Formation and persistence of safrole-DNA adducts over a 10,000-fold dose range in mouse liver.
The spice constituent safrole (1-allyl-3,4-methylenedioxybenzene) 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-1 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/monophosphate version of the 32P-postlabeling assay. An approximately 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.
Gupta
K P
KP
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
van Golen
K L
KL
Putman
K L
KL
Randerath
K
K
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology; D004247:DNA / Q000187:drug effects / Q000378:metabolism*; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D009711:Nucleotides / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D011116:Polynucleotide 5'-Hydroxyl-Kinase / Q000378:metabolism; D012451:Safrole / Q000378:metabolism* / Q000633:toxicity*; D013997:Time Factors
D009711:Nucleotides; D010710:Phosphates; D010761:Phosphorus Radioisotopes; D004247:DNA; D011116:Polynucleotide 5'-Hydroxyl-Kinase; D012451:Safrole