Synthesis, Purification, and Structural Characterization of the Dimethyldiselenoarsinate Anion

Gailer, Jürgen; George, Graham N.; Harris, Hugh H.; Pickering, Ingrid J.; Prince, Roger C.; Somogyi, Árpád; Buttigieg, Gavin A.; Glass, Richard S.; Denton, M. Bonner

doi:10.1021/ic0113146

Cited by 27 publications

(16 citation statements)

References 46 publications

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“…DMA III is also less toxic to cells in culture, likely because of the inability to target the vicinal dithiol of lipoic acid–containing enzymes of the Krebs cycle. It should be noted that a dimethyldiselenoarsinate anion (Gailer et al 2002a) has been synthesized in vitro , but has yet to be identified in either animal or cell culture studies. Formation of this compound could possibly facilitate uptake of selenium, although this has yet to be tested.…”

Section: Discussionmentioning

confidence: 99%

Impact of Trivalent Arsenicals on Selenoprotein Synthesis

Ganyc

Talbot

Konate

et al. 2007

Environ Health Perspect

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BackgroundExposure to arsenic has been associated with development of skin, lung, bladder, liver, and kidney cancer. Recent evidence suggests that an increase in oxidative stress in cells treated with arsenicals represents the molecular mechanism behind arsenic-induced carcinogenesis. Selenium, in the form of selenocysteine, is necessary for the activity of several enzymes with a role in defense against reactive oxygen species. A mutual sparing effect between arsenic and selenium has been shown in animal studies when both metalloids are present in high concentrations.ObjectivesTo determine whether changes in selenoprotein synthesis may be an underlying mechanism behind arsenic-induced carcinogenesis, we analyzed the new synthesis of selenoproteins within cells after exposure to inorganic or methylated arsenicals using a human keratinocyte cell model.ResultsAddition of arsenite to culture medium blocked new synthesis of selenoproteins when selenium was present in the form of selenite, and appeared to stimulate the use of serum-derived selenium. Monomethylarsonous acid (MMAIII) treatment of cells, in contrast, did not block all new synthesis of selenoproteins but did result in an increase in cytosolic thioredoxin reductase (TrxR1) at both the mRNA and protein levels. MMAIII also reduced the new synthesis of cellular glutatione peroxidase (cGpx) and other smaller selenoproteins. Dimethylarsinous acid (DMAIII) stimulated selenoprotein synthesis by an as yet unknown mechanism.ConclusionsThese results suggest that arsenite and MMAIII are key metabolites that trigger higher levels of TrxR1, and both lead to a reduction in the expression of cGpx. Together these effects certainly could lead to carcinogenesis given the knowledge that many cancers have higher levels of TrxR, and reduced Gpx levels will reduce the cell’s ability to defend against reactive oxygen species. Based on these results, the impact of the trivalent arsenicals arsenite and MMAIII on selenoprotein synthesis may indeed represent a potential molecular mechanism for the higher rates of cancer observed in populations exposed to high levels of arsenic.

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Section: Discussionmentioning

confidence: 99%

Impact of Trivalent Arsenicals on Selenoprotein Synthesis

Ganyc

Talbot

Konate

et al. 2007

Environ Health Perspect

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“…76,81 The rapid formation of [(GS) 2 AsSe] À in blood, 73 and its equally rapid biliary excretion (and thus the removal of highly toxic trivalent arsenic from the organism itself), suggests that the formation and excretion of [(GS) 2 AsSe] À represents an important mammalian detoxification mechanism. Any excess arsenite that is left over after this step in blood will be shuttled to the liver to undergo biomethylation (Scheme 1).…”

Section: Discussionmentioning

confidence: 99%

Review: Reactive selenium metabolites as targets of toxic metals/metalloids in mammals: a molecular toxicological perspective

Gailer

2002

Applied Organom Chemis

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Human activities have been contaminating the environment with toxic heavy metal and metalloid compounds. Since the toxicity of one metal or metalloid can be dramatically modulated by the simultaneous ingestion of another, studies addressing the molecular basis of chemical interactions between toxic and essential elements are increasingly important. The intravenous injection of rabbits with selenite and arsenite or with selenite and mercuric mercury resulted in the in vivo formation of the seleno-bis (S-glutathionyl) arsinium ion, [(GS) 2 AsSe] À , or a glutathione-coated mercuric selenide, (GS) 5 (HgSe) core , in blood. The formation of these species (and the formation of a cadmium±selenium species in blood after the exposure of rats to selenite and cadmium) critically involves reactive selenite metabolites, such as GS±Se À and/or HSe À , which indicates that these physiologically important metabolites are molecular targets of ingested toxic metals and metalloids. The fate and stability of [(GS) 2 AsSe] À and (GS) 5 (HgSe) core in vivo imply that the chronic exposure of mammals to inorganic arsenic and mercury will cumulatively affect the bioavailability of selenium, which could lead to selenium deficiency. Since selenium deficiency is significantly associated with the etiology of cancer in humans, the GSH-driven in vivo formation of selenium-containing metal and metalloid species provides a likely molecular mechanism for the chronic toxicity of environmentally persistent inorganic arsenic, mercury and cadmium.

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“…A metabolite containing glutathione (GSH) and equimolar amounts of As and Se, [(GS) 2 AsSe] − , was identified in bile from rabbits injected with selenite [Se(IV)] and As(III) (Gailer et al 2000). This metabolite is thought to be synthesized in hepatocytes (Gailer et al 2002a) and erythrocytes (Manley et al 2006) − can be synthesized chemically by reacting DMA(V) with GSH and Se(IV) (Gailer et al 2002b). Even though these metabolites are present in marine mammals, seabirds, and sea turtles, the levels may be low.…”

Section: Future Areas Of Studymentioning

confidence: 99%