Evaluation of the cytotoxicity, genotoxicity and mutagenicity of diphenyl ditelluride in several biological models

Abstract

Diphenyl ditelluride (DPDT) is a potential prototype for the development of novel biologically active molecules. Thus, it is important to evaluate the toxic effects of this compound. In the present study, we evaluated the cytotoxic, genotoxic and mutagenic properties of DPDT in Chinese hamster fibroblast (V79) cells, in strains of the yeast Saccharomyces cerevisiae both proficient and deficient in several DNA repair pathways and in Salmonella typhimurium. DPDT induced frameshift mutations in both S.typhimurium and a haploid wild-type strain of S.cerevisiae. Mutants of S.cerevisiae defective in base excision repair and recombinational repair were more sensitive to DPDT. The results of a lactate dehydrogenase leakage assay suggest that DPDT is cytotoxic to V79 cells. At cytotoxic concentrations, this compound increased thiobarbituric reactive species levels and decreased the glutathione:GSSH ratio in yeast and V79 cells. DPDT generated single- and double-strand DNA breaks in V79 cells, both with and without metabolic activation, as revealed by alkaline and neutral comet assays. Moreover, an induction of oxidative DNA base damage was indicated by a modified comet assay using formamidopyrimidine DNA glycosylase and endonuclease III. Treatment with DPDT also induced micronucleus formation in V79 cells. Pre-incubation with N-acetylcysteine reduced DPDT's oxidative, genotoxic and mutagenic effects in yeast and V79 cells. Our results suggest that the toxic and mutagenic properties of DPDT may stem from its ability to disturb the redox balance of the cell, which leads to oxidative stress and the induction of DNA damage.

Diphenyl Ditelluride‐Induced Cell Cycle Arrest and Apoptosis: A Relation with Topoisomerase I Inhibition

“…2). As expected, the cytotoxic threshold of DPDT was consistent with the results obtained by Degrandi et al [16]. Recently, a significant decrease in cell viability was observed in human colon carcinoma (HT-29) treated at a concentration range of 62.5-1000 lM DPDT and heterogeneous human epithelial colorectal adenocarcinoma cells (Caco-2), in MTT and luminescence assays [21].…”

“…*Significantly different from the control group *p < 0.05; **p < 0.01; ***p < 0.001. frameshift mutation in bacterial and yeast systems and as clastogenicity in mammalian systems. So, the results reported by Degrandi et al [16] showing frameshift mutation induction by DPDT in Salmonella typhimurium and S. cerevisiae and an increase in DSBs in V79 cells, suggested intercalation activity and/or interaction with DNA topoisomerase enzymes. To determine the possible interaction of DPDT with Top1p and Top3p, we studied the response of S. cerevisiae mutants defective in these topoisomerase enzymes to treatment with this OT compound.…”

“…In this context, data from our laboratory showed that DPDT-induced DNA double-strand breaks (DSBs) in permanent lung fibroblast cell line derived from Chinese hamster (V79 cells). The observed DSBs formation could indicate the ability of this compound to intercalate into DNA and/or affect topoisomerase activity [16].…”

Differential genotoxicity of diphenyl diselenide (PhSe)2 and diphenyl ditelluride (PhTe)2

“…Recently, our research group demonstrated that organoselenium and organotellurium present hemolytic and genotoxic effects in human blood cells Carean Bueno et al 2013), which is in accordance with results published by other laboratories in experimental bacteria and rodent models (Degrandi et al, 2010). Similarly,organoselenides and tellurides can be toxic in different in vivo and in vitro models of animal pathologies (Maciel et al, 2000;Taylor, 1996;Stangherlin et al, 2009;Moretto et al, 2007;Heimfarth et al, 2011;Heimfarth et al, 2012 b;Comparsi et al, 2012).…”

“…Tellurium (Te) has the potential of redox cycling which leads to formation of reactive oxygen species (ROS) which can damage biomolecules (Maciel et al,2000;Nogueira, Zeni & Rocha, 2004;Degrandi et al, 2010;Sailer et al, 2004;Caeran Bueno et al 2013). Organotellurium-induced intracellular ROS accumulation has been reported to be the cause of cell death in HL-60 and different types of cancer cells (McNaughton et al, 2004;Juan et al, 2010;Ding et al,2002;Rigobello et al, 2009).…”