期刊
MUTATION RESEARCH-DNA REPAIR
卷 461, 期 4, 页码 289-299出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/S0921-8777(00)00057-4
关键词
oxidative DNA damage; alkoxyl radicals; mutagenicity; 8-hydroxyguanine
Like hydroxyl radicals, alkoxyl radicals have been implicated in the generation of cellular oxidative DNA damage under physiological conditions; however, their genotoxic potential has not yet been established. We have analyzed the DNA damage induced by a photochemical source of tert-butoxyl radicals, the water soluble peroxy ester [4-(tert-butyldioxycarbonyl)-benzyl]triethylammonium chloride (BCBT), using various repair endonucleases as probes. The irradiation (UV360) of BCBT in the presence of bacteriophage PM2 DNA was found to generate a DNA damage profile that consisted mostly of base modifications sensitive to the repair endonuclease Fpg protein. Approximately 90% of the modifications were identified as 7.8-dihydro-8-oxoguanine (8-oxoGua) residues by HPLC/ECD analysis. Oxidative pyrimidine modifications (sensitive to endonuclease III), sites of base loss (AP sites) and single-strand breaks were only minor modifications. Experiments with various scavengers and quenchers indicated that the DNA damage by BCBT + UV360 was caused by tert-butoxyl radicals as the ultimate reactive species. The mutagenicity associated with the induced damage was analyzed in the gpt gene of plasmid pSV2gpt, which was exposed to BCBT + UV360 and subsequently transfected into Escherichia coli. The results were in agreement with the specific generation of 8-oxoGua. Nearly all point mutations (20 out of 21) were found to be GC --> TA transversions known to he characteristic for 8-oxoGua. In conclusion, alkoxyl radicals generated from BCBT + UV360 induce 8-oxoGua in DNA with a higher selectivity than any other reactive oxygen species analyzed so far. (C) 2001 Elsevier Science B.V. All rights reserved.
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