Reduction of Diphenyl Diselenide and Analogs by Mammalian Thioredoxin Reductase Is Independent of Their Gluthathione Peroxidase-Like Activity: A Possible Novel Pathway for Their Antioxidant Activity

Abstract

Abstract:Since the successful use of the organoselenium drug ebselen in clinical trials for the treatment of neuropathological conditions associated with oxidative stress, there have been concerted efforts geared towards understanding the precise mechanism of action of ebselen and other organoselenium compounds, especially the diorganyl diselenides such as diphenyl diselenide, and its analogs. Although the mechanism of action of ebselen and other organoselenium compounds has been shown to be related to their ability to generally mimic native glutathione peroxidase (GPx), only ebselen however has been shown to serve as a substrate for the mammalian thioredoxin reductase (TrxR), demonstrating another component of its pharmacological mechanisms. In fact, there is a dearth of information on OPEN ACCESSMolecules 2010, 15 7700 the ability of other organoselenium compounds, especially diphenyl diselenide and its analogs, to serve as substrates for the mammalian enzyme thioredoxin reductase. Interestingly, diphenyl diselenide shares several antioxidant and neuroprotective properties with ebselen. Hence in the present study, we tested the hypothesis that diphenyl diselenide and some of its analogs (4,4'-bistrifluoromethyldiphenyl diselenide, 4,4'-bismethoxy-diphenyl diselenide, 4.4'-biscarboxydiphenyl diselenide, 4,4'-bischlorodiphenyl diselenide, 2,4,6,2',4',6'-hexamethyldiphenyl diselenide) could also be substrates for rat hepatic TrxR. Here we show for the first time that diselenides are good substrates for mammalian TrxR, but not necessarily good mimetics of GPx, and vice versa. For instance, bis-methoxydiphenyl diselenide had no GPx activity, whereas it was a good substrate for reduction by TrxR. Our experimental observations indicate a possible dissociation between the two pathways for peroxide degradation (either via substrate for TrxR or as a mimic of GPx). Consequently, the antioxidant activity of diphenyl diselenide and analogs can be attributed to their capacity to be substrates for mammalian TrxR and we therefore conclude that subtle changes in the aryl moiety of diselenides can be used as tool for dissociation of GPx or TrxR pathways as mechanism triggering their antioxidant activities.

Effects of Diphenyl Diselenide on Methylmercury Toxicity in Rats

“…Recently, diphenyl diselenide was demonstrated to be a substrate for cerebral and hepatic rat TrxR, which could account, at least in part, for the antioxidant properties of (PhSe) 2 [23]. Herein, rats treated solely with (PhSe) showed an increase in the activity of renal TrxR (Figures 9(a) and 9(b), resp.).…”

“…(PhSe) 2 (which is the simplest of the diaryl diselenides [22]) protected against an array of toxic effects of MeHg and lowered the Hg burden in the brain, liver, and kidneys of adult mice [21]. The molecular mechanism(s) which underlie(s) the protective effects of (PhSe) 2 in mice likely reflect the direct interaction of MeHg with “selenol intermediate” of (PhSe) 2 after its reaction with thiols, or indirectly, by modulating oxidative stress levels [21, 23]. In short, the protective effects of (PhSe) 2 against MeHg-induced toxicity are likely related to its antioxidant properties and its ability to form stable complexes with MeHg, which can increase Hg excretion and decrease the MeHg body burden.…”

Organotellurium and organoselenium compounds attenuate Mn-induced toxicity in Caenorhabditis elegans by preventing oxidative stress

“…The potential for organochalcogens to offer efficacious treatment for disease models associated with oxidative stress has been of interest to several research groups [1–2, 23, 32–34]. The ROS scavenging activity and glutathione peroxidase mimetic property of the organochalcogens likely accounts for their efficacy in attenuating oxidative stress both in in vitro and in vivo rodent models [8, 32, 34–36]. Notably, ebselen was deemed a promising molecule and it entered clinical trials [37].…”

Interaction Profile of Diphenyl Diselenide with Pharmacologically Significant Thiols

“…There is also increasing evidence for thiol involvement in metabolic regulation, signal transduction and regulation of gene expression [ 1 ]. Organoselenium compounds, including diphenyl diselenide (DPDS) are known to possess neuroprotective, anticancer, anti-nociceptive, anti-hypercolesterolemic, pro-apoptotic and anti-inflammatory activities in different experimental models of human pathologies [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. Organoselenium compounds can interact directly with low molecular thiols, oxidizing them to disulfides [ 9 ].…”