title: Nucleobase-dependent reactivity of a quinone metabolite of pentachlorophenol.
abstract: Pentachlorophenol (PCP) is a possible human carcinogen detected widely in the environment. A quinone metabolite of PCP, tetrachloro-1,4-benzoquinone (Cl4BQ), 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 Cl4BQ, 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 Cl4BQ. 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 Cl4BQ have been identified. The results indicate that, in the structural context of DNA, Cl4BQ reacts most readily with dGuo compared to the other DNA bases and that the mode of Cl4BQ reactivity is dependent on the base structure; i.e., multiple types of adducts are formed. Finally, DNA adducts consistent with Cl4BQ reactions are observed when DNA or dGuo is treated with PCP and a peroxidase-based bioactivating system.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: V G
authors.initials: VG
authors.lastname: Vaidyanathan
authors.forename: Peter W
authors.initials: PW
authors.lastname: Villalta
authors.forename: Shana J
authors.initials: SJ
authors.lastname: Sturla
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D002417:Cattle; D002703:Chloranil / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry* / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000737:chemistry / Q000378:metabolism; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D006735:Horseradish Peroxidase / Q000737:chemistry / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010416:Pentachlorophenol / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D011684:Purine Nucleosides / Q000737:chemistry / Q000378:metabolism; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D016227:Benzoquinones; D018736:DNA Adducts; D004785:Environmental Pollutants; D011684:Purine Nucleosides; D011741:Pyrimidine Nucleosides; D002703:Chloranil; C004532:quinone; D004247:DNA; C427203:calf thymus DNA; D006861:Hydrogen Peroxide; D010416:Pentachlorophenol; D006735:Horseradish Peroxidase; D004121:Dimethyl Sulfoxide