Enhancement of cyclosporin A induced hepato- and nephrotoxicity by glutathione depletion

Abstract The role of glutathione in cyclosporin A (cyclosporin) hepato- and nephrotoxicity has not been clarified yet. The hypothesis that a glutathione deficit enhances the hepato- and nephrotoxicity of cyclosporin was tested in an animal model. Glutathione depletion was achieved by administration of diethyl maleate (DEM). Adult Sprague Dawley rats were divided into four groups (A–D; n≥ 8) and treated for 8 d as follows: group A, glucose 5% (0·4 ml kg^-1, i.p.) + 3 h later olive oil (0·5 ml kg^-1, oral); group B, DEM (0·4 ml kg^-1, i.p.) + 3 h later olive oil (0·5 ml kg^-1, oral); group C, glucose 5% (0·4 ml kg^-1, i.p.) + 3 h later cyclosporin (50 mg kg^-1, oral); group D, DEM (0·4 ml kg^-1, i.p.) + 3 h later cyclosporin (50 mg kg^-1, oral). Cyclosporin alone increased bilirubin concentration from 1·0 ± 0·6 μmol l^-1 to 8·4 ± 1·9 μmol l^-1 (P < 0·05) without changing transaminases. In glutathione depleted rats cyclosporin caused a further elevation of serum bilirubin up to 23·4 ± 5·5 μmol l^-1. This was accompanied by a 50% increase of serum glutamic oxaloacetic transaminase (GOT). Cyclosporin alone significantly decreased creatinine clearance to 50% of controls (P < 0·05). Cyclosporin treatment following glutathione depletion resulted in a further decline of creatinine clearance to 22% of controls. DEM had no effect on kidney or liver function. In conclusion glutathione depletion increases the susceptibility to cyclosporin-induced liver and kidney injury. The results support the hypothesis that sufficient cellular glutathione concentrations may be important to prevent cyclosporin-induced hepato- and nephrotoxicity.