Enhancement of cyclosporin A induced hepato- and nephrotoxicity by glutathione depletion.
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.
Inselmann
G
G
Medizinische Poliklinik der Universität Würzburg, Germany.
Lawerenz
H U
HU
Nellessen
U
U
Heidemann
H T
HT
D000818:Animals; D016572:Cyclosporine / Q000633:toxicity*; D005978:Glutathione / Q000502:physiology*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D008099:Liver / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008298:Maleates / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley
D008298:Maleates; D016572:Cyclosporine; C014476:diethyl maleate; D005978:Glutathione