Kinetics of formation of specific styrene oxide adducts in double-strandedDNA

The possible carcinogenicity of styrene is believed to be related to the DN A-binding properties of styrene 7,8-oxide (SO). In order to compare the int rinsic reactivity of the different nucleophilic sites in DNA towards SO and to evaluate the candidates for human biomonitoring we have determined the second-order rate constants and stabilities of several SO-adducts in double -stranded DNA. These include alpha- and beta -isomers of N7-substituted and alphaN(2)-substituted guanines, alpha- and beta N3-substituted and alphaN( 6)-substitated adenines as well as beta N3- and alphaN(4)-substituted cytos ines. The highest rate constants were found for the spontaneously depurinat ing N7-guanines being ca. 3-15-fold higher than those for the stable adduct s. When the relative proportions of different alkylation products were dete rmined in course of time. after a single addition of SO, the labile N7-guan ines and N3-adenines were the major products at early time points. After 14 4 h of incubation at 37 degreesC, alphaN(6)-SO-adenine and alphaN(2)-SO-gua nine as well as beta N3-SO-uracil were the major adducts. Regarding human b iomonitoring, the N7-substituted guanines should be one of the main targets because of the high reactivity of the N7-atom of guanine. However, in the case of chronic styrene exposures the chemically more stable DNA adducts ma y become important. (C) 2001 Elsevier Science Ireland Ltd. All rights reser ved.