ADENOSINE-MEDIATED INHIBITION OF GLUTATHIONE SYNTHESIS IN RAT ISOLATED HEPATOCYTES

The modulatory effect of adenosine on hepatic glutathione (GSH) synthe sis has been investigated in an experimental model in which GSH synthe sis from methionine was monitored in rat isolated hepatocytes previous ly depleted of GSH. Adenosine inhibited GSI-I synthesis in this system , with complete inhibition occurring at 1 mM. Studies with adenosine r eceptor agonists and antagonists and adenosine analogues devoid of ago nist activity have indicated that this effect of adenosine is not rece ptor-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, pro bably at the level of the enzyme S-adenosylhomocysteine hydrolase. Sub maximal inhibitory concentrations of adenosine produced an effect on G SH synthesis additive to that obtained with a maximal inhibitory conce ntration oi adrenaline, which inhibits GSH synthesis at the level of g amma-glutamylcysteinyl synthetase. Furthermore, exposure of hepatocyte s to adenosine subsequent to brief treatment with the toxicant menadio ne precipitated cytotoxicity. These results suggest that adenosine-med iated inhibition of hepatic GSH synthesis may have a role in various p athological or toxicological states. Copyright (C) 1996 Elsevier Scien ce Inc.