The importance of hyperhomocysteinemia in the pathogenesis of arteriosclerosis
was first recognized by study of vascular pathology in children with homocystinuria
caused by 2 different enzymatic abnormalities of homocysteine metabolism.1 Homocystinuria caused by deficiency of cystathionine
synthase, a pyridoxal phosphate-dependent enzyme, is characterized by vascular
abnormalities and frequent arterial and venous thromboses.2
In 1968 a 2-month-old boy with a rare form of homocystinuria caused by deficiency
of methyltetrahydrofolate homocysteine methyl transferase, a cobalamin-dependent
enzyme, was discovered to have rapidly progressive arteriosclerosis.1 Because of the different metabolic patterns caused
by these 2 enzymatic abnormalities, it was suggested that homocysteine causes
arteriosclerotic plaques by a direct effect on the cells and tissues of the
arteries. A third enzyme abnormality leading to homocystinuria, deficiency
of methylenetetrahydrofolate reductase, a folate-dependent enzyme, was found
to cause arteriosclerotic plaques,3 also supporting
the conclusion that homocysteine is atherogenic. This interpretation explains
the origin of arteriosclerosis observed in vitamin B6–deficient
monkeys and choline-deficient rats, 2 important animal models in which hyperhomocysteinemia
also leads to atherogenesis. The atherogenic effect of homocysteine was subsequently
demonstrated experimentally by parenteral and alimentary administration of
the amino acid to rabbits4,5 and
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