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Notizen: Abstract We investigated whether S -adenosyl-L-methionine(SAMe), dilinoleoylphosphatidylcholine (DLPC), or SAMe+ DLPC influence liver lipid composition as well asacute ethanol hepatotoxicity in the isolated perfused rat liver (IPRL). SAMe (25 mg/kgintramuscularly three times a day) was administered forfive consecutive days, while DLPC was administeredintraperitoneally for five days. The liver was thenisolated, perfused with taurocholate to stabilize bilesecretion, and exposed to 0.5% ethanol for 70 min. SAMe,without changing total phospholipid (PL) content,induced an increase in the phosphatidylcholine/phosphatidylethanolamine (PC/PE) molar ratio in both liver homogenateand microsomes and a significant enrichment of 16:0-20:4and 18:0-20:4 PC molecular species. DLPC induced asignificant enrichment of PL in liver homogenate and microsomes due to a contemporary increasein PC and PE. The PC enrichment specifically involved16:0-20:4 and 18:0-20:4 PC molecular species besides theHPLC peak containing the administered 18:2- 18:2 PC species. DLPC + SAMe increased theconcentration of PC in liver homogenate and microsomesdue to a specific enrichment of 16:0-22:6, 16:0-20:4,and 18:0-20:4 PC molecular species, and the HPLC peakcontaining the administered 18:2-18:2 PC species. Ethanolacute exposure in the control IPRLs for 70 min induceda depletion of cholesterol in both liver homogenate andmicrosomes without significant changes in the composition of PL classes and PC molecularspecies. SAMe, DLPC, or SAMe + DLPC counteracted thecholesterol depletion induced by ethanol, indicatingthat phospholipid changes promoted by these treatments all induce a major resistance of livermembranes to the effect of ethanol. Ethanoladministration in control IPRLs induced a fivefoldincrease of AST and LDH release in the perfusate,depletion of glutathione in homogenates and mitochondria, decreasedoxygen liver consumption, and inhibition of bile flow.These effects of ethanol were significantly antagonizedby SAMe. In contrast, DLPC alone only minimally attenuated enzyme release in the perfusate andthe inhibitory effect of ethanol on bile flow, but itfailed to influence the depletion of total andmitochondrial glutathione or the depressed oxygenconsumption induced by ethanol. DLPC, administered togetherwith SAMe, added nothing to the protective effect ofSAMe against ethanol hepatotoxicity and cholestasis. Inconclusion, this study demonstrates that both SAMe and DLPC induced marked modifications inthe lipid composition of liver membranes with a similarenrichment of polyunsaturated PC molecular species. OnlySAMe, however, significantly protected against the hepatotoxic and cholestatic effect of acuteethanol administration, an effect associated withmaintained normal glutathione mitochondrial levels andoxygen liver consumption. This indicates that the protective effect of SAMe against ethanoltoxicity is linked to multiple mechanisms, themaintenance of glutathione levels probably being one ofthe most important.