title: Cytotoxic, mutagenic and genotoxic effects of new anti-T. cruzi 5-phenylethenylbenzofuroxans. Contribution of phase I metabolites on the mutagenicity induction.
abstract: 5-Phenylethenylbenzofuroxans have displayed in vitro and in vivo activity against Trypanosoma cruzi, the etiologic agent of American Trypanosomiasis. On the basis of benzofuroxans pre-clinical studies we evaluated the potential of six 5-phenylethenyl derivatives to induce cytotoxicity, mutagenicity and genotoxicity using different in vitro models. Cytotoxic effects were evaluated using a set of cells, mammal pre-monocytic macrophages, V-79 lung fibroblast from Chinese hamster, and colorectal adenocarcinoma Caco-2 cells, in the MTT viability assay. Mutagenicity was tested in the Ames assay using Salmonella typhimurium TA98 strain with and without metabolic activation by S9-rat liver homogenate. The genotoxic potentials were evaluated with the alkaline single cell gel electrophoresis (comet assay) in V-79 cells. In view of the Ames test results we study whether the main mammals' phase I metabolites, the corresponding o-nitroanilines, are involved in the mechanism of mutagenicity. These metabolites are produced by NADPH-dependent enzymes in cytosol and by xanthine oxidase and cytochrome P450 in microsomes from rat liver. Among them, the electronic property of phenyl substituent seems to be responsible for this effect. It could be pointed out that the equimolecular mixture of compounds 1 and 2 (5E- and 5Z-(2-phenylethenyl)benzofuroxan, respectively) could be used in further clinical studies as anti-T. cruzi drug.
authors: Departamento de Química Orgánica, Facultad de Ciencias-Facultad de Química, Universidad de la República, 11400 Montevideo, Uruguay.
authors: Mauricio
authors: M
authors: Cabrera
authors: María Laura
authors: ML
authors: Lavaggi
authors: Paola
authors: P
authors: Hernández
authors: Alicia
authors: A
authors: Merlino
authors: Alejandra
authors: A
authors: Gerpe
authors: Williams
authors: W
authors: Porcal
authors: Mariana
authors: M
authors: Boiani
authors: Ana
authors: A
authors: Ferreira
authors: Antonio
authors: A
authors: Monge
authors: Adela López
authors: AL
authors: de Cerain
authors: Mercedes
authors: M
authors: González
authors: Hugo
authors: H
authors: Cerecetto
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D002470:Cell Survival / Q000187:drug effects*; D004396:Coloring Agents; D020552:Comet Assay; D006224:Cricetinae; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013778:Tetrazolium Salts; D013844:Thiazoles; D014344:Trypanocidal Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D010069:Oxadiazoles
chemical_list: D001583:Benzoxazoles; D004396:Coloring Agents; D009153:Mutagens; D013778:Tetrazolium Salts; D013844:Thiazoles; D014344:Trypanocidal Agents; C014354:benzofuroxan; D010069:Oxadiazoles; C022616:thiazolyl blue