Grattagliano I, Vendemiale G, Deiss V B, Junker E, Lauterburg B H
Department of Clinical Pharmacology, University of Berne, Berne, Switzerland.
J Pharmacol Exp Ther. 2000 Jul;294(1):155-9.
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 of S,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.
谷胱甘肽（GSH）在氧的活性代谢产物和外源性物质的解毒、基因表达以及作为半胱氨酸来源方面的作用已得到充分证实。由于在多种临床情况下，循环和细胞内GSH浓度降低可能与发病机制相关，因此人们对纠正紊乱的巯基状态的药理干预越来越感兴趣。在本研究中，对大鼠静脉注射和十二指肠内（i.d.）给药后，研究了S，N - 二乙酰半胱氨酸单乙酯（DACE）对巯基的处置和影响。DACE在血浆中迅速水解并脱乙酰化为N - 乙酰半胱氨酸和半胱氨酸。静脉注射和十二指肠内给予5 mmol/kg DACE后，循环和肝脏中达到高浓度的半胱氨酸，静脉注射和十二指肠内给药后，肝脏和血浆中GSH的生理水平分别提高了30%和300%。用1 mM DACE孵育外周血单核细胞24小时后，细胞内半胱氨酸和GSH的浓度高于分别用等摩尔浓度的半胱氨酸、N - 乙酰半胱氨酸或氧噻唑烷羧酸孵育后的浓度。得出的结论是，DACE为半胱氨酸提供了一种有效的递送系统，静脉注射和十二指肠内给药后可显著增加细胞内和细胞外的半胱氨酸和GSH。由于其进入细胞可能不依赖于主动转运过程，DACE导致细胞内半胱氨酸浓度高于其他半胱氨酸前药和半胱氨酸本身所导致的浓度。因此，该化合物在纠正紊乱的巯基状态方面可能比其他化合物具有优势。
