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1. The effects of cyclosporine A (CyA) treatment on liver morphology, bile flow and biliary secretion of bile acid, cholesterol and phospholipid and some plasma biochemical indicators of liver function were examined. 2. Wistar rats were treated i.p. with 10 or 20 mg of CyA/kg per day for 1, 2, 3 or 4 weeks. 3. Treatment increased bile acid and bilirubin plasma concentration. Bile flow and biliary secretion of bile acid, cholesterol and phospholipid were reduced in CyA-treated animals. 4. All these effects of the drug appeared at 1 week after the start of treatment and were enhanced during prolonged treatment. Cyclosporine A-induced cholestasis was due to a decrease in both the bile acid-dependent and -independent fractions of bile flow. 5. The reduction in cholesterol and phospholipid biliary output may be secondary to the inhibition of the hepatobiliary flux of bile acid; however, perturbations in the removal of lipids from the canalicular membrane as well as intracanalicular interaction between CyA and lipid vesicles/micelles could also be involved.

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.

Free radicals and oxidative stress are involved in the pathogenic mechanisms of cardiovascular disease (CVD), diabetes and cancer. Exercise is a useful strategy for preventing CVD but in elderly persons it can enhance oxidative stress, which is why some studies recommend antioxidant supplementation for exercising elderly subjects. This intervention study was performed on 320 elderly subjects following a Geriatric Revitalization Program (GEREPRO) to maintain physical health and reduce CVD risk. GEREPRO was based on regular exercise concurrent with a nutritional antioxidant treatment based on daily intake of a functional antioxidant food, Biofrutas. Sustained exercise (10 months, 3 sessions/week) significantly increased cardiorespiratory fitness and plasma HDL-cholesterol; it reduced some predictors of cardiovascular risk (arterial pressure, LDL-cholesterol, total cholesterol/LDL-C, LDL-C/HDL-C), but significantly enhanced some biomarkers of oxidative stress. Concurrent antioxidant supplementation did not produce any ergogenic effects but, meaningfully, enhanced some positive effects of exercise on physical health and the CDV risk index, and it totally prevented the exercise-induced oxidative stress. Our results show that regular and moderate exercise improves cardiorespiratory function and reduces CVD risk in elderly people, while concurrent antioxidant supplementation modulates oxidative insult during exercise in the elderly and enhances the beneficial effects of exercise.