S-adenosylmethionine protects against cyclosporin A-induced alterations in rat liver plasma membrane fluidity and functions

We studied the effect of cyclosporin A (CyA) on liver plasma membrane (LPM) composition, fluidity, and functions and on hepatic glutathione (GS) and oxidative status. We also evaluated the ability of S-adenosylmethionine (SAMe) to antagonize the CyA-induced disturbances in rats. The animals were randomly divided into four groups and treated daily with saline, CyA vehicle, CyA, and SAMe plus CyA, respectively, for 1 week. Bile, blood, and liver samples and LPM vesicles were obtained at the end of the treatments. CyA-induced cholestasis was associated with alterations in LPM composition and fluidity. The contents of total phospholipids, phosphatidylcholine, and proteins were decreased and cholesterol and the cholesterol/phospholipid molar ratio increased. Na+, K+-ATPase activity was decreased, whereas those of 5'-nucleotidase, Mg2+-ATPase, and gamma-glutamyltransferase increased. The hepatic contents of proteins and GS and the reduced/oxidized glutathione molar ratio were decreased and hepatic malondialdehyde increased. SAMe cotreatment 1) significantly improved or abolished the CyA-induced changes in LPM fluidity and composition and the changes in the activity of the carrier and enzymes tested, 2) counteracted the hepatic depletion of GS and proteins caused by CyA and normalized the reduced/oxidized glutathione ratio, and, as expected, 3) prevented cholestasis and the inhibitory effect of CyA on hepatobiliary transport of the major bile components. We conclude that CyA-induced cholestasis and hepatotoxicity in the rat is associated with changes in LPM composition and fluidity, liver GS depletion, and oxidative stress. SAMe cotreatment significantly improves or totally protects against these hepatotoxic effects.