The protective effect of S-adenosyl-L-methionine teine, glutathione, and taurine. Consequently, SAMe (SAMe) on bromobenzene (BB)-or D-galactosamine is involved in the transmethylation and transsulphura-(GalN)-induced damage to isolated rat hepatocytes and tion of the synthesis and metabolism of hormones, neuits effect on cellular glutathione (GSH) levels were invesrotransmitters, nucleic acids, phospholipids, and protigated. SAMe at concentrations of 0.5 to 3.0 mmol/L sigteins. The synthesis of SAMe from methionine and nificantly reduced lactate dehydrogenase leakage from adenosine triphosphate requires a specific enzyme, cells exposed to 1.6 mmol/L BB (P õ .05 to .001) during SAMe-synthetase. 1 There is growing evidence that 2 hours' incubation. GalN at 25 to 50 mmol/L induced a SAMe exerts protective effects both in vivo and in vitro marked increase of LDH leakage from the cells during on liver cell damage induced by a number of hepatothe later stage of 24 hours' incubation and SAMe at 1.0 toxic agents, such as acetaminophen, 2 carbon tetrachlommol/L clearly attenuated the LDH leakage in GalN (25 mmol/L)-exposed cells. The GSH content in the cells ex-ride, 3,4 D-galactosamine (GalN), 5 ethanol, or by biliposed to 2.4 mmol/L BB for 150 minutes was markedly ary obstruction. Recent data have shown that SAMe decreased, and further decreased during 24 hours' incuis able to attenuate liver damage induced by chronic bation. SAMe (1.5 mmol/L) both reduced LDH leakage intoxication of carbon tetrachloride and inhibit develand corrected GSH depletion in cells exposed to 2.4 opment of liver fibrosis in rat. 9 Clinical studies 10, have mmol/L BB. The GSH content in 25 and 50 mmol/L GalNshown that administration of SAMe to patients with exposed cells was strikingly diminished to 51.2% and chronic cholestatic liver disorders improves liver func-32.8% of the controls, respectively, during 24 hours' of tion tests and bile secretion, modifies the pattern of exposure. SAMe at 1.5 mmol/L significantly reduced the biliary bile acids in primary biliary cirrhosis, and ameloss in GSH content in 25 mmol/L GalN-exposed cells.
liorates symptoms. Therefore, SAMe seems to have im-
The findings show that SAMe has beneficial effects on both BB-and GalN-induced toxicity to rat hepatocytes. portant physiological functions and a great potential The main mechanism behind the protective effect of for clinical applications in acute liver damage and SAMe on BB and GalN toxicity seems to be associated chronic liver disorders. 12,13 with enhancement of GSH synthesis in the cells. (HEPA-Bromobenzene (BB) is one of the classic hepatotoxic TOLOGY 1996;23:359-365.) agents, and its toxicity to the liver is suggested to be mainly caused by covalent binding of its reactive inter-S-Adenosyl-L-methionine (SAMe) is a metabolite in mediate metabolites to vital chemical constituents of the transsulphuration pathway for the metabolism of the cells. Progressive depletion of cellular glutathione methionine. This pathway is responsible for biosynthe-(GSH) is the first event to occur after exposure to BB, sis of important substances, such as polyamines, cysand subsequent lipid peroxidation has been shown in vivo when the GSH content is decreased to less than a Abbreviations: SAMe, S-adenosyl-L-methionine; GalN, D-galactosamine; threshold level. [14][15][16][17] We have previously studied acute BB, bromobenzene; GSH, glutathione; DMSO, dimethyl sulfoxide; LDH, lac-injury to isolated rat hepatocytes exposed to BB during tate dehydrogenase. short-term incubation and observed that calcium chan-From the