Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Nutr Res. 2010 Jul;30(7):492-500. doi: 10.1016/j.nutres.2010.06.017.
Betaine homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to homocysteine (Hcy), forming dimethylglycine and methionine. We previously showed that inhibiting BHMT in mice by intraperitoneal injection of S-(alpha-carboxybutyl)-DL-homocysteine (CBHcy) results in hyperhomocysteinemia. In the present study, CBHcy was fed to rats to determine whether it could be absorbed and cause hyperhomocysteinemia as observed in the intraperitoneal administration of the compound in mice. We hypothesized that dietary administered CBHcy will be absorbed and will result in the inhibition of BHMT and cause hyperhomocysteinemia. Rats were meal-fed every 8 hours an L-amino acid-defined diet either containing or devoid of CBHcy (5 mg per meal) for 3 days. The treatment decreased liver BHMT activity by 90% and had no effect on methionine synthase, methylenetetrahydrofolate reductase, phosphatidylethanolamine N-methyltransferase, and CTP:phosphocholine cytidylyltransferase activities. In contrast, cystathionine beta-synthase activity and immunodetectable protein decreased (56% and 26%, respectively) and glycine N-methyltransferase activity increased (52%) in CBHcy-treated rats. Liver S-adenosylmethionine levels decreased by 25% in CBHcy-treated rats, and S-adenosylhomocysteine levels did not change. Furthermore, plasma choline decreased (22%) and plasma betaine increased (15-fold) in CBHcy-treated rats. The treatment had no effect on global DNA and CpG island methylation, liver histology, and plasma markers of liver damage. We conclude that CBHcy-mediated BHMT inhibition causes an elevation in total plasma Hcy that is not normalized by the folate-dependent conversion of Hcy to methionine. Furthermore, metabolic changes caused by BHMT inhibition affect cystathionine beta-synthase and glycine N-methyltransferase activities, which further deteriorate plasma Hcy levels.
甜菜碱同型半胱氨酸 S-甲基转移酶 (BHMT) 催化甜菜碱向同型半胱氨酸 (Hcy) 的甲基转移，形成二甲基甘氨酸和蛋氨酸。我们之前的研究表明，通过腹腔注射 S-(α-羧基丁基)-DL-同型半胱氨酸 (CBHcy) 抑制小鼠中的 BHMT 会导致高同型半胱氨酸血症。在本研究中，我们用 CBHcy 喂养大鼠，以确定它是否可以被吸收并导致像在小鼠中腹腔给予该化合物时观察到的高同型半胱氨酸血症。我们假设，膳食中给予的 CBHcy 将被吸收，并导致 BHMT 抑制，从而导致高同型半胱氨酸血症。大鼠每 8 小时进食一次含有或不含有 CBHcy（每餐 5mg）的 L-氨基酸定义的饮食，持续 3 天。该处理使肝 BHMT 活性降低 90%，对蛋氨酸合成酶、亚甲基四氢叶酸还原酶、磷酸乙醇胺 N-甲基转移酶和 CTP：磷酸胆碱胞苷转移酶活性没有影响。相比之下，CBHcy 处理的大鼠中胱硫醚 β-合酶活性和免疫可检测蛋白分别降低（分别为 56%和 26%），甘氨酸 N-甲基转移酶活性增加（52%）。CBHcy 处理的大鼠肝 S-腺苷甲硫氨酸水平降低 25%，S-腺苷同型半胱氨酸水平不变。此外，CBHcy 处理的大鼠血浆胆碱降低（22%），血浆甜菜碱增加（15 倍）。该处理对总 DNA 和 CpG 岛甲基化、肝组织学和血浆肝损伤标志物没有影响。我们得出结论，CBHcy 介导的 BHMT 抑制导致总血浆 Hcy 升高，而依赖叶酸的 Hcy 向蛋氨酸的转化不能使 Hcy 正常化。此外，BHMT 抑制引起的代谢变化影响胱硫醚 β-合酶和甘氨酸 N-甲基转移酶活性，这进一步使血浆 Hcy 水平恶化。
