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  • Title: Oxidative DNA damage by a common metabolite of carcinogenic nitrofluorene and N-acetylaminofluorene.
    Author: Murata M, Yoshiki Y, Tada M, Kawanishi S.
    Journal: Int J Cancer; 2002 Dec 01; 102(4):311-7. PubMed ID: 12402298.
    Abstract:
    Both carcinogenic NF and AAF are metabolized to a common N-hydroxy metabolite, N-OH-AF. We investigated oxidative DNA damage by N-OH-AF, using (32)P-labeled human DNA fragments from the human p53 and p16 tumor-suppressor genes and the c-Ha-ras-1 protooncogene. N-OH-AF caused Cu(II)-mediated DNA damage, and endogenous reductant NADH markedly enhanced this process. Catalase and bathocuproine, a Cu(I)-specific chelator, decreased the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). N-OH-AF induced piperidine-labile lesions frequently at thymine and cytosine residues. With formamidopyrimidine-DNA glycosylase treatment, N-OH-AF induced cleavage at guanine residues, especially of the ACG sequence complementary to codon 273, a well-known hot spot of the p53 gene. N-OH-AF dose-dependently induced 8-oxodG formation in the presence of Cu(II) and NADH. Treatment with N-OH-AF increased amounts of 8-oxodG in HL-60 cells compared to the H(2)O(2)-resistant clone HP100, supporting the involvement of H(2)O(2). The present study demonstrates that the N-hydroxy metabolite of NF and AAF induces oxidative DNA damage through H(2)O(2) in both a cell-free system and cultured human cells. We conclude that oxidative DNA damage may play an important role in the carcinogenic process of NF and AAF in addition to previously reported DNA adduct formation.
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