Effects of aging on the susceptibility to the toxic effects of cyclosporinA in rats. Changes in liver glutathione and antioxidant enzymes

Free radicals are involved in aging and cyclosporin A-induced toxicity. The age-related changes in the liver oxidative status of glutathione, lipid pe roxidation, and the activity of the enzymatic antioxidant defense system, a s well as the influence of aging on the susceptibility to the hepatotoxic e ffects of cyclosporin (CyA) were investigated in rats of different ages (1, 2, 4, and 24 months). The hepatic content of reduced glutathione (GSH) inc reased with aging, peaked at 4 months, and decreased in senescent rats. By contrast, glutathione disulfide (GSSG) and thiobarbituric acid-reactive sub stances (TBARS) concentrations and superoxide dismutase, catalase, and glut athione peroxidase activities were higher in the oldest than in the younges t rats. CyA treatment, besides inducing the well-known cholestatic syndrome , increased liver GSSG and TEARS contents and the GSSG/GSH molar ratio, and altered the nonenzymatic and enzymatic antioxidant defense systems. The Cy A-induced cholestasis and hepatic depletion of GSH, and the increases in th e GSSG/GSH ratio, and in GSSG and TEARS concentrations were higher in the o lder than the mature rats. Moreover, superoxide dismutase and catalase acti vities were found to be significantly decreased only in treated senescent r ats. The higher CyA-induced oxidative stress, lipoperoxidation, and decreas es in the antioxidant defense systems in the aged animals render them more susceptible to the hepatotoxic effects of cyclosporin. (C) 2001 Elsevier Sc ience Inc.