Glutathione, a first line of defense against cadmium toxicity

Abstract

Experimental modulation of cellular glutathione levels has been used to explore the role of glutathione in cadmium toxicity. Mice treated with buthionine sulfoximine [an effective irreversible inhibitor of γ‐glutamylcysteine synthetase (EC 6.3.2.2) that decreases cellular levels of glutathione markedly] were sensitized to the toxic effects of CdC1 2 . Mice pretreated with a sublethal dose of Cd 2+ to induce metallothionein synthesis were not sensitized to Cd 2+ by buthionine sulfoximine. Mice sensitized to Cd 2+ by buthionine sulfoximine were protected against a lethal dose of Cd 2+ by glutathione mono isopropyl ester ( l ‐γ‐glutamyl‐ l ‐cysteinylglycylisopropyl ester), but not by glutathione. These results are in accord with studies that showed that glutathione mono esters (in contrast to glutathione) are efficiently transported into cells and converted intracellularly to glutathione. The findings indicate that intracellular glutathione functions in protection against Cd 2+ toxicity, and that this tripeptide provides a first line of defense against Cd 2+ before induction of metallothionein synthesis occurs. The experimental approach used here in which cellular levels of glutathione are decreased or increased seems applicable to investigation of other types of metal toxicity and of other glutathione‐dependent biological phenomena.— S inghal , R. K.; A nderson , M. E.; M eister , A. Glutathione, a first line of defense against cadmium toxicity. FASEB J. 1: 220‐223; 1987.