Mechanism of oxidative DNA damage induced by carcinogenic 4-aminobiphenyl.
DNA adduct formation is thought to be a major cause of DNA damage by carcinogenic aromatic amines. We investigated the ability of an aromatic amine, 4-aminobiphenyl (4-ABP) and its N-hydroxy metabolite (4-ABP(NHOH)) to cause oxidative DNA damage, using (32)P-labeled human DNA fragments from the p53 tumor suppressor gene and the c-Ha-ras-1 protooncogene. 4-ABP(NHOH) was found to cause Cu(II)-mediated DNA damage, especially at thymine residues. Addition of the endogenous reductant NADH led to dramatic enhancement of this process. Catalase and bathocuproine, a Cu(I)-specific chelator, reduced the amount of DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). 4-ABP(NHOH) dose-dependently induced 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in the presence of Cu(ll) and NADH. 4-ABP(NHOH) conversion to nitrosobiphenyl, as measured by UV-visible spectroscopy, occurred rapidly in the presence of Cu(II), suggesting Cu(II)-mediated autoxidation. Increased amounts of 8-OHdG were found in HL-60 cells compared to the H(2)O(2)-resistant clone HP100 following 4-ABP(NHOH) treatment, further supporting the involvement of H(2)O(2). The present study demonstrates that an N-hydroxy derivative of 4-ABP induces oxidative DNA damage through H(2)O(2) in both a cell-free system and in cultured human cells. We conclude that, in addition to DNA adduct formation, oxidative DNA damage may play an important role in the carcinogenic process of 4-ABP.
Department of Hygiene, Mie University School of Medicine, Tsu, Mie, Japan.
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Murata
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Tamura
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Tada
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Kawanishi
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000611:Aminobiphenyl Compounds / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D002417:Cattle; D002614:Chelating Agents / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D004249:DNA Damage; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology; D016158:Genes, p53; D018922:HL-60 Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009243:NAD / Q000494:pharmacology; D010084:Oxidation-Reduction; D010618:Phenanthrolines / Q000494:pharmacology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D013056:Spectrophotometry, Ultraviolet
D000611:Aminobiphenyl Compounds; D002273:Carcinogens; D002614:Chelating Agents; D016166:Free Radical Scavengers; D010618:Phenanthrolines; D009243:NAD; C006757:4-biphenylamine; C014593:N-hydroxy-4-aminobiphenyl; D003300:Copper; D000080242:8-Hydroxy-2'-Deoxyguanosine; C002478:bathocuproine; D006861:Hydrogen Peroxide; D002374:Catalase; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D003849:Deoxyguanosine