Formation and persistence of DNA adducts of anticancer drug ellipticine in rats.
Ellipticine is an antineoplastic agent, whose mode of antitumor and/or toxic side effects is based on DNA intercalation, inhibition of topoisomerase II and formation of DNA adducts mediated by cytochromes P450 and peroxidases. We investigated the formation and persistence of DNA adducts generated in rat, the animal model mimicking the bioactivation of ellipticine in human. Using (32)P-postlabeling, ellipticine-DNA adducts were found in liver, kidney, lung, spleen, heart and brain of female and male rats exposed to ellipticine (4, 40 and 80 mg/kg body weight, i.p.). The two major adducts were identical to the deoxyguanosine adducts generated in DNA by 13-hydroxy- and 12-hydroxyellipticine in vitro as confirmed by HPLC of the isolated adducts. At four post-treatment times (2 days, 2, 10 and 32 weeks) DNA adducts in rats treated with 80 mg/kg of ellipticine were analyzed in each tissue to study their long-term persistence. In all organs maximal adduct levels were found 2 days after administration. At all time points highest total adduct levels were in liver (402 adducts/10(8) nucleotides after 2 days and 3.6 adducts/10(8) nucleotides after 32 weeks), kidney and lung followed by spleen, heart and brain. Total adduct levels decreased over time to 0.8-8.3% of the initial levels till the latest time point and showed a biphasic profile, a rapid loss during the first 2 weeks was followed by a much slower decline till 32 weeks. These results, the first characterization of persistence of ellipticine-DNA adducts in vivo, are necessary to evaluate genotoxic side effects of ellipticine.
Stiborová
Marie
M
Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, 12840 Prague 2, Czech Republic. stiborov@natur.cuni.cz
Rupertová
Martina
M
Aimová
Dagmar
D
Ryslavá
Helena
H
Frei
Eva
E
D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts; D004305:Dose-Response Relationship, Drug; D004611:Ellipticines / Q000633:toxicity*; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013154:Spleen / Q000187:drug effects / Q000378:metabolism
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004611:Ellipticines; C034192:ellipticine