Cytotoxicity and Genotoxicity Evaluation of Organochalcogens in Human Leucocytes: A Comparative Study between Ebselen, Diphenyl Diselenide, and Diphenyl Ditelluride

Abstract

Organochalcogens, particularly ebselen, have been used in experimental and clinical trials with borderline efficacy. (PhSe)2 and (PhTe)2 are the simplest of the diaryl dichalcogenides and share with ebselen pharmacological properties. In view of the concerns with the use of mammals in studies and the great number of new organochalcogens with potential pharmacological properties that have been synthesized, it becomes important to develop screening protocols to select compounds that are worth to be tested in vivo. This study investigated the possible use of isolated human white cells as a preliminary model to test organochalcogen toxicity. Human leucocytes were exposed to 5–50 μM of ebselen, (PhSe)2, or (PhTe)2. All compounds were cytotoxic (Trypan's Blue exclusion) at the highest concentration tested, and Ebselen was the most toxic. Ebselen and (PhSe)2 were genotoxic (Comet Assay) only at 50 μM, and (PhTe)2 at 5–50 μM. Here, the acute cytotoxicity did not correspond with in vivo toxicity of the compounds. But the genotoxicity was in the same order of the in vivo toxicity to mice. These results indicate that in vitro genotoxicity in white blood cells should be considered as an early step in the investigation of potential toxicity of organochalcogens.

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

“…Recently, our research group demonstrated that organoselenium and organotellurium present hemolytic and genotoxic effects in human blood cells ( Santos et al, 2009a ; Santos et al, 2009b ; Caeran 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, Rocha & Nogueira, 2009 ; Moretto et al, 2007 ; Heimfarth et al, 2011 ; Heimfarth et al, 2012a ; Heimfarth et al, 2012b ; Comparsi et al, 2012 ).…”

“…The results presented here indicate clear toxic effects of (PhTe) 2 when compared with (PhSe) 2 . 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, Zen & Rocha, 2004 ; Santos et al, 2009a ; Santos et al, 2009b ; 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 ; Sandoval et al, 2010 ; Ding et al, 2002 ; Rigobello et al, 2009 ).…”

The 125Te Chemical Shift of Diphenyl Ditelluride: Chasing Conformers over a Flat Energy Surface

“…Interesting studies about the toxicity of Ph 2 Te 2 are available in the literature [20,21,22,23,24]. However, the toxicological data on Ph 2 Te 2 and organotellurium compounds, in general, are not exhaustive and conflicting results were obtained, the majority of which lean towards the view that organotellurides have a higher toxicity compared to their selenium analogs [25].…”

Inhibitors of the Hydrolytic Enzyme Dimethylarginine Dimethylaminohydrolase (DDAH): Discovery, Synthesis and Development

“…A wide range of molecular targets are modulated by ebselen including: NADPH oxidase 2 [150,151], H + /K + ATPase transporter [152], Ca 2+ - and phospholipid-dependent protein kinase C [151], lipoxygenase [153], thioredoxin reductase [154], and metallothionein [155]). Moreover, cellular toxicity in leukocytes and hepatocytes has been reported, further reducing the likelihood of ebselen’s use in clinical practice [156,157].…”