• P C Fanapour, B Yug, and M S Kochar.
• Medical College of Wisconsin, USA.
• WMJ. 1999 Dec 1; 98 (8): 51-4.

AbstractOver 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.

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