Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: protection by betaine.

Previous studies from our laboratory have shown that ethanol consumption results in an increase in hepatocellular S-adenosylhomocysteine levels. Because S-adenosylhomocysteine is a potent inhibitor of methylation reactions, we propose that increased intracellular S-adenosylhomocysteine levels could be a major contributor to ethanol-induced pathologies. To test this hypothesis, hepatocytes isolated from rat livers were grown on collagen-coated plates in Williams' medium E containing 5% FCS and exposed to varying concentrations of adenosine in order to increase intracellular S-adenosylhomocysteine levels.

A comparison of the effects of betaine and S-adenosylmethionine on ethanol-induced changes in methionine metabolism and steatosis in rat hepatocytes.

Previous studies showed that chronic ethanol administration alters methionine metabolism in the liver, resulting in increased intracellular S-adenosylhomocysteine (SAH) levels and increased homocysteine release into the plasma. We showed further that these changes appear to be reversed by betaine administration. This study compared the effects of betaine and S-adenosylmethionine (SAM), another methylating agent, on ethanol-induced changes of methionine metabolism and hepatic steatosis.

Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats.

Previous studies showed that chronic ethanol administration inhibits methionine synthase activity, resulting in impaired homocysteine remethylation to form methionine. This defect in homocysteine remethylation was shown to increase plasma homocysteine and to interfere with the production of hepatic S-adenosylmethionine (SAM) in ethanol-fed rats. These changes were shown to be reversed by the administration of betaine, an alternative methylating agent.

Methionine synthase. a possible prime site of the ethanolic lesion in liver.

Among the most important pathways for liver integrity in the body are the two that synthesize methionine and S-adenosylmethionine (SAM) through methylation of homocysteine. Results of studies in this laboratory have demonstrated ethanolic inhibition of one of these pathways catalyzed by methionine synthetase. It has been shown elsewhere that alcohol per se does not inhibit the enzyme, but that the metabolite of ethanol, acetaldehyde, is responsible through the formation of an inhibiting covalent adduct.