In vitro inhibition of glutathione reductase by arsenotriglutathione.
Arsenotriglutathione, a product of the reaction of arsenate or arsenite with glutathione, is a mixed-type inhibitor (Ki = 0.34 mM) of the in vitro reduction of glutathione disulfide by purified yeast glutathione reductase. Notably, arsenotriglutathione was a 10-fold more potent inhibitor than either arsenite or glutathione. The inhibition of glutathione reductase by arsenotriglutathione was partly reversed by the addition of meso-2,3-dimercaptosuccinic acid (DMSA). However, high concentrations of DMSA also inhibited the reduction of glutathione disulfide by the yeast enzyme (IC50 of 7 mM with 0.1 mM glutathione disulfide). Ultrafiltration of the enzyme-arsenotriglutathione complex recovered about 74% of the original (non-inhibited) activity, suggesting that the inhibition of glutathione reductase by arsenotriglutathione had both reversible and irreversible components. The relatively high potency of arsenotriglutathione as an inhibitor of glutathione reductase may alter the reduction of glutathione disulfide and affect the availability of glutathione that is required for the reduction of arsenate to arsenite and for the formation of the arsenotriglutathione complex.
Stýblo
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Curriculum in Toxicology, University of North Carolina, Chapel Hill 27599, USA.
Thomas
D J
DJ
D000818:Animals; D001152:Arsenicals / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018053:Arsenites / Q000494:pharmacology; D004355:Drug Stability; D005978:Glutathione / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology; D019803:Glutathione Disulfide; D005980:Glutathione Reductase / Q000037:antagonists & inhibitors*; D010084:Oxidation-Reduction; D011817:Rabbits; D004113:Succimer / Q000494:pharmacology; D015003:Yeasts
D001152:Arsenicals; D018053:Arsenites; C093363:arsenotriglutathione; D004113:Succimer; D005980:Glutathione Reductase; D005978:Glutathione; C015001:arsenite; D019803:Glutathione Disulfide