Enhancement of cyclosporin A induced hepato‐ and nephrotoxicity by glutathione depletion

Abstract

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.

Effects of erdosteine on cyclosporine-A–induced hepatotoxicity in rats

“…Duruibe et al (1989) found that the total amount of liver GSH content decreased in CsA-treated rats. Another study showed that CsA-induced hepatotoxicity was exacerbated by GSH depletion (Inselmann et al, 1994). In the current study, there was no significant alteration in the GSH-Px activities among the study groups.…”

Cyclosporine reduces hepatic antioxidant capacity: protective roles of antioxidants

“…It has been known that CsA causes hepatotoxicity in some transplant recipients [1 -3,16 -18] and in some animal models [5,6,19]. In a study, 49% of the patients receiving renal allografts under CsA/prednisone immunosuppression were reported to have at least one episode of posttransplantation hepatotoxicity and a reduction in CsA dose was found to be effective in normalizing the liver function abnormalities [1].…”

“…Similar observations and suggestions were made by others, implicating free radicals in the CsA-induced hepatotoxicity. For example, Inselman et al [19] reported that CsA-induced hepatotoxicity was deteriorated by glutathione depletion, and Moran et al [5] found that total amount of liver glutathione decreased in the rats treated with CsA. It has also been reported that increased oxidised glutathione concentrations can modulate the activity of various regulatory enzymes and it might be a cause of the impaired hepatocellular functions induced by CsA [26].…”

Molecular mechanisms of the protective role of wheat germ oil against cyclosporin A-induced hepatotoxicity in rats

“…The most important endogenous antioxidants are GSH, SOD, and CAT. GSH plays a major role in cells protection against oxidative damage and detoxification of xenobiotics including CsA (Inselmann et al, 1994;Meister & Anderson, 1983). Also, SOD and CAT play an important role in cellular protection by scavenging ROS from the cell where SOD metabolizes superoxide radical into hydrogen peroxide (less toxic) that can be detoxified by catalase, which converts H 2 O 2 into H 2 O and O 2 (Deisseroth & Dounce, 1970;McCord et al, 1971).…”