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 > or = 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 mumol l-1 to 8.4 +/- 1.9 mumol 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 mumol 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.
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