TOXIC EFFECTS OF ORGANOSELENIUM COMPOUNDS

University Of Calif-Los Alamos Nat Lab, Los Alamos NM

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Abstract

The SIR provided 77 Se (94% enriched)Ebselen; 55mg 94% (77 Se)-diselenide (C26H2ON2 J2 Se2); 50mg Ebselen [60940-34-3] exhibits glutathioneperoxidase (GPO)-like activity and has been proposed as an anti-inflammatory drug. Its acute p.o. toxicity in mice is low (>6000mg/kg). However, it has been reported that ebselen reacts rapidly with sulfhydryl compounds which cleave the Se-N bond. Based on these findings one would expect ebselen to react with SH-dependent enzymes, e.g., pyruvate dehydrogenase, and to be considerably toxic. This paradoxon might be resolved by examining the Se compounds when isolated cells are exposed to ebselen. We plan to investigate covalent interactions of ebselen (and its derivatives) with enzymes containing functional SH groups and ebselen redox cycling in isolated cells. The chemical nature of covalent Se interactions is deduced from chemical shifts of the corresponding 77Se NMR signals in vitro using a JEOL SX270 NMR spectrometer. Highly enriched 77Se-ebselen is required for appropriate S/N ratios. Calibration is performed with ebselen and its diselenide. Pre-tests will use various commercial preparations of SH-functional enzymes. Whole cell turnover of ebselen after incubation with rat hepatoma cells (HTC) is assessed by measuring the appearance / disappearance of specific signals at approx. 920ppm and 450ppm in chloroform extracts. In contrast to studies with purified enzymes, the fate of ebselen in cultured cells is likely to be affected by cellular glutathione (GSH) contents. Thus, formation of mixed selenosulfides (GSSeR) has to be considered when dealing with intermediates of ebselen turnover. These intermediates may provide an explanation for the observed low toxicity of ebselen in vivo. Dismutation of GSSeR yielding GSSG + RSeSeR provides an important role for the diselenide in future studies