Discovery of the Homocysteine Theory of Arteriosclerosis
The American biochemist Vincent DuVigneaud discovered a new amino acid in 1932 by treating methionine with sulfuric acid. The structure of this amino acid is similar to cysteine, except for one extra carbon atom, hence the name homocysteine. Subsequent investigation established the role of homocysteine as an intermediate in sulfur amino acid metabolism and transmethylation reactions. Little was known, however, about the biomedical significance of homocysteine until 1962, when children with mental retardation, accelerated growth, osteoporosis, dislocated ocular lenses, and frequent thrombosis of arteries and veins were discovered to excrete homocysteine in the urine.
Most children with homocystinuria are deficient in the enzyme cystathionine synthase, a pyridoxal phosphate-dependent enzyme that catalyzes the synthesis of cystathionine from homocysteine and serine. Because of this enzyme deficiency, homocysteine and methionine accumulate to high levels in plasma, and homocystine, the disulfide dimer of homocysteine, is excreted in the urine. In a 1969 review1 of an archival case of homocystinuria in an eight-year-old boy, originally published in 1933, it was discovered that the cause of death was a massive stroke resulting from carotid arteriosclerosis and thrombosis. In addition, arteriosclerotic plaques were found to be scattered through arteries to major organs of the body, suggesting a possible connection between homocysteine and atherogenesis.
In a second case of homocystinuria in a two-month-old boy, caused by deficiency of a different enzyme, methionine synthase, widespread, advanced arteriosclerotic plaques were discovered, scattered through the arteries. Because the enzyme deficiency caused elevated blood levels of cystathionine and homocysteine, and decreased levels of methionine, it was concluded that homocysteine causes arteriosclerotic plaques by a direct effect on the cells and tissues of the arteries, since homocysteine elevation was the only metabolic abnormality shared by these two cases. Several years later, investigators in Chicago demonstrated similar arteriosclerotic plaques in a child with methylenetetrahydrofolate reductase deficiency, the third major type of homocystinuria, independently corroborating the conclusion that homocysteine is an atherogenic amino acid. In the original publication of these cases of homocystinuria, it was suggested that elevation of blood homocysteine is important in the pathogenesis of arteriosclerosis in the general population without these rare inherited disorders of homocysteine metabolism.1 Thus, individuals with hereditary, dietary, environmental, hormonal, metabolic, or toxic predispositions to arteriosclerosis develop arterial plaques from damage by homocysteine to the lining cells and tissues of arteries.
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- McCully K S, "Chemical pathology of homocysteine", I. Atherogenesis Ann. Clin. Lab. Sci. (1993), 23: pp. 477-493.
- McCully K S, "Homocysteine and vascular disease", Nature Med. (1996), 2: pp. 386-389.
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- McCully K S, "Homocysteine, folate, vitamin B6 and cardiovascular disease", J.Am. Med.Assoc. (1998), 279: pp. 392-393.
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- McCully K S,"Atherosclerosis, serum cholesterol and the homocysteine theory: a study of 194 consecutive autopsies", J.Am. Med. Sci. (1990), 299: pp. 217-221.
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- Jamison R L, Hartigan P, Gaziano J M, Fortman S P, Goldfarb D S, Haroldson J A, Kaufman J, Lavori P, McCully K S and Robinson K, "Design and statistical issues in the Homocysteinemia in Kidney and End Stage Renal Disease (HOST) Study", Clin.Trials (2004), In Press.