title: Benzoyl peroxide-induced damage to DNA and its components: direct evidence for the generation of base adducts, sugar radicals, and strand breaks.
abstract: Benzoyl peroxide is a known tumor promoter and progression agent in mouse skin, though it is not an initiator or complete carcinogen. Previous studies have suggested that this activity may be due to the generation of strand breaks in cells exposed to this compound. This may be as a result of free radical generation, though there is controversy as to which radicals are responsible for this damage; previous workers have variously implicated benzoyloxyl (PhCO2,) phenyl (Ph.), and hydroxyl radicals (HO.) as the initiating agent. In the present study a detailed examination of the radicals generated on reaction of benzoyl peroxide with Cu(I) has been carried out by electron paramagnetic resonance (EPR) spectroscopy and spin trapping; the results obtained are consistent with the formation of PhCO2. and Ph. but not HO. The subsequent reactions of these benzoyl peroxide-derived radicals with nucleobases, sugars, nucleosides, nucleotides, RNA, and DNA have been examined and the intermediate species have been identified in many cases. Comparison of these data with those obtained with Ph. alone has allowed the reactions of PhCO2. and Ph. to be distinguished. Evidence has been obtained which is consistent with both the addition of these radicals to the C5-C6 double bond of the pyrimidines to give adduct species, and hydrogen abstraction from the sugar rings. The former process is the major reaction for nucleosides and nucleotides. Studies with RNA and DNA also provide strong evidence for the formation of base adducts, though the exact identity of the species detected in these cases could not be determined due to the complexity of the spectra. Hydrogen abstraction at the sugar-phosphate backbone is also believed to occur with these substrates as strand breakage is observed; the extent of the latter is dependent on the radical flux and the attacking species, with PhCO2. appearing to be a much more effective inducer of fragmentation than Ph. The nature of the species detected with all the substrates examined, with the exception of the isolated sugars where essentially random attack by both radicals is observed, suggests that of the two possible radicals generated by benzoyl peroxide, PhCO2. and Ph., it is the former which is responsible for the majority of the observed degradation. The results obtained in this study are consistent with the genetic damage produced by this compound being due to the formation of both strand breaks and high yields of altered bases via the formation of base adducts.
authors.affiliation: Department of Chemistry, University of York, United Kingdom.
authors.forename: C
authors.initials: C
authors.lastname: Hazlewood
authors.forename: M J
authors.initials: MJ
authors.lastname: Davies
mesh_terms: D000818:Animals; D001585:Benzoyl Peroxide / Q000633:toxicity*; D002241:Carbohydrates / Q000737:chemistry; D002273:Carcinogens / Q000633:toxicity*; D003300:Copper / Q000737:chemistry; D004247:DNA / Q000737:chemistry* / Q000187:drug effects*; D018736:DNA Adducts / Q000737:chemistry; D004249:DNA Damage; D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000737:chemistry; D066298:In Vitro Techniques; D051379:Mice; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry; D009711:Nucleotides / Q000737:chemistry; D012313:RNA / Q000737:chemistry / Q000187:drug effects
chemical_list: D002241:Carbohydrates; D002273:Carcinogens; D018736:DNA Adducts; D005609:Free Radicals; D009705:Nucleosides; D009711:Nucleotides; D012313:RNA; D003300:Copper; D004247:DNA; D001585:Benzoyl Peroxide