Unraveling Arsenic—Glutathione Connections

The paper by Muniz Ortiz et al. (2009) in this issue of Toxicological Sciences extends a long line of research on the role of glutathione (GSH) in the metabolism and toxicity of arsenic (As). These investigators used Drosophila as their model organism and the tools of classical and molecular genetics to investigate the genetic basis of variation in sensitivity to the toxic effects of inorganic As. By measuring eclosion (egg hatching) rates for different Drosophila strains cultured on arsenite-containing medium, they identified strains that differed manyfold in sensitivity to As. Using As-sensitive or -resistant strains, they showed an As-resistant phenotype to be related to the genotype for glutathione synthetase (GS). The GS gene encodes the enzyme that catalyzes the second and final step in a pathway that produces GSH from its constituent amino acids. Armed with this information, they used RNA interference to show that altered expression of the GS gene affects sensitivity to As in cultured cells and in flies. Taken in sum, these results emphasize the potential importance of GS genotype that determines the capacity to produce GSH in determining the phenotype for sensitivity to the toxic and carcinogenic effects of As. To appreciate the significance of this research, it is useful to consider the context in which this research developed, our current knowledge of the linkages between As and GSH metabolism, and the prospects for future research to elucidate this relation.