Mobilization of exogenous and endogenous selenium to bile after the intravenous administration of environmentally relevant doses of arsenite to rabbits

Abstract

Extending our studies of the effect of arsenite on the metabolism of inorganic selenium (selenite and selenate) to lower doses, we intravenously injected New Zealand white rabbits with aqueous solutions of arsenite, selenite, arsenite + selenite, selenate and selenate + arsenite at 50 µg and 5 µg metalloid per kilogram body weight. Bile samples were collected for 25 min, acid-digested and analyzed for total arsenic and selenium by double focusing magnetic sector field inductively coupled plasma mass spectrometry. At both dose levels, and in accord with previous observations, an increased mutual biliary excretion of arsenic and selenium was observed regardless of whether selenium was coadministered with arsenite in the form of selenite or selenate. Based on our previous investigations into the in vivo interaction between arsenite and selenite (or selenate), these findings can be rationalized in terms of the biliary excretion of the seleno-bis(S-glutathionyl) arsinium ion, [(GS) 2 AsSe] − . In addition, the treatment of rabbits with 50 µg arsenic per kilogram body weight in form of arsenite alone also resulted in a significantly increased bile selenium concentration compared with bile from untreated animals (p < 0.05), which implies a mobilization of endogenous selenium to bile. Combined, these results establish a causal relationship between the exposure of mammals to arsenite and selenium deficiency.

In Situ Imaging of Metals in Cells and Tissues

“…Evidence directly supporting the aforementioned claim was provided by studies performed on rabbits showing a mobilization of Se to the liver and bile following exposure to arsenic 470. The proposed antagonistic relationship between As and Se, where one modifies the toxic effects induced by the other,471 prompted Berry and co-workers to directly analyze their interaction at the sub-cellular level in rat kidney cells using EPXMA combined TEM 472.…”

Strong poison revisited

“…At the simplest level, it suggests that the chronic dietary ingestion of arsenite (e.g. through drinking water) will likely deplete the body of selenium [16,17] and render ingested selenium physiologically unavailable through coordination to arsenic in the blood. Since selenium is an essential nutrient, with a well-known protective activity against at least some cancers [18], this may help to explain the long known carcinogenicity of inorganic arsenic in humans [19].…”

Metal Species in Biology: Bottom-Up and Top-Down LC Approaches in Applied Toxicological Research

“…In principle, the toxicity of any metal species may be attributed to interactions with endogenous target ligands that occur either in the bloodstream [70] {in case of a gastrointestinally absorbed metal, one must also consider metal-amino acid complexes, since these may be the species that are absorbed into the bloodstream [71]; with regard to the metal-based drugs cis-platin (Figure 1 appreciably interact with endogenous ligands [53]} and/or within organs [72,73]. It is also important to note that the biological response of an organism to any given metal species is dose-dependent ("the dose makes the poison") and that a different set of endogenous ligands appear to be targeted in acute [74] as opposed to chronic As III toxicity [64]. Blood plasma alone may contain up to 10,000 potential protein ligands [75].…”

“…Considering that free selenite has been detected in human blood plasma [154], this intriguing trace element antagonism was hypothesized to be implicated in the chronic toxicity of As(OH) 3 . Investigations aimed at uncovering its biomolecular basis revealed that it appeared to be based on the rapid in vivo assembly of the seleno-bis(S-glutathionyl) arsinium ion, (GS) 2 AsSe − (Figure 1(d)) in the bloodstream (in erythrocytes [91]) followed by its translocation to the plasma, the liver and its eventual excretion in bile [62,64]. Since the structure of this species was entirely derived from EXAFS and Raman spectroscopy, its unequivocal confirmation required an alternative technique.…”

“…In contrast, the "topdown" or "systems biology" approach attempts to directly analyze complex biological samples with an appropriate analytical technique to unravel the molecular mechanism of action of a particular toxin therein [19,60]. This alternative approach hinges on identifying an analytical technique that is capable of detecting a toxin-induced change in a likely biological compartment (e.g., blood plasma [26,61]) or to infer that a relevant biotransformation of the toxin of interest has occurred in a particular organ (e.g., the liver) by analyzing an appropriate effluent stream (e.g., bile [62][63][64][65]). Importantly, the "top-down" approach offers the advantage that no a priori information about a likely mechanism of toxicity is required and that fundamentally new insights into hitherto unknown mechanisms of action may be obtained.…”