Methyl iodide toxicity in rat cerebellar granule cells in vitro: the role of glutathione

The monohalomethane methyl iodide (MeI) is toxic to a number of organ systems including the central nervous system. Clinical symptoms of neurotoxicity suggest that the cerebellum is the target within the brain, and we have now modelled the toxicity of Mel in cultured rat cerebellar granule cells. Cytotoxicity is maximal 24 h after a 5 min exposure to Mel, and the EC50 for Mel under these conditions was calculated to be 1.6 mM. The glutathione S-transferase (GST) dependent metabolism of Mel was investigated in these cultures. There was a marked decrease in intracellular glutathione (GSH) 15 min after exposure to Mel, and GSH concentrations then increased, reaching 130% of control levels 7 h after exposure. To investigate the role of conjugation with GSH in the toxicity of Mel, GSH levels were modulated prior to exposure. Depletion of GSH exacerbated the cytotoxicity of Mel while provision of a bioavailable source of GSH was protective. Inclusion of antioxidants [vitamin E, butylated hydroxytoluene (BHT) or desferrioxamine mesylate (DF)] also protected against the cytotoxicity of Mel. Our in vitro data suggest that Mel is conjugated with GSH in the cerebellum, and the resulting extensive depletion of GSH may be the first step en route to toxicity, rendering the tissue susceptible to methylation and/or oxidative stress. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.