Villanueva Jesus A, Esfandiari Farah, White Mollie E, Devaraj Sridevi, French Samuel W, Halsted Charles H
Department of Internal Medicine, School of Medicine, University of California, Davis, CA 95616, USA.
Alcohol Clin Exp Res. 2007 Nov;31(11):1934-43. doi: 10.1111/j.1530-0277.2007.00511.x. Epub 2007 Sep 11.
To demonstrate a causative role for abnormal methionine metabolism in the pathogenesis of alcoholic steatohepatitis (ASH), we measured the preventive effects of supplementing folate deficient and ethanol containing diets in the micropig with S-adenosylmethionine (SAM), a metabolite that regulates methionine metabolism.
Yucatan micropigs were fed folate-deficient diets as control, with ethanol at 40% of kcal, or with ethanol supplemented with SAM at 0.4 g/1000 kcal for 14 weeks. Histopathology, markers of liver injury, and regulatory enzymes were measured in terminal liver samples.
Among the ethanol group, livers showed hepatocellular necrosis together with increased levels of S-adenosylhomocysteine (SAH) and reduced levels of SAM and its ratio to SAH and glutathione (GSH), together with increased malondialdehyde plus hydroxynonenol (MDA + HNE) and nitrotyrosine (NT), transcripts and protein levels of cytochrome P4502E1 (CYP2E1), activity of NADPH oxidase, and activity and protein levels of inducible nitric oxide (iNOS). These findings were attenuated partially or completely to control levels by SAM supplementation of the ethanol diet.
The present results indicate that SAM supplementation attenuates ethanol induced liver injury through its effects on the expressions and activities of oxidative stress pathways, and are consistent with the concept that the pathogenesis of oxidative liver injury is regulated in part through altered hepatic methionine metabolism.
为了证明蛋氨酸代谢异常在酒精性脂肪性肝炎（ASH）发病机制中的因果作用，我们测定了在小型猪的叶酸缺乏且含乙醇的饮食中补充S-腺苷甲硫氨酸（SAM，一种调节蛋氨酸代谢的代谢物）的预防效果。
将尤卡坦小型猪喂食叶酸缺乏饮食作为对照，其中乙醇占热量的40%，或在乙醇中补充0.4 g/1000 kcal的SAM，持续14周。在终末期肝脏样本中测量组织病理学、肝损伤标志物和调节酶。
在乙醇组中，肝脏显示肝细胞坏死，同时S-腺苷同型半胱氨酸（SAH）水平升高，SAM水平及其与SAH和谷胱甘肽（GSH）的比率降低，丙二醛加羟基壬烯醛（MDA + HNE）和硝基酪氨酸（NT）增加，细胞色素P4502E1（CYP2E1）的转录本和蛋白质水平、NADPH氧化酶活性以及诱导型一氧化氮（iNOS）的活性和蛋白质水平升高。通过在乙醇饮食中补充SAM，这些发现部分或完全减弱至对照水平。
目前的结果表明，补充SAM通过其对氧化应激途径的表达和活性的影响减轻乙醇诱导的肝损伤，并且与氧化肝损伤的发病机制部分通过肝脏蛋氨酸代谢改变来调节的概念一致。
