[Introduction of changes in the DNA of Trypanosoma cruzi by trypanocidal agents].
Incubation of Trypanosoma cruzi culture (epimastigote) forms with nifurtimox (10 or 100 microM), benznidazole (38 or 380 microM) and beta-lapachone (1.6 or 7.8 microM) produced damage of nuclear DNA, as shown by the increased rate of the "unscheduled DNA synthesis" in epimastigotes arrested at phase S (9-, 3-, and 6-fold, respectively). alpha-lapachone, a position isomer of beta-lapachone, was completely ineffective. In order to demonstrate the "unscheduled repair of DNA", the semiconservative replication was inhibited by preincubating the epimastigotes for 16 hours with 10 mM hydroxyurea and 0.3 mM cycloheximide. Kinetoplast DNA (kDNA) extracted from epimastigotes pretreated with the trypanocidal agents revealed an increased number of single-strand breaks. After alkaline agarose-gel electrophoresis, a fast moving DNA fraction was detected in the kDNA from nifurtimox, benznidazole and beta-lapachone-treated parasites, while trapping of alkali-denatured kDNA by nitrocellulose filters, was significantly increased after treating the epimastigotes with the same drugs. Reincubation of these epimastigotes in fresh medium for 24 h, reestablished kDNA electrophoretic and filtration patterns to normality, except with 7.8 microM beta-lapachone, thus proving the reversibility of DNA lesions. Redox-cycling of nifurtimox and beta-lapachone in T. cruzi generates oxygen radicals, and accordingly, the higher effectiveness of these drugs (as compared with benznidazole and alpha-lapachone) supports the role of oxygen radicals for the trypanocidal action.
D000818:Animals; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D005609:Free Radicals; D009285:Naphthoquinones / Q000494:pharmacology; D009547:Nifurtimox / Q000494:pharmacology; D009593:Nitroimidazoles / Q000494:pharmacology; D010084:Oxidation-Reduction; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000235:genetics
D005609:Free Radicals; D009285:Naphthoquinones; D009593:Nitroimidazoles; D014344:Trypanocidal Agents; C014638:beta-lapachone; D004247:DNA; D009547:Nifurtimox; C009999:benzonidazole
Inducción de alteraciones en el DNA del Trypanosoma cruzi por agentes tripanocidas.