ENHANCEMENT OF CYCLOSPORINE-A-INDUCED HEPATOTOXICITY AND NEPHROTOXICITY BY GLUTATHIONE DEPLETION

The role of grutathione 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 greater than or equal to 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 (04 ml kg(-1), i.p.) + 3 h later cyclosporin (50 mg kg(-1) oral). Cyclosporin alone increased bilirubin concentration from 1.0 + 0.6 mu mol 1(-1) to 84 +/- 1.9 mu mol 1(-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 mu mol 1(-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.