EVIDENCE OF DIFFERENTIAL-EFFECTS PRODUCED BY ETHANOL ON SPECIFIC PHOSPHOLIPID BIOSYNTHETIC PATHWAYS IN RAT HEPATOCYTES

1 The aim of the present study was to investigate the effects of ethan ol in vitro on the phospholipid biosynthetic pathways in hepatocytes i solated from the rat. We have used [methyl-C-14]-choline, [1-H-3]ethan olamine and L-[3-H-3]-serine as exogenous precursors of the correspond ing phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS). 2 Incubation of hepatocytes in the p resence of ethanol significantly alters the incorporation of radiolabe l from [C-14]-choline and [H-3]-ethanolamine into the metabolic interm ediates and the final products of the CDP-choline and CDP-ethanolamine pathways. Radioactivity in the metabolic intermediates of both pathwa ys was significantly decreased and the amount of label in PE was reduc ed whilst that of PC was not modified. 3 In the presence of 4-methylpy razole, an inhibitor of alcohol dehydrogenase (ADH) activity, ethanol produces a reduction in the label of choline phosphate, ethanolamine p hosphate and a significant decrease in the amount of PC and PE radiola bel. 4 On the other hand, ethanol increases the incorporation of serin e into phosphatidylserine, phosphatidylethanolamine and phosphatidylch oline, although this effect is observed only in the absence of 4-methy lpyrazole, indicating that this alteration is produced by some metabol ite generated as a consequence of hepatic alcohol metabolism. 5 Ethano l also interferes with the methylation of phosphatidylethanolamine pro duced via the CDP-ethanolamine pathway but it does not alter phosphati dylethanolamine methylation when this phospholipid is produced by mito chondrial phosphatidylserine decarboxylation, suggesting the existence of different intramembrane pools of phosphatidylethanolamine, which m ay exhibit different sensitivity to alcohol. 6 Our results indicate th at ethanol exerts two different effects on phospholipid metabolism in hepatocytes: a stimulatory effect on the incorporation of exogenous su bstrates into different phospholipids probably related to an alteratio n in the availability of lipogenic substrates as a consequence of etha nol metabolism, and another inhibitory effect produced by ethanol per se, which can be observed only when ethanol metabolism is inhibited by the presence of a specific inhibitor of alcohol dehydrogenase activit y.