The effect of glutathione (GSH) synthesis modulators - L-buthionine sulfoximine (BSO), N-acetyl cysteine (NAC) and D-penicillamine (DPA) - on the susceptibility of rat CNS to O2 toxicity was investigated. The animals were given 5% sucrose or 40 mM solutions of BSO, NAC or DPA in 5% sucrose as drinking water for one week and sacrificed prior to or after exposure to 4.5 ATA O2. The GSH content in brain, liver, lung and blood, and the activity of glutathione peroxidase (GSH-Px), glutathione reductase (GSSG-R), glucose-6-phosphate dehydrogenase (G-6-PD) and superoxide dismutase (SOD) in brain and lungs were measured. The brain GSH content and the enzyme activities were not changed by any of the drugs. BSO decreased the GSH content in all the other tissues; NAC and DPA treatments increased the GSH content in lungs, blood and/or liver. The CNS toxicity threshold as measured by the time of appearance of first electrical discharge (FED) on ECoG recording was not changed by NAC or DPA, but BSO brought about a significant delay in FED time. It is suggested that increased extracerebral GSH levels do not protect against CNS oxygen toxicity, and that BSO provides some protection, probably via a glutathione-independent mechanism.