Glutathione is one of the most abundant thiols in mammalian tissues and plays important roles in the defense mechanism and detoxification of various metabolites, such as reactive xenobiotics and free radicals. Nitric oxide (NO) readily reacts with thiol compounds, thereby generating chemically stable S-nitrosothiols. Although endotoxin has been known to induce NO synthase in various organs, particularly liver and spleen, and enhances the production of NO, correlation between NO and glutathione metabolism in endotoxemic subjects remains to be elucidated. The present work examines the changes in NO and glutathione metabolism in endotoxemic rats. Administration of lipopolysaccharide (LPS) markedly decreased the glutathione levels in plasma and bile, whereas it decreased the hepatic level only slightly. NG-nitro-L-arginine (L-NNA), a NO synthase inhibitor, inhibited the LPS-induced decrease of glutathione in plasma and bile. Administration of LPS increased the biliary levels of gamma-glutamyl transpeptidase (gamma-GTP) without affecting its thiol levels. Acivicin, a gamma-GTP inhibitor, inhibited the LPS-induced decrease of glutathione in plasma and bile without affecting its hepatic levels. Analysis with the use of L-buthionine sulfoximine revealed that the turnover of hepatic glutathione significantly increased in LPS-treated rats by some L-NNA-inhibitable mechanism. These results suggest that endotoxin might enhance the NO production in the liver and other tissues and significantly modulate the interorgan metabolism of reduced glutathione.