Mechanism of Protection by S-(1, 2-Dicarboxyethyl)glutathione Triester against Acetaminophen-Induced Hepatotoxicity in Rat Hepatocytes

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Treatment with the triester of S-(1, 2-dicarboxyethyl)glutathione(DCE-GS)prevented the hepatotoxicity induced by acetaminophen via elevation of the glutathione(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-fold in 24h with 0.5m_M). DCE-GS triester increased the GSH level much more effectively than GSH, DCE-GS, and DCE-GS monoester and diester. Furthermore, the activity of γ-glutamylcysteine synthetase(γ-GCS), the rate-limiting enzyme in GSH biosynthesis, was also increased by DCE-GS triester treatment(1.4-fold in 24h with 1.0m_M). In contrast, with a rat liver homogenate, DCE-GS increased the γ-GCS activity, whereas DCE-GS triester had no effect on this activity. These results suggested that DCE-GS triester, which is transported into hepatocytes much more effectively than DCE-GS and other DCE-GS esters due to its greater lipophilicity, was hydrolyzed to DCE-GS, and then the DCE-GS produced increased the GSH level via activation of γ-GCS in rat hepatocytes.
社団法人日本薬学会の論文
2001-07-01