title: Hydroxyl radical-induced oxidation of a phenolic C-linked 2'-deoxyguanosine adduct yields a reactive catechol.
abstract: Phenolic toxins stimulate oxidative stress and generate C-linked adducts at the C8-site of 2'-deoxyguanosine (dG). We previously reported that the C-linked adduct 8-(4″-hydroxyphenyl)-dG (p-PhOH-dG) undergoes oxidation in the presence of Na(2)IrCl(6) or horseradish peroxidase (HRP)/H(2)O(2) to generate polymeric adducts through phenoxyl radical production [       Weishar          (  2008  )   Org. Lett.  10  ,   1839 - 1842  ]. We now report on reaction of p-PhOH-dG with two radical-generating systems, Cu(II)/H(2)O(2) or Fe(II)-EDTA/H(2)O(2), which were utilized to study the fate of the C-linked adduct in the presence of hydroxyl radical (HO(•)). The radical-generating systems facilitate (i) hydroxylation of the phenolic ring to afford the catechol adduct 8-(3″,4″-dihydroxyphenyl)-dG (3″,4″-DHPh-dG) and (ii) H-atom abstraction from the sugar moiety to generate the deglycosylated base p-PhOH-G. The ratios of 3″,4″-DHPh-dG to p-PhOH-G were ∼1 for Cu(II)/H(2)O(2) and ∼0.13 for Fe(II)-EDTA/H(2)O(2). The formation of 3″,4″-DHPh-dG was found to have important consequences in terms of reactivity. The catechol adduct has a lower oxidation potential than p-PhOH-dG and is sensitive to aqueous basic media, undergoing decomposition to generate a dicarboxylic acid derivative. In the presence of excess N-acetylcysteine (NAC), oxidation of 3″,4″-DHPh-dG produced mono-NAC and di-NAC conjugates. Our results imply that secondary oxidative pathways of phenolic-dG lesions are likely to contribute to toxicity.
authors.affiliation: Departments of Chemistry and Toxicology, University of Guelph , Guelph, Ontario, Canada N1G 2W1.
authors.forename: Aaron A
authors.initials: AA
authors.lastname: Witham
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Beach
authors.forename: Wojciech
authors.initials: W
authors.lastname: Gabryelski
authors.forename: Richard A
authors.initials: RA
authors.lastname: Manderville
mesh_terms: D000111:Acetylcysteine / Q000737:chemistry; D002396:Catechols / Q000737:chemistry*; D003300:Copper / Q000737:chemistry; D018736:DNA Adducts; D003849:Deoxyguanosine / Q000737:chemistry*; D004492:Edetic Acid / Q000737:chemistry; D005296:Ferrous Compounds / Q000737:chemistry; D006861:Hydrogen Peroxide / Q000737:chemistry; D017665:Hydroxyl Radical / Q000737:chemistry*; D010636:Phenols / Q000737:chemistry*
chemical_list: D002396:Catechols; D018736:DNA Adducts; D005296:Ferrous Compounds; D010636:Phenols; C055526:Fe(II)-EDTA; D017665:Hydroxyl Radical; D003300:Copper; D004492:Edetic Acid; D006861:Hydrogen Peroxide; D003849:Deoxyguanosine; D000111:Acetylcysteine