title: Genotoxic investigation of a thiazolidinedione PPARγ agonist using the in vitro micronucleus test and the in vivo homozygotization assay.
abstract: Pioglitazone (PTZ) is an oral antidiabetic agent whose anti-cancer properties have been described recently. Since PTZ increases the production of reactive oxygen species in mammalian cells, the aim of current study was to evaluate the cytotoxic, mutagenic and recombinogenic effects of PTZ using respectively the in vitro mitotic index assay and the in vitro mammalian cell micronucleus test in human peripheral lymphocytes, and the in vivo homozygotization assay in Aspergillus nidulans, which detects the loss of heterozygosity due to somatic recombination. Although the lowest PTZ concentrations (4-36 μM) did not show any significant rise in the micronucleus production, the higher PTZ concentration (108 μM) produced a statistically higher number of micronuclei than the negative control and significantly altered the cell-proliferation kinetics, demonstrating the mutagenic and antiproliferative effects of PTZ, respectively. The recombinogenic activity of PTZ, demonstrated here for the first time, was observed at the highest tested concentration (400 μM) through the homozygotization index rates significantly different from the negative control. Taken together, our results show that PTZ is genotoxic at a concentration higher than the therapeutic plasma concentration. This PTZ genotoxicity may be a potential benefit to its previously described antitumour activity.
authors.forename: Janicélle Fernandes
authors.initials: JF
authors.lastname: Morais
authors.forename: Juliane Rocha de
authors.initials: JR
authors.lastname: Sant'Anna
authors.forename: Tais Susane
authors.initials: TS
authors.lastname: Pereira
authors.affiliation: Departamento de Biotecnologia, Genética e Biologia Celular, Laboratório de Biologia Celular e Secreção, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, bloco H67, sala 17, Maringá, Paraná, Brazil.
authors.forename: Claudinéia Conationi da Silva
authors.initials: CC
authors.lastname: Franco
authors.affiliation: Departamento de Biotecnologia, Genética e Biologia Celular, Laboratório de Biologia Celular e Secreção, Universidade Estadual de Maringá, Avenida Colombo, 5790, 87020-900, bloco H67, sala 17, Maringá, Paraná, Brazil.
authors.forename: Paulo Cezar de Freitas
authors.initials: PC
authors.lastname: Mathias
authors.forename: Marialba Avezum Alves
authors.initials: MA
authors.lastname: de Castro-Prado
mesh_terms: D001233:Aspergillus nidulans / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity; D019656:Loss of Heterozygosity; D008214:Lymphocytes / Q000187:drug effects*; D048629:Micronuclei, Chromosome-Defective / Q000139:chemically induced*; D009152:Mutagenicity Tests; D018384:Oxidative Stress / Q000187:drug effects; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000009:adverse effects* / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D004247:DNA; D000077205:Pioglitazone