofluorene / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008748:Methylcholanthrene / Q000633:toxicity; D009152:Mutagenicity Tests; D009153:Mutagens; D009154:Mutation; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D009153:Mutagens; D008748:Methylcholanthrene; D004247:DNA; D015073:2-Acetylaminofluorene