Chronic toxicity of AsIII in mammals: The role of (GS)2AsSe−

Millions of people are currently exposed to a multitude of environmentally persistent toxic metals and metalloid compounds mainly through the ingestion of drinking water and food. Despite the fact that biomonitoring studies have revealed several toxic metals to be present in the bloodstream of the general population, the interpretation of the established blood concentrations with regard to their health relevance continues to be an active research area. To this end, a better understanding of the bioinorganic chemistry of individual metals and metalloid compounds in the mammalian bloodstream could greatly advance the interpretation of the available biomonitoring data. Arsenite represents a case in point, since >100 million people are currently exposed to unsafe levels of inorganic arsenic via drinking water. The elucidation of the underlying biomolecular mechanism(s) of toxicity is therefore of the utmost importance and could involve the antagonistic toxic effect between arsenite and selenite, which was discovered in mammals ∼70 years ago. After a concise overview of animal studies that aimed to understand this trace element antagonism at the molecular level, the in vivo formation and biliary excretion of the seleno-bis(S-glutathionyl) arsinium ion, (GS)2AsSe−, is introduced as a likely biomolecular basis. Arguments in favor of a critical involvement of (GS)2AsSe− in the chronic toxicity and carcinogenicity of arsenite are presented. The in vivo formation of this toxicologically relevant metabolite in the mammalian bloodstream (mediated by erythrocytes) indicates that the elucidation of bioinorganic chemistry-related mechanisms that take place in the bloodstream represents a promising research strategy to better understand the etiology of numerous human diseases some of which may be ultimately caused by the low level exposure to certain inorganic pollutants.