Glutathione metabolism in cyclosporine A-treated rats: dose- and time-related changes in liver and kidney.

1. We investigated the simultaneous effects of cyclosporine A (CsA) treatment in rats on glutathione metabolism, oxidative status and their interorgan relationship in the liver and kidney. 2. Reduced and oxidized glutathione (GSH and GSSG, respectively), lipid peroxidation and the activity of several enzymes of the glutathione cycle were evaluated in adult Wistar rats treated daily (i.p.) with saline, CsA vehicle (olive oil) or CsA (10 and 20mg/kg per day) for either 1 or 4 weeks (short- and long-term treatments, respectively). 3. Cyclosporine A treatment elicited a significant depletion in liver GSH content and a decrease in the GSH/GSSG ratio that was unrelated to either the time of treatment or the dose used; these effects were already evident after 1 week of treatment. Renal GSH levels remained unaffected or increased, while those of GSSG increased markedly in all CsA-treated rats, leading to decreases in the GSH/GSSG ratio, except in rats treated in the short term with the lower dose of CsA. These changes in the GSH/GSSG ratio were time and dose dependent. Short-term CsA treatment using the higher dose and long-term treatment with both doses of CsA progressively enhanced lipid peroxidation, which was reflected by increased levels of thiobarbituric acid-reactive substances in both hepatic and renal homogenates. Hepatic gamma-glutamylcysteine synthetase activity was increased after long-term treatment with both doses of CsA, whereas the activity of GSH hepatic peroxidase and GSH transferase was not significantly modified in any of the experimental groups. In contrast, renal gamma-glutamyl transpeptidase activity decreased in a progressive fashion, with the magnitude of this decrease being dose and time dependent. The plasma levels of total glutathione increased only in rats treated in the long term, regardless of the dose of CsA used, and remained unaltered in animals treated in the short term. 4. In summary, the data collected indicate that CsA treatment alters the interorgan homeostasis of glutathione and the oxidative status of the rat liver and kidney, which is associated with increases in lipid peroxidation in both organs, and also induces modifications in the activity of some enzyme related to the glutathione cycle.