Genotoxicity and cell death induced by tinidazole (TNZ)

Tiniclazole (TNZ), a second-generation 5-nitroirniclazole compound chemically related to metroniclazole (M17), has been widely used throughout Europe and developing countries for the treatment of amoebic and parasitic infections. Despite TNZ's increasing use in therapeutics, scarce experimental reports are available in literature on its potential genotoxicity in human cells. Therefore, the aim of the present study was to achieve a precise characterization of the cytotoxic and genotoxic activities of this nitroirniclazole in cultured human lymphocytes at therapeutic concentrations (0.1, 1, 10 and 50 Vtg/ml of culture) and evaluate the possible cell death mechanism associated with it. The endpoints analyzed included: mitotic index (MI), replication index (RI), sister chromatid exchange (SCE) and chromosomal aberrations (CA). A significant decrease (p < 0.0001) in N41 as well as an increase in SCE (p < 0.0001) and CA (p < 0.0001) frequencies were observed. No modifications in RI were found. The results suggest a genotoxic and cytotoxic effect of TNZ related with cell death process. Therefore, we evaluated this mechanism by DNA fragmentation (laddering), fluorescence microscopy using acricline orange/ethidium bromide (AO/EB) staining and flow cytometry propidium iodide (PI'l. DNA extracts of TNZ-treated cells resulted in nucleosomal DNA]adder pattern after 48 h of cell treatment; meanwhile no differences were detected in untreated cells. This pattern correlated with the observed decrease in cellular viability (p < 0.05), morphological evidence of apoptosis and increase in the percentage of nuclei with hypocliploid DNA content of TNZ exposed cultures compared with control (p < 0.05). WE: concluded that TNZ is genotoxic, cytotoxic and is able to modulate cell death through apoptotic mechanisms in the experimental design employed. (c) 2008 Elsevier Ireland Ltd. All rights reserved.