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Volume 15: Number 1: Article 1
The Biomedical Significance of Homocysteine
Kilmer S. McCully, Pathology and Laboratory Medicine Service, VA
Medical Center, 830 Chalkstone Avenue, Providence RI 02908-4799
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 fats in atherogenesis. For this reason
the homocysteine theory was actively suppressed in the 1970s by adherents
of the cholesterol approach and by academic and administrative officials
at Harvard Medical School and Massachusetts General Hospital.
Within the past decade, hundreds of major prospective and retrospective
clinical and epidemiological studies have proven the underlying validity
of the homocysteine theory by showing that hyperhomocysteinemia is a
potent independent major risk factor for vascular disease. At present
at least 18 major interventional trials are in progress worldwide to
prove that lowering blood homocysteine by dietary improvement and supplemental
B vitamins will prevent vascular disease.
Recent research on homocysteine has also implicated abnormal homocysteine
metabolism in a wide range of other important disease processes, including
developmental birth defects, neurodegenerative diseases like Alzheimer's
disease, autoimmune diseases like rheumatoid arthritis, hormonal imbalances,
renal failure, cancer, and degenerative diseases of aging. In the future
the biomedical significance of homocysteine will become extraordinarily
important for prevention and therapy of a wide range of major diseases.
Keywords: homocysteine, heart disease, cholesterol, Dinsdale Award
FULL TEXT:
The Biomedical Significance of Homocysteine
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