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

Kusum K. Kharbanda, David D. Rogers, Mark E. Mailliard, Gerri L. Siford, Anthony J. Barak, Harriet C. Beckenhauer, Michael F. Sorrell, Dean J. Tuma

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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. We observed increases in caspase-3 activity following exposure to adenosine. This increase in caspase activity correlated with increases in intracellular S-adenosylhomocysteine levels and DNA hypoploidy. The adenosine-induced changes could be significantly attenuated by betaine administration. The mechanism of betaine action appeared to be via the methylation reaction catalyzed by betaine-homocysteine-methyltransferase. To conclude, our results indicate that the elevation of S-adenosylhomocysteine levels in the liver by ethanol is a major factor in altering methylation reactions and in increasing apoptosis in the liver. We conclude that ethanol-induced alteration in methionine metabolic pathways may play a crucial role in the pathologies associated with alcoholic liver injury and that betaine administration may have beneficial therapeutic effects.

Original languageEnglish (US)
Pages (from-to)1883-1890
Number of pages8
JournalBiochemical Pharmacology
Volume70
Issue number12
DOIs
StatePublished - Dec 5 2005

Keywords

  • Adenosine
  • Apoptosis
  • Betaine
  • Hepatocytes
  • Methylation
  • S-adenosylhomocysteine

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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