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The modulatory effect of adenosine on hepatic glutathione (GSH) synthesis has been investigated in an experimental model in which GSH synthesis from methionine was monitored in rat isolated hepatocytes previously depleted of GSH. Adenosine inhibited GSH synthesis in this system, with complete inhibition occurring at 1 mM. Studies with adenosine receptor agonists and antagonists and adenosine analogues devoid of agonist activity have indicated that this effect of adenosine is not receptor-mediated nor is it mediated through changes in ATP level or redox balance. Rather, the data are consistent with an inhibitory effect of adenosine on the methionine → cysteine transsulphuration pathway, probably at the level of the enzyme S-adenosylhomocysteine hydrolase. Submaximal inhibitory concentrations of adenosine produced an effect on GSH synthesis additive to that obtained with a maximal inhibitory concentration of adrenaline, which inhibits GSH synthesis at the level of γ-glutamylcysteinyl synthetase. Furthermore, exposure of hepatocytes to adenosine subsequent to brief treatment with the toxicant menadione precipitated cytotoxicity. These results suggest that adenosine-mediated inhibition of hepatic GSH synthesis may have a role in various pathological or toxicological states.