Mechanism of protection by S-(1,2-dicarboxyethyl)glutathione triester against acetaminophen-induced hepatotoxicity in rat hepatocytes

Treatment with the triester of S-(1,2-dicarboxyethyl)glutathione (DCE-GS) p revented the hepatotoxicity induced by acetaminophen via elevation of the g lutathione (GSH) level in rat hepatocytes, This elevation of the GSH level in rat hepatocytes by DCE-GS triester was dose- and time-dependent (2.1-fol d in 24 h with 0.5 MM). DCE-GS triester increased the GSH level much more e ffectively than GSH, DCE-GS, and DCE-GS monoester and diester, Furthermore, the activity of gamma -glutamylcysteine synthetase (gamma -GCS), the rate- limiting enzyme in GSH biosynthesis, was also increased by DCE-GS triester treatment (1.4-fold in 24h with 1.0 MM), In contrast, with a rat liver homo genate, DCE-GS increased the gamma -GCS activity whereas DCE-GS triester ha d no effect on this activity. These results suggested that DCE-GS triester, which is transported into hepatocytes much more effectively than DCE-GS an d other DCE-GS esters due to its greater lipophilicity, was hydrolgzed to D CE-GS, and then the DCE-GS produced increased the GSH level via activation of gamma -GCS in rat hepatocytes.