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

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 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.

Diphenyl diselenide diet intake improves spatial learning and memory deficits in hypothyroid female rats

“…Here we have not determined the neuroprotective role of diphenyl diselenide and/or the deleterious action of MTZ exposure in terms of mechanism(s); and this fact could limit an analysis more detailed of our results. However, it is well established in other works that the neuroprotective action of this compound, in different animal models, possibly is associated with its potent antioxidant property, which is mediated by its glutathione peroxidase activity and also by its reduction by cerebral TrxR (thioredoxin reductase) (Nogueira and Rocha, 2010; Sausen de Freitas et al, 2010; de Freitas and Rocha, 2011). Corroborating this idea, there is evidence in the literature indicating that diphenyl diselenide molecule is able to cross the blood‐brain barrier and increase the selenium levels in the brain (Maciel et al, 2003; Nogueira et al, 2004; Prigol et al, 2009).…”

Methylmercury-induced alterations in astrocyte functions are attenuated by ebselen

“…Ebselen was demonstrated to be neuroprotective in preclinical and clinical studies (Saito et al, 1998; Yamaguchi et al, 1998; Davalos, 1999) and in a variety of in vitro and in vivo animal models of neuropathological conditions, including ischemia (Dawson et al, 1995; Imai et al 2003; Porciuncula et al, 2003), quinolinic acid- or glutamate-induced excitotoxicity (Porciuncula et al, 2001; Rossato et al, 2002a,b) and exposure to MeHg (Farina et al, 2003; Moretto et al, 2005; Funchal et al, 2006; Roos et al, 2009). The antioxidant activity of ebselen has been tentatively attributed to its GSH peroxidase-like activity (Muller et al, 1984; Wendel et al, 1984) and to its ability to serve as a substrate for mammalian thioredoxin reductase (TrxR), which metabolizes ebselen to its selenol/selenolate intermediate (Zhao and Holmegren, 2002; De Freitas et al 2010). I n vivo treatment with ebselen and diphenyl diselenide can reduce MeHg neurotoxicity in rodents (Farina et al 2003a,b; de Freitas et al 2009).…”

“…The antioxidant activity of organoselenides has been attributed to their GSH peroxidase-like activity (Muller et al, 1984; Wendel et al, 1984). More recently it has been demonstrated that ebselen is reduced by mammalian thioredoxin reductase (TrxR) forming ebselen selenol/selenolate (Zhao and Holmegren, 2002; De Freitas et al 2010). Selenolate intermediates are potent nucleophiles and can readily react with electrophilic species, including reactive oxygen species (ROS) (Masumoto et al 1996; Zhao and Holmegren 2002)…”

Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

“…Such activities include scavenging of free radicals [60], metal complexation [61], or mimicry of natural antioxidant enzymes for the removal of deleterious hydrogen peroxide and alkyl peroxides (e.g., GPx), the so-called bioinspired antioxidants [46]. Interestingly, diselenides and selenides can be substrates in vivo for mammalian thioredoxin reductase (TrxR), furnishing selenols/selenolates, stronger nucleophiles than their sulfur counterparts; as a result, the corresponding selenol has a stronger reducing power than isosteric thiol [62,63].…”