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. 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.
Kharbanda
Kusum K
KK
VA Alcohol Research Center, Department of Veterans Affairs Medical Center, Research Service (151), 4101 Woolworth Avenue, Omaha, NE 68105, USA. kkharbanda@unmc.edu
Rogers
David D
DD
Mailliard
Mark E
ME
Siford
Gerri L
GL
Barak
Anthony J
AJ
Beckenhauer
Harriet C
HC
Sorrell
Michael F
MF
Tuma
Dean J
DJ
D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001622:Betaine / Q000494:pharmacology; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D019610:Cytoprotection; D053938:DNA Fragmentation; D000431:Ethanol / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008745:Methylation; D051381:Rats; D017208:Rats, Wistar; D012435:S-Adenosylhomocysteine / Q000378:metabolism*
D000431:Ethanol; D001622:Betaine; D012435:S-Adenosylhomocysteine; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D000241:Adenosine