Halsted Charles H, Villanueva Jesus A, Devlin Angela M
University of California, Davis, 95616, USA.
Alcohol. 2002 Jul;27(3):169-72. doi: 10.1016/s0741-8329(02)00225-2.
Methionine metabolism is regulated by folate, and both folate deficiency and abnormal hepatic methionine metabolism are recognized features of alcoholic liver disease (ALD). Previously, histological features of ALD were induced in castrated male micropigs fed diets containing ethanol at 40% of kilocalories for 12 months, whereas in male micropigs fed the same diets for 12 months abnormal methionine metabolism and hepatocellular apoptosis developed. Folate deficiency may promote the development of ALD by accentuating abnormal methionine metabolism. Intact male micropigs received eucaloric diets that were folate sufficient, folate deficient, or each containing 40% of kilocalories as ethanol for 14 weeks. Folate deficiency alone reduced hepatic folates by one half, and ethanol feeding alone reduced methionine synthase, S-adenosylmethionine (SAM), and glutathione (GSH) levels and elevated plasma malondialdehyde (MDA) levels. The combined regimen elevated plasma homocysteine, hepatic S-adenosylhomocysteine (SAH), urinary 8-hydroxy-2-deoxyguanosine (oxy(8)dG), an index of DNA oxidation, and serum aspartate aminotransferase (AST) levels. Terminal hepatic histopathologic characteristics included typical features of steatonecrosis and focal inflammation in pigs fed the combined diet, with no changes in the other groups. Hepatic SAM levels correlated with those of GSH, whereas urinary oxy(8)dG and plasma MDA levels correlated with the SAM:SAH ratio and to hepatic GSH. The results demonstrate the linkage of abnormal methionine metabolism to products of DNA and lipid oxidation and to liver injury. The finding of steatonecrosis and focal inflammation only in the combined diet group supports the suggestion that folate deficiency promotes and folate sufficiency protects against the early onset of methionine cycle-mediated ALD.
蛋氨酸代谢受叶酸调节,叶酸缺乏和肝脏蛋氨酸代谢异常都是酒精性肝病(ALD)的公认特征。此前,给去势雄性小型猪喂食含40%千卡热量乙醇的日粮12个月,可诱导出ALD的组织学特征,而给雄性小型猪喂食相同日粮12个月,则会出现蛋氨酸代谢异常和肝细胞凋亡。叶酸缺乏可能通过加剧蛋氨酸代谢异常来促进ALD的发展。完整雄性小型猪接受等热量日粮,分别为叶酸充足、叶酸缺乏或每种日粮含40%千卡热量乙醇,持续14周。仅叶酸缺乏使肝脏叶酸减少一半,仅乙醇喂养降低了蛋氨酸合成酶、S-腺苷甲硫氨酸(SAM)和谷胱甘肽(GSH)水平,并升高了血浆丙二醛(MDA)水平。联合方案使血浆同型半胱氨酸、肝脏S-腺苷同型半胱氨酸(SAH)、尿液8-羟基-2-脱氧鸟苷(oxy(8)dG,DNA氧化指标)和血清天冬氨酸转氨酶(AST)水平升高。肝脏终末组织病理学特征包括联合日粮喂养组猪出现典型的脂肪坏死和局灶性炎症特征,其他组无变化。肝脏SAM水平与GSH水平相关,而尿液oxy(8)dG和血浆MDA水平与SAM:SAH比值及肝脏GSH相关。结果表明蛋氨酸代谢异常与DNA和脂质氧化产物以及肝损伤之间存在联系。仅联合日粮组出现脂肪坏死和局灶性炎症这一发现支持了以下观点:叶酸缺乏促进蛋氨酸循环介导的ALD早期发病,而叶酸充足则可预防。