S-adenosylmethionine protects against cyclosporin A-induced alterations inrat 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 o xidative status. We also evaluated the ability of S-adenosylmethionine (SAM e) to antagonize the CyA-induced disturbances in rats. The animals were ran domly divided into four groups and treated daily with saline, CyA vehicle, CyA, and SAMe plus CyA, respectively, for 1 week. Bile, blood, and liver sa mples and LPM vesicles were obtained at the end of the treatments. CyA-indu ced cholestasis was associated with alterations in LPM composition and flui dity. The contents of total phospholipids, phosphatidylcholine, and protein s were decreased and cholesterol and the cholesterol/phospholipid molar rat io increased. Na+, K+-ATPase activity was decreased, whereas those of 5'-nu cleotidase, Mg2+-ATPase, and gamma-glutamyltransferase increased. The hepat ic contents of proteins and GS and the reduced/oxidized glutathione molar r atio were decreased and hepatic malondialdehyde increased. SAMe cotreatment 1) significantly improved or abolished the CyA-induced changes in LPM flui dity and composition and the changes in the activity of the carrier and enz ymes tested, 2) counteracted the hepatic depletion of GS and proteins cause d by CyA and normalized the reduced/oxidized glutathione ratio, and, as exp ected, 3) prevented cholestasis and the inhibitory effect of CyA on hepatob iliary transport of the major bile components. We conclude that CyA-induced cholestasis and hepatotoxicity in the rat is associated with changes in LP M composition and fluidity, liver GS depletion, and oxidative stress. SAMe cotreatment significantly improves or totally protects against these hepato toxic effects.