Distribution of initial and persistent 2-acetylaminofluorene-induced DNA adducts within DNA loops.
The intranuclear distribution of initial and persistent DNA adducts induced in vivo after four weekly injections of the hepatocarcinogen 2-acetylaminofluorene was examined in rat liver by using a protocol that fractionates chromatin from various regions of each of the multiple nuclear DNA loops. Ten hours after the initial dose, two acetylated [(N-acetyl-N-(deoxyguanosin-8-yl)-2-aminofluorene and 3-(deoxyguanosin-N2-yl)-2-acetylaminofluorene] and one deacetylated [N-(deoxyguanosin-8-yl)-2-aminofluorene] adduct were detected by a 32P-labeling assay and were found to have a random genomic distribution, as evident by their relative concentrations in various chromatin fractions. These data suggest that all regions of the DNA loops are equally susceptible to adduct formation. A nonrandom persistence of the deacetylated adduct in the regions where the DNA loops are constrained by the nuclear matrix was evident by 6 days after the last dose and was markedly apparent by 60 days. In contrast, all chromatin fractions had equally inefficient removal of the N2-acetylated adduct by 6 days as well as 60 days but had complete removal of the C8-acetylated adduct. These findings suggest that pronounced regional differences in adduct repair along the DNA loops may play a role in chemically induced hepatocarcinogenesis.
D015073:2-Acetylaminofluorene / Q000494:pharmacology*; D000818:Animals; D002467:Cell Nucleus / Q000648:ultrastructure; D002843:Chromatin / Q000302:isolation & purification; D004247:DNA / Q000032:analysis*; D006151:Guanosine / Q000031:analogs & derivatives; D008099:Liver / Q000032:analysis / Q000187:drug effects; D008297:Male; D009690:Nucleic Acid Conformation; D051381:Rats; D011919:Rats, Inbred Strains
D002843:Chromatin; D006151:Guanosine; D004247:DNA; D015073:2-Acetylaminofluorene