Site-Specific Oxidation at GG and GGG Sequences in Double-Stranded DNA by Benzoyl Peroxide as a Tumor Promoter
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- 作者：Shosuke Kawanishi ; Shinji Oikawa ; Mariko Murata ; Hideyuki Tsukitome ; and Isao Saito
- 刊名：Biochemistry
- 出版年：1999
- 出版时间：December 21, 1999
- 年：1999
- 卷：38
- 期：51
- 页码：16733 - 16739
- 全文大小：155K
- 年卷期：v.38,no.51(December 21, 1999)
- ISSN：1520-4995
文摘
Benzoyl peroxide (BzPO), a free-radical generator, has tumor-promoting activity. As a methodfor approaching the mechanism of tumor promoter function, the ability of oxidative DNA damage byBzPO was investigated by using 32P-labeled DNA fragments obtained from the human p53 tumor suppressorgene and c-Ha-ras-1 protooncogene. BzPO induced piperidine-labile sites at the 5'-site guanine of GGand GGG sequences of double-stranded DNA in the presence of Cu(I), whereas the damage occurred atsingle guanine residues of single-stranded DNA. Both methional and dimethyl sulfoxide (DMSO) inhibitedDNA damage induced by BzPO and Cu(I), but typical hydroxyl radical (
OH) scavengers, superoxidedismutase (SOD) and catalase, did not inhibit it. On the other hand, H2O2 induced piperidine-labile sitesat cytosine and thymine residues of double-stranded DNA in the presence of Cu(I). Phenylhydrazine,which is known to produce phenyl radicals, induced Cu(I)-dependent damage at thymine residues but notat guanine residues. These results suggest that the BzPO-derived reactive species causing DNA damageis different from OH and phenyl radicals generated from benzoyloxyl radicals. BzPO/Cu(I) induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation in double-stranded DNA more effectively than thatin single-stranded DNA. Furthermore, we observed that BzPO increased the amount of 8-oxodG in humancultured cells. Consequently, it is concluded that benzoyloxyl radicals generated by the reaction of BzPOwith Cu(I) may oxidize the 5'-guanine of GG and GGG sequences in double-stranded DNA to lead to8-oxodG formation and piperidine-labile guanine lesions, and the damage seems to be relevant to thetumor-promoting activity of BzPO.
OH) scavengers, superoxidedismutase (SOD) and catalase, did not inhibit it. On the other hand, H2O2 induced piperidine-labile sitesat cytosine and thymine residues of double-stranded DNA in the presence of Cu(I). Phenylhydrazine,which is known to produce phenyl radicals, induced Cu(I)-dependent damage at thymine residues but notat guanine residues. These results suggest that the BzPO-derived reactive species causing DNA damageis different from OH and phenyl radicals generated from benzoyloxyl radicals. BzPO/Cu(I) induced 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) formation in double-stranded DNA more effectively than thatin single-stranded DNA. Furthermore, we observed that BzPO increased the amount of 8-oxodG in humancultured cells. Consequently, it is concluded that benzoyloxyl radicals generated by the reaction of BzPOwith Cu(I) may oxidize the 5'-guanine of GG and GGG sequences in double-stranded DNA to lead to8-oxodG formation and piperidine-labile guanine lesions, and the damage seems to be relevant to thetumor-promoting activity of BzPO.