The Biomedical Significance of Homocysteine

In recent years the amino acid homocysteine has achieved the status of an important factor in vascular disease, diseases of aging, and other fundamental processes in biology and medicine. After its discovery in 1932, homocysteine was characterized as an important intermediate in methionine metabolism. Little was known about its biomedical significance until 1962, when children with mental retardation, accelerated growth, and propensity to thrombosis of arteries and veins were found to excrete homocysteine in the urine. My analysis of an archival case of homocystinuria from 1933 disclosed widespread arteriosclerotic plaques and thrombosis of carotid artery with death from stroke in an 8-year-old boy. The cause of homocystinuria in most of these cases is deficiency of the enzyme cystathionine synthase, a pyridoxal phosphate-dependent enzyme. In 1968, my analysis of a second case of homocystinuria caused by deficiency of a different enzyme, methionine synthase, a folate and vitamin B12–dependent enzyme, was critical in the discovery of the atherogenic potential of homocysteine. This 2-month-old baby boy was demonstrated to have advanced arteriosclerotic plaques in arteries of organs throughout the body. Because of the difference in enzyme abnormality in these two cases, it was possible for me to conclude that homocysteine causes arteriosclerosis by a direct effect of the amino acid on the cells and tissues of the arteries. Several years later, arteriosclerotic plaques were demonstrated in a third major type of homocystinuria caused by deficiency of the enzyme methylenetetrahydrofolate reductase, independently corroborating this conclusion. The conclusion that homocysteine is atherogenic is supported by demonstration of arteriosclerotic plaques in experimental animals with hyperhomocysteinemia produced by injection or feeding of the amino acid. The homocysteine theory of arteriosclerosis attributes the underlying cause of the disease to dietary deficiencies of vitamin B6 and folic acid, which lead to hyperhomocysteinemia in the general population. Dietary deficiencies of these B vitamins are caused by losses of these sensitive vitamins through important methods of food processing, including milling of grains, canning, extraction of sugar and oils, radiation, and chemical additives. This revolutionary new view of the underlying cause of arteriosclerosis appeared to contradict the conventional wisdom concerning the role of dietary cholesterol and saturated Journal of Scientific Exploration, Vol. 15, No. 1, pp. 5–20, 2001 0892-3310/01 © 2001 Society for Scientific Exploration