Hepatocarcinogenesis in the preweanling male B6C3F1 mouse with alkenylbenzene derivatives: hepatic DNA adducts, structure-carcinogenicity relationships, and activating mutations in the C-HA-ras proto-oncogene

Hepatomas can be induced in preweanling male B6C3F1 mice by a single carcinogen treatment. Several alkenylbenzene derivatives related to the naturally occurring hepatocarcinogens safrole and estragole have been examined in this sensitive system. New DNA adducts formed by reaction of 1'-acetoxy derivative of safrole and estragole at the C-8 and N-7 positions of guanine were characterized; they were also demonstrated in the hepatic DNA of 12-day-old B6C3F1 mice treated with [3H]-1'-hydroxysafrole (HOS). Likewise, adducts tentatively identified in earlier work as N2-(safrol-1'-yl)- or N2-(estragol-1'-yl)-deoxyguanosine were each characterized and resolved into a pair of diastereomers. Analogous N2-adducts were characterized and shown to account for 85% of the hepatic DNA adducts formed by [3H]-1'-hydroxy-2',3'-dehydroestragole (HOHDE). Induction of apurinic/apyrimidinic sites in supercoiled DNA differed 20-fold for 7 electrophilic alkenylbenzene derivatives. Although the mutagenic activities of these electrophiles in Salmonella typhimurium TA100 generally correlated well with B6C3F1 hepatoma induction by the parent 1'- or 3'-hydroxy derivatives, the mutagenic and carcinogenic activities did not correlate with apurinic/apyrimidinic site induction