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Enhancement of cyclosporin A induced hepato‐ and nephrotoxicity by glutathione depletion
Author(s) -
INSELMANN G.,
LAWERENZ H. U.,
NELLESSEN U.,
HEIDEMANN H. T.
Publication year - 1994
Publication title -
european journal of clinical investigation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.164
H-Index - 107
eISSN - 1365-2362
pISSN - 0014-2972
DOI - 10.1111/j.1365-2362.1994.tb01097.x
Subject(s) - nephrotoxicity , glutathione , chemistry , medicine , endocrinology , renal function , bilirubin , oral administration , toxicity , creatinine , pharmacology , biochemistry , enzyme
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.