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  • Title: DNA adduct formation and removal in hepatic chromatin fractions from rats chronically fed 2-acetylaminofluorene.
    Author: Poirier MC, Fullerton NF, Patterson ED, Beland FA.
    Journal: Carcinogenesis; 1990 Aug; 11(8):1343-7. PubMed ID: 2387020.
    Abstract:
    Continuous dietary administration of the hepatocarcinogen 2-acetylaminofluorene (AAF) to rats produces a gradual increase in hepatic DNA adducts until a plateau is reached after approximately 2 weeks. The rate of DNA adduct formation remains constant through 1 month of AAF feeding, while adduct removal profiles are biphasic during both carcinogen feeding and subsequent time on control diet. In the present experiments, we tested the hypothesis that biphasic adduct removal is due to differential repair kinetics taking place in different chromatin fractions. Rats were fed 0.02% AAF for times up to 30 days and control diet for a subsequent 28 days. HPLC analysis of nuclear DNA indicated that the deacetylated adduct, N-(deoxyguanosin-8-yl)-2-aminofluorene, comprised approximately 90% of the total C8-substituted deoxyguanosine adducts after 3 days of feeding and greater than 98% after 20 days. The nuclear DNA was partitioned into endogenous nuclease sensitive (approximately 2%), low salt soluble (approximately 70%), high salt soluble (approximately 20%) and nuclear matrix (approximately 8%) fractions. During 28 days of AAF feeding, each fraction showed a profile of adduct formation similar to that observed in whole nuclei; however, the adduct concentration in nuclear matrix-associated DNA was consistently less than that in the other fractions. In rats fed AAF for 28 days followed by control diet, adduct removal in each of the fractions showed biphasic kinetics that were similar to those observed in nuclear DNA. When rats were fed AAF for 7 days, however, adduct removal kinetics could be best described by a single first-order rate constant. These data indicate that biphasic adduct removal may be due to the presence of particular nucleotide sequences that are common to all fractions and are relatively resistant to adduct formation and removal. The low concentration of adducts found in the nuclear matrix may be due to a decreased rate of adduct formation in this region and/or the proximity of membrane-bound beta-polymerases that are responsible for repair.
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