Effect of oral and intravenous S,N-diacetylcysteine monoethyl ester on circulating and hepatic sulfhydryls in the rat

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 estab lished. Because decreased circulating and intracellular concentrations of G SH might be of pathogenetic relevance in several clinical conditions, there is a growing interest in pharmacological interventions to correct a derang ed sulfhydryl status. In this study, the disposition and the effect of S,N- diacetylcysteine monoethyl ester (DACE) on sulfhydryls were investigated af ter i.v. and intraduodenal (i.d.) administrations to rats. DACE was rapidly hydrolyzed and deacetylated to N-acetylcysteine and cysteine in plasma. Hi gh concentrations of cysteine were attained in the circulation and in the l iver after i.v. and i.d. administrations of 5 mmol/kg DACE, and physiologic al levels of GSH in the liver and in plasma increased by 30 and 300%, respe ctively, with i.v. and i.d. administrations. Incubation of peripheral blood mononuclear cells with 1 mM DACE resulted in higher intracellular concentr ations of cysteine and GSH after 24 h than incubations with equimolar conce ntrations of cysteine, N-acetylcysteine, or oxothiazolidine carboxylic acid , respectively. It is concluded that DACE provides an efficient delivery sy stem 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 o ther prodrugs of cysteine and cysteine itself. The compound may thus have a dvantages over other compounds for the correction of a deranged sulfhydryl status.