Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation
Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation
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DOI：
10.1074/jbc.m002725200
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发表时间：
2000-09-22
影响因子：
4.8
通讯作者：
James, SJ
中科院分区：
文献类型：
--
作者：
Yi, P;Melnyk, S;James, SJ
S-腺苷蛋氨酸和S-腺苷高半胱氨酸（SAH）作为细胞甲基转移酶反应的底物和产物，是细胞甲基化状态的重要代谢指标。继发于同型半胱氨酸介导的SAH水解酶反应逆转的SAH慢性升高降低了DNA、RNA、蛋白质和磷脂的甲基化。SAH与细胞甲基转移酶活性位点的高亲和力结合导致酶的产物抑制。采用一种灵敏的新型高压液相色谱库仑电化学检测方法，发现健康年轻女性血浆SAH水平随同型半胱氨酸水平轻度升高而线性增加（r = 0.73; p < 0.001）;然而，S-腺苷甲硫氨酸水平不受影响，血浆SAH水平与细胞内淋巴细胞SAH水平呈正相关（r = 0.81; p < 0.001），也与淋巴细胞DNA低甲基化（r = 0.74，p < 0.001）有关。这些结果表明，血浆同型半胱氨酸水平的慢性升高，如与营养缺乏或叶酸途径中的遗传多态性相关，可能通过伴随的细胞内SAH水平的增加对细胞甲基化反应产生间接和负面影响。
S-Adenosylmethionine and S-adenosylhomocysteine (SAH), as the substrate and product of essential cellular methyltransferase reactions, are important metabolic indicators of cellular methylation status. Chronic elevation of SAH, secondary to the homocysteine-mediated reversal of the SAH hydrolase reaction, reduces methylation of DNA, RNA, proteins, and phospholipids. High affinity binding of SAH to the active site of cellular methyltransferases results in product inhibition of the enzyme. Using a sensitive new high pressure liquid chromatography method with coulometric electrochemical detection, plasma SAH levels in healthy young women were found to increase linearly with mild elevation in homocysteine levels (r = 0.73; p < 0.001); however, S-adenosylmethionine levels were not affected, Plasma SAH levels were positively correlated with intracellular lymphocyte SAH levels (r = 0.81; p < 0.001) and also with lymphocyte DNA hypomethylation (r = 0.74, p < 0.001). These results suggest that chronic elevation in plasma homocysteine levels, such as those associated with nutritional deficiencies or genetic polymorphisms in the folate pathway, may have an indirect and negative effect on cellular methylation reactions through a concomitant increase in intracellular SAH levels.