Hydroxyl Radical-Induced Oxidation of a Phenolic C-Linked 2 %26apos;-Deoxyguanosine Adduct Yields a Reactive Catechol

作者：Witham Aaron A; Beach Daniel G; Gabryelski Wojciech; Manderville Richard A^*

来源：Chemical Research in Toxicology, 2012, 25(2): 315-325.

DOI：10.1021/tx200365r

Phenolic toxins stimulate oxidative stress and generate C-linked adducts at the C8-site of 2%26apos;-deoxyguanosine (dG). We previously reported that the C-linked adduct 8-(4 %26apos;%26apos;-hydroxyphenyl)-dG (p-PhOH-dG) undergoes oxidation in the presence of Na2IrCl6 or horseradish peroxidase (HRP)/H2O2 to generate polymeric adducts through phenoxyl radical production [Weishar et al. (2008) Org. Lett. 10, 1839-1842]. We now report on reaction of p-PhOH-dG with two radical-generating systems, Cu-II/H2O2 or Fe-II-EDTA/H2O2, which were utilized to study the fate of the C-linked adduct in the presence of hydroxyl radical (HO center dot). The radical-generating systems facilitate (i) hydroxylation of the phenolic ring to afford the catechol adduct 8-(3 %26apos;%26apos;,4 %26apos;%26apos;-dihydroxypheny1)-dG (3 %26apos;%26apos;,4 %26apos;%26apos;-DHPh-dG) and (ii) H-atom abstraction from the sugar moiety to generate the deglycosylated base p-PhOH-G. The ratios of 3 %26apos;%26apos;,4 %26apos;%26apos;-DHPh-dG to p-PhOH-G were similar to 1 for Cu-II/H2O2 and similar to 0.13 for Fe-II-EDTA/H2O2. The formation of 3 %26apos;%26apos;,4 %26apos;%26apos;-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 %26apos;%26apos;,4 %26apos;%26apos;-DHPh-dG produced mono-NAC and di-NAC conjugates. Our results imply that secondary oxidative pathways of phenolic-dG lesion g are likely to contribute to toxicity.

• 出版日期2012-2