Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: Protection by betaine
Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: Protection by betaine
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DOI：
10.1016/j.bcp.2005.09.021
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发表时间：
2005-12-05
影响因子：
5.8
通讯作者：
Tuma, DJ
中科院分区：
文献类型：
--
作者：
Kharbanda, KK;Rogers, DD;Tuma, DJ
我们实验室以前的研究表明，乙醇消耗导致肝细胞S-腺苷高半胱氨酸水平增加。由于S-腺苷高半胱氨酸是一种有效的甲基化反应抑制剂，我们认为细胞内S-腺苷高半胱氨酸水平的增加可能是乙醇诱导的病理学的主要贡献者。为了检验这一假设，将从大鼠肝脏分离的肝细胞在胶原包被的平板上在含有5%FCS的威廉姆斯培养基E中生长，并暴露于不同浓度的腺苷以增加细胞内S-腺苷高半胱氨酸水平。我们观察到暴露于腺苷后caspase-3活性增加。这种caspase活性的增加与细胞内S-腺苷高半胱氨酸水平和DNA亚倍体的增加相关。腺苷诱导的变化可以显着减弱甜菜碱管理。甜菜碱的作用机制似乎是通过甜菜碱-同型半胱氨酸-甲基转移酶催化的甲基化反应。总之，我们的研究结果表明，S-腺苷高半胱氨酸水平的升高，在肝脏中的乙醇是一个主要因素，在改变甲基化反应，并在增加肝脏细胞凋亡。我们的结论是，乙醇诱导的蛋氨酸代谢途径的改变可能在酒精性肝损伤相关的病理学中起着至关重要的作用，甜菜碱的管理可能具有有益的治疗效果。爱思唯尔公司出版
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. Published by Elsevier Inc.