Apurinic/apyrimidinic site induction in supercoiled DNA and mutagenesis in Salmonella typhimurium TA100 by 1′-acetoxysafrole and related electrophilic alkenylbenzene derivatives

The abilities of seven electrophilic alkenylbenzene derivatives related to 1'-acetoxysafrole to induce apurinic/apyrimidinic (AP) sites in supercoiled SV40 DNA were quantitated by gel electrophoresis after neutral thermal hydrolysis of DNA adducts with unstable N-glycosidic bonds and putrescine/Mg2+ ion-enhanced cleavage of the adjacent phosphodiester linkages. A 20-fold range in AP site production was observed for this series of closely related electrophiles. Analysis of SV40 DNA modified with [2',3'-3H]-1'-acetoxysafrole indicated that approximately 14% of the total safrole-DNA adducts generated AP sites under the conditions used. Neutral thermal hydrolysis of the modified DNA released a product with the same h.p.l.c. retention time as N7-(isosafrol-3'-yl)guanine. The mutagenic potencies in Salmonella typhimurium strain TA100 of these seven electrophilic alkenylbenzene derivatives covered a 75-fold range (from 0.1 to 7.7 revertants/nmol). Although the mutagenic activities of these electrophiles generally correlated well with the hepatocarcinogenic activities of the parent 1'- or 3'-hydroxy derivatives on administration to preweanling male mice, the mutagenic and carcinogenic activities did not correlate with the abilities to induce AP sites.