Effects of aging and cyclosporin treatment on the hepatobiliary efflux of glutathione

The aim of this study was to investigate the effects of cyclosporin (CyA) treatment on biliary glutathione efflux in rats of different ages (1, 2, 4, and 24 months). CyA treatment reduced the liver content of total glutathione in 1-, 2- and 24 month old rats (-30%, -43% and -30%, respectively). By contrast, oxidized glutathione (GSSG) concentration in liver tended to increase, although non significantly, in the rats aged 4 and 24 month (+36% and +28%, respectively). The oxidized-to-reduced glutathione ratio was significantly increased in 2-, 4- and 24 month old animals (+23%, +36% and >100%, respectively). Regarding biliary glutathione, our data indicate that efflux rates of total glutathione in control (untreated) rats increased to a maximum at 4 months, and decreased (-56%) in 24 month old rats, although values were still higher than those from young animals. CyA treatment significantly reduced biliary glutathione secretion except in 24 month old rats (-98%, -66% and -32%, at 1, 2 and 4 month, respectively). In addition, following inhibition of the intrabiliary catabolism of the tripeptide by acivicin, glutathione efflux rates into bile were significantly reduced by the drug only in 1- and 2 month old rats (-29% and -55%, respectively) and even tended to increase, although non significantly, in oldest animals. Our data indicate that inhibition of biliary glutathione efflux by CyA was greater in younger rats and support the view that increased intrabiliary catabolism of the tripeptide and inhibition of its canalicular transport could contribute to the decline in biliary glutathione secretion induced by the drug.