Abstract

The role of GSH in the detoxification of reactive metabolites of oxygen and xenobiotics, in gene expression, and as a source of cysteine is well established. Because decreased circulating and intracellular concentrations of GSH might be of pathogenetic relevance in several clinical conditions, there is a growing interest in pharmacological interventions to correct a deranged sulfhydryl status. In this study, the disposition and the effect ofS,N-diacetylcysteine monoethyl ester (DACE) on sulfhydryls were investigated after i.v. and intraduodenal (i.d.) administrations to rats. DACE was rapidly hydrolyzed and deacetylated to N-acetylcysteine and cysteine in plasma. High concentrations of cysteine were attained in the circulation and in the liver after i.v. and i.d. administrations of 5 mmol/kg DACE, and physiological levels of GSH in the liver and in plasma increased by 30 and 300%, respectively, with i.v. and i.d. administrations. Incubation of peripheral blood mononuclear cells with 1 mM DACE resulted in higher intracellular concentrations of cysteine and GSH after 24 h than incubations with equimolar concentrations of cysteine,N-acetylcysteine, or oxothiazolidine carboxylic acid, respectively. It is concluded that DACE provides an efficient delivery system for cysteine that markedly increases intra- and extracellular cysteine and GSH after i.v. and i.d. administrations. Because its uptake into cells is probably not dependent on an active transport process, DACE results in higher intracellular concentrations of cysteine than those resulting from other prodrugs of cysteine and cysteine itself. The compound may thus have advantages over other compounds for the correction of a deranged sulfhydryl status.