Oxidation of 5'-site guanine at GG and GGG sequences induced by a metabolite of carcinogenic heterocyclic amine PhIP in the presence of Cu(II) and NADH.


:Adduct formation has been considered to be a major causal factor of DNA damage by carcinogenic heterocyclic amines. By means of experiments with an electrochemical detector coupled to a high-performance liquid chromatograph, we revealed that N-hydroxy metabolite of 2-amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) induced the formation of 8-hydroxy-2'-deoxyguanosine (8-OH-dG) in the presence of Cu(II). Addition of an endogenous reductant NADH enhanced the 8-OH-dG formation. Experiments with (32)P-labeled DNA fragments showed that this metabolite [PhIP(NHOH)] caused 8-hydroxylation of guanines in the presence of Cu(II) and NADH, and subsequent treatment with formamidopyrimidine-DNA glycosylase led to chain cleavages at the 5'-site guanine of GG and GGG sequences. Interestingly, antioxidant enzyme SOD enhanced the intensity of DNA damage, and thymine residues were appended to its guanine-predominant cleavage sites. Catalase and bathocuproine, a Cu(I)-specific chelator, inhibited the DNA damage, suggesting the involvement of H(2)O(2) and Cu(I). A UV-visible spectroscopic study indicated that Cu(II) and SOD catalyze the autoxidation of PhIP(NHOH). These results suggest that Cu(II)-dependent autooxidation of PhIP(NHOH) coupled with NADH-mediated reduction of its oxidized product form redox cycle, resulting in oxidative DNA damage by low concentrations of PhIP(NHOH). We conclude that in addition to DNA adduct formation, oxidative DNA damage may be involved in the carcinogenic process of PhIP.






Murata M,Kawanishi S





Has Abstract


2002-05-01 00:00:00












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    pub_type: 杂志文章


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