Kinetics of formation of specific styrene oxide adducts in double-stranded DNA

Abstract

The possible carcinogenicity of styrene is believed to be related to the DNA-binding properties of styrene 7,8-oxide (SO). In order to compare the intrinsic 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 α- and β-isomers of N7-substituted and α N 2-substituted guanines, α- and βN3-substituted and α N 6-substituted adenines as well as βN3- and α N 4-substituted cytosines. The highest rate constants were found for the spontaneously depurinating N7-guanines being ca. 3–15-fold higher than those for the stable adducts. When the relative proportions of different alkylation products were determined in course of time, after a single addition of SO, the labile N7-guanines and N3-adenines were the major products at early time points. After 144 h of incubation at 37 °C, α N 6-SO-adenine and α N 2-SO-guanine as well as βN3-SO-uracil were the major adducts. Regarding human biomonitoring, 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 may become important.