5 '-methylthioadenosine administration prevents lipid peroxidation and fibrogenesis induced in rat liver by carbon-tetrachloride intoxication

Background: 5'-Methylthioadenosine (MTA) a product of S-adenosylmethionine (SAM) catabolism, could undergo oxidation by mono-oxygenases and auto-oxida tion, MTA and SAM effects on oxidative liver injury were evaluated in CCl4- treated rats. Methods: Male Wistar rats were killed 1-48 h after poisoning with a single intraperitoneal CCl4 dose (0.15 ml/100 g) or with the same dose twice a wee k for 14 weeks. Daily doses of MTA or SAM (384 mu mol/kg), started 1 week b efore acute CCl4 administration or with chronic treatment, were continued u p to the time of sacrifice. Results: Acute and chronic CCl4 intoxication decreased MTA and, to a lesser extent, SAM and reduced glutathione (GSH) liver levels. MTA administration increased liver MTA without affecting SAM and GSH. SAM treatment caused co mplete/partial recovery of these compounds, MTA and, to a lesser extent, SA M prevented an increase in liver phospholipid hydroperoxides in acutely and chronically intoxicated rats and in prolyl hydroxylase activity and trichr ome-positive areas in chronically treated rats. MTA prevented upregulation of Tgf-beta1, Collagen-alpha1 (I) and Tgf-alpha genes in liver of chronically intoxicated rats, and TGF-betal-induced trans differentiation to myofibroblasts and growth stimulation by platelet-derive d growth factor-b of stellate cells in vitro. Conclusions: MTA and SAM protect against oxidative liver injury through par tially different mechanisms. (C) 2001 European Association for the Study of the Liver. Published by Elsevier Science B,V, All rights reserved.