Fanapour P C, Yug B, Kochar M S
Medical College of Wisconsin, USA.
WMJ. 1999 Dec;98(8):51-4.
Over the past few years, a substantial body of evidence has accumulated that indicates hyperhomocysteinemia as a significant risk factor for cardiovascular disease. Hyperhomocysteinemia arises from a lack of key enzymes or vitamins such as methylenetetrahydrofolate reductase, vitamin B6, and folate which are involved in homocysteine metabolism. Heavy coffee consumption is also known to elevate homocysteine levels. The adverse effects associated with hyperhomocysteinemia are extensive. It increases risk of myocardial infarction, cardiovascular-related morbidity and mortality, peripheral vascular disease, atherosclerosis, coronary heart disease, and cerebrovascular disease. Its seriousness as a risk factor has been equated to hypercholesterolemia and smoking, two leading causes for cardiovascular disease. It also has been shown to produce a multiplicative effect with these and other risk factors such as hypertension. Two major hypotheses have been proposed to explain how homocysteine induces its harmful effects. It can damage endothelial cells lining the vasculature, allowing plaque formation. Simultaneously, it interferes with the vasodilatory effect of endothelial derived nitric oxide. Also, homocysteine has been found to promote vascular smooth muscle cells hypertrophy. Both of these processes induce vessel occlusion. Maintaining a normal plasma level of homocysteine as a means to prevent cardiovascular disease appears promising. This is achieved through increased intake of folate and vitamin B6 through diet or supplementation. Despite the overwhelming evidence suggesting homocysteine as a significant risk factor, no long-term prospective studies have been completed to demonstrate that folate and vitamin B6 can prevent cardiovascular disease related morbidity and mortality in patients with hyperhomocysteinemia. Homocysteine is a key metabolite in amino acid synthesis. During the process of methylation, S-adenosylmethionine (Ado Met), derived from methionine, is converted to S-Adenosylhomocysteine (Figure 1). This product is quickly hydrolyzed to form homocysteine and adenosine. Homocysteine can undergo 1 of 3 reactions depending on the status of the organism. If cysteine levels are inadequate, homocysteine utilizes the coenzyme pyridoxal phosphate (vitamin B6) to condense with serine, forming the intermediate cystathionine. Subsequent reactions with cystathionine lead to the formation of cysteine. When methionine levels are low, homocysteine is remethylated in a reaction involving the coenzyme N5-methyltetrahydrofolate or betaine. Finally, when both amino acids are in adequate supply, homocysteine is cleaved by the enzyme homocysteine desulthydrase (cystathionase) to form a-ketobutyrate, ammonia, and H2S. Thus, homocysteine's physiological role is to assist in maintaining sulfur-amino acid homeostasis. Beyond these metabolic processes, homocysteine is beginning to be recognized as a significant risk factor for cardiovascular disease including atherosclerosis, coronary artery disease, cerebrovascular disease, and myocardial infarction.
在过去几年中，大量证据不断积累，表明高同型半胱氨酸血症是心血管疾病的一个重要危险因素。高同型半胱氨酸血症源于缺乏参与同型半胱氨酸代谢的关键酶或维生素，如亚甲基四氢叶酸还原酶、维生素B6和叶酸。大量饮用咖啡也会使同型半胱氨酸水平升高。与高同型半胱氨酸血症相关的不良影响广泛。它会增加心肌梗死、心血管相关发病率和死亡率、外周血管疾病、动脉粥样硬化、冠心病和脑血管疾病的风险。其作为危险因素的严重性已等同于高胆固醇血症和吸烟这两个心血管疾病的主要病因。研究还表明，它与这些以及其他危险因素（如高血压）会产生相乘效应。已提出两个主要假说来解释同型半胱氨酸如何引发其有害作用。它会损害血管系统的内皮细胞，导致斑块形成。同时，它会干扰内皮衍生一氧化氮的血管舒张作用。此外，已发现同型半胱氨酸会促进血管平滑肌细胞肥大。这两个过程都会导致血管阻塞。将同型半胱氨酸的血浆水平维持在正常水平作为预防心血管疾病的一种手段似乎很有前景。这可以通过饮食或补充剂增加叶酸和维生素B6的摄入量来实现。尽管有大量证据表明同型半胱氨酸是一个重要危险因素，但尚未完成长期前瞻性研究来证明叶酸和维生素B6可以预防高同型半胱氨酸血症患者的心血管疾病相关发病率和死亡率。同型半胱氨酸是氨基酸合成中的关键代谢产物。在甲基化过程中，由甲硫氨酸衍生而来的S-腺苷甲硫氨酸（Ado Met）会转化为S-腺苷同型半胱氨酸（图1）。该产物会迅速水解形成同型半胱氨酸和腺苷。同型半胱氨酸可根据机体状态进行三种反应中的一种。如果半胱氨酸水平不足，同型半胱氨酸会利用辅酶磷酸吡哆醛（维生素B6）与丝氨酸缩合，形成中间产物胱硫醚。随后与胱硫醚的反应会导致半胱氨酸的形成。当甲硫氨酸水平较低时，同型半胱氨酸会在涉及辅酶N5-甲基四氢叶酸或甜菜碱的反应中重新甲基化。最后，当两种氨基酸供应充足时，同型半胱氨酸会被同型半胱氨酸脱硫酶（胱硫醚酶）裂解，形成α-酮丁酸、氨和H2S。因此，同型半胱氨酸的生理作用是协助维持含硫氨基酸的稳态。除了这些代谢过程，同型半胱氨酸正开始被认为是包括动脉粥样硬化、冠状动脉疾病、脑血管疾病和心肌梗死在内的心血管疾病的重要危险因素。
