Identification of covalent DNA adducts in vitro from bioactivation of pentachlorophenol

TOXI 74

V G Vaidyanathan, vaidychem@yahoo.com1, Peter W. Villalta, villa001@umn.edu2, and Shana J. Sturla1. (1) Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN 55455, (2) University of Minnesota Cancer Center, 420 Delaware St SE - MMC 806, Minneapolis, MN 55455
Pentachlorophenol (PCP), a possible human carcinogen widely occuring in the environment, can undergo metabolic oxidation by various peroxidases. A major metabolite of pentachlorophenol is tetrachlorobenzoquinone (Cl4BQ), a reactive electrophile with the capacity to form covalent DNA adducts. These adducts may be involved in chlorophenol carcinogenesis, but their structures, occurrence, and biological consequences are not known. Previous studies have indicated that several DNA adducts are formed in vivo from Cl4BQ, but these adducts were not structurally identified. We have characterized new Cl4BQ adducts of dGuo, dCyd and Thd by ESI-MS, HPLC, UV and NMR techniques. These adducts are formed in vitro in calf thymus DNA and the reaction pathways leading to the formation of adducts, such as imine-formation, conjugate addition, hydrolysis, and cyclization, vary with the identity of the reacting base. DNA adducts identified during the reaction of Cl4BQ with DNA are consistent with adducts obtained after bioactivation of PCP by peroxidase/peroxide and reaction with dGuo or DNA.
 

Poster Session and Awards
6:00 PM-10:00 PM, Tuesday, August 21, 2007 BCEC -- 204 A/B, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix

Division of Chemical Toxicology

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007