Doshi Sagar, McDowell Ian, Goodfellow Jonathan, Stabler Sally, Boger Rainer, Allen Robert, Newcombe Robert, Lewis Malcolm, Moat Stuart
Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park CF14 4XN Cardiff, UK.
Metabolism. 2005 Mar;54(3):351-60. doi: 10.1016/j.metabol.2004.09.015.
Experimental hyperhomocysteinemia after an oral methionine or homocysteine load is associated with impaired nitric oxide-dependent vasodilatation in healthy human beings. However, it remains unproven that this effect is mediated by elevations in plasma homocysteine. There is evidence that an increase in plasma homocysteine may increase the formation of asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase. The methyl groups within ADMA are derived from the conversion of S -adenosylmethionine to S -adenosylhomocysteine intermediates in the methionine/homocysteine pathway. No previous study has assessed the role of methylation status, its impact on ADMA formation, and their association with endothelial function in healthy human beings. In a randomized, placebo-controlled, crossover study, 10 healthy subjects (mean age, 29.1 +/- 3.9 years) were administered an oral dose of methionine (0.1 g/kg), l -homocysteine (0.01 g/kg), N-acetylcysteine (NAC) (0.1 g/kg), or placebo. Endothelial function as assessed by flow-mediated dilatation (FMD) of the brachial artery was impaired after both the methionine and homocysteine load compared with placebo at 4 hours (36 +/- 15, 67 +/- 23 vs 219 +/- 26 microm, respectively, P < .001). N-Acetylcysteine had no effect on flow-mediated dilatation. Plasma total homocysteine was significantly elevated at 4 hours after methionine (23.1 +/- 6.2) and homocysteine (41.5 +/- 8.9) loading, but significantly reduced after NAC 2.4 +/- 0.6 vs 7.1 +/- 2.1 micromol/L in the placebo (P < .001). Plasma S-adenosylmethionine/S-adenosylhomocysteine ratio was significantly (P < .001) increased at 4 hours after methionine (10.9 +/- 0.7) compared with homocysteine (5.4 +/- 0.4), NAC (5.0 +/- 0.3), and placebo (6.0 +/- 0.5). Plasma ADMA concentrations were not altered by any intervention. Our results suggest that endothelial dysfunction due to methionine or homocysteine loading is not associated with an increase in plasma ADMA or a disruption in methylation status.
口服蛋氨酸或同型半胱氨酸负荷后实验性高同型半胱氨酸血症与健康人体内一氧化氮依赖性血管舒张受损有关。然而，这种效应是否由血浆同型半胱氨酸升高介导仍未得到证实。有证据表明，血浆同型半胱氨酸增加可能会增加不对称二甲基精氨酸（ADMA）的形成，ADMA是一氧化氮合酶的抑制剂。ADMA中的甲基来源于蛋氨酸/同型半胱氨酸途径中S-腺苷甲硫氨酸向S-腺苷同型半胱氨酸中间体的转化。此前尚无研究评估甲基化状态的作用、其对ADMA形成的影响以及它们与健康人体内内皮功能的关联。在一项随机、安慰剂对照、交叉研究中，10名健康受试者（平均年龄29.1±3.9岁）口服蛋氨酸（0.1 g/kg）、L-同型半胱氨酸（0.01 g/kg）、N-乙酰半胱氨酸（NAC）（0.1 g/kg）或安慰剂。与安慰剂相比，在4小时时，蛋氨酸和同型半胱氨酸负荷后通过肱动脉血流介导的血管舒张（FMD）评估的内皮功能受损（分别为36±15、67±23与219±26微米，P<.001）。N-乙酰半胱氨酸对血流介导的血管舒张无影响。蛋氨酸（23.1±6.2）和同型半胱氨酸（41.5±8.9）负荷后4小时血浆总同型半胱氨酸显著升高，但NAC后显著降低（2.4±0.6与安慰剂组的7.1±2.1微摩尔/升，P<.001）。与同型半胱氨酸（5.4±0.4）、NAC（5.0±0.3）和安慰剂（6.0±0.5）相比，蛋氨酸负荷后4小时血浆S-腺苷甲硫氨酸/S-腺苷同型半胱氨酸比值显著升高（P<.001）（10.9±0.7）。任何干预均未改变血浆ADMA浓度。我们的结果表明，蛋氨酸或同型半胱氨酸负荷引起的内皮功能障碍与血浆ADMA增加或甲基化状态破坏无关。
