© 1993 Oxford University Press
research-article |
Formation and persistence of safrole-DNA adducts over a 10 000-fold dose range in mouse liver
Division of Toxicology, Department of Pharmacology, Baylor College of Medicine Houston, TX 77030, USA
1To whom correspondence should be addressed
The spice constituent safrole (l-allyl-3, 4-methylenedioxy-benzene) and related allylbenzenes form DNA adducts and are rodent carcinogens. This study examined both dose and time dependence of hepatic safrole-DNA adduct formation over a 10 000-fold dose range up to 30 days after single administration. Female CD-I mice were treated with safrole i.p. at 0.001, 0.01, 0.1, 1.0, and 10.0 mg/mouse in 0.2 ml tricaprylin or with vehicle alone. Liver DNA was analyzed at 0.5, 1, 2, 3, 7, 15 and 30 days via the dinucleotide/mono-phosphate version of the 32P-postlabeling assay. An 
10-fold increase in total safrole adduct levels with each successive 10-fold increase in dose was observed, giving relative adduct labeling (RAL) values of 10-9-10-5. Each dose elicited identical kinetics of adduct formation, showing peak levels at 2 days and only slight decreases thereafter. The time course of adduct persistence was independent of the dose (0.01 –10 mg/mouse). An in vitro experiment established that the assay responded in strictly linear fashion to adduct concentration over a 10 000-fold range, and thus was suitable for in vivo dosimetry. DNA synthesis, as measured by [3H]thymidine incorporation, was enhanced only for the 10.0 mg dose at 2, 3 and 7 days. These results indicate a linear response of safrole-DNA adduct formation and persistence in mouse liver following administration of minute (0.001 mg/mouse) to high (10.0 mg/mouse) doses of the carcinogen.