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

The role of grutathione in cyclosporin A (cyclosporin) hepato- and nep hrotoxicity has not been clarified yet. The hypothesis that a glutathi one deficit enhances the hepato- and nephrotoxicity of cyclosporin was tested in an animal model. Glutathione depletion was achieved by admi nistration of diethyl maleate (DEM). Adult Sprague Dawley rats were di vided 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 la ter 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 tran saminases. In glutathione depleted rats cyclosporin caused a further e levation of serum bilirubin up to 23.4 + 5.5 mu mol 1(-1). This was ac companied 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 glutathi one depletion resulted in a further decline of creatinine clearance to 22% of controls. DEM had no effect on kidney or liver function. In co nclusion glutathione depletion increases the susceptibility to cyclosp orin-induced liver and kidney injury. The results support the hypothes is that sufficient cellular glutathione concentrations may be importan t to prevent cyclosporin-induced hepato- and nephrotoxicity.