Nucleobase-dependent reactivity of a quinone metabolite of pentachlorophenol

Pentachlorophenol (PCP) is a possible human carcinogen detected widely in the environment. A quinone metabolite of PCP, tetrachloro-1,4-benzoquinone (Cl(4)BQ), is a reactive electrophile with the capacity to damage DNA by forming bulky covalent DNA adducts. These quinone adducts may contribute to chlorophenol carcinogenesis, but their structures, occurrence, and biological consequences are not known. Previous studies have indicated that several DNA adducts are formed in vivo in rats exposed to Cl(4)BQ, but these adducts were not identified structurally. In the present study, we have elucidated the structure of new agent-specific DNA adducts resulting from the reaction of dGuo, dCyd, and Thd with Cl(4)BQ. These have been characterized chemically by liquid chromatography-electrospray ionization mass spectrometry, HPLC, UV, and NMR analysis. Two dGuo adducts and one dCyd adduct resulting from the reaction of double-stranded DNA with Cl(4)BQ have been identified. The results indicate that, in the structural context of DNA, Cl(4)BQ reacts most readily with dGuo compared to the other DNA bases and that the mode of Cl(4)BQ reactivity is dependent on the base structure; i.e., multiple types of adducts are formed. Finally, DNA adducts consistent with Cl(4)BQ reactions are observed when DNA or dGuo is treated with PCP and a peroxidase-based bioactivating system.