The Vascular Toxicity of Homocysteine and How to Control It

Mark F. McCarty, Ph.D.
Pantox Laboratories, San Diego
Charles A. Thomas, Jr., Ph.D.
Pantox Laboratories, San Diego

Summary: Homocysteine, a metabolite of the amino acid methionine, has been linked to an elevated risk of vascular disease. Supplementation with vitamins B6, B12, and folic acid, as well as betaine, has been shown to effectively lower homocysteine levels in the blood and may be expected to offer some protection against vascular disease. 

Homocysteine Emerges as a Vascular Risk Factor 

It has long been known that homocystinuria—a genetic disorder in which blood levels of homocysteine, a metabolite of the amino acid methionine, are about 20-fold the normal concentration—is associated with greatly increased risk for premature vascular disease, sometimes leading to strokes or heart attacks in teenagers. In 1969, Dr. Kilmer McCully was the first to suggest that high-normal serum levels of homocysteine likewise constitute a risk factor for cardiovascular disease. Early support for this concept came from a study published in 1976 by Wilcken and Wilcken, who reported that, following an oral dose of methionine, serum homocysteine levels tended to be higher in patients with premature coronary disease than in healthy controls. Nonetheless, the thesis that homocysteine is an important determinant of vascular disease in the general population attracted little interest until Dr. Meir Stampfer and his colleagues at Harvard, using data from the large Physicians' Health Study, provided striking confirmation: the risk of myocardial infarction was threefold higher in subjects with homocysteine levels in the top 5% of values, compared to subjects with homocysteine in the bottom 90%.

Subsequently, a number of other studies have concluded that high homocysteine levels represent an important independent risk factor for coronary heart disease, heart attack, stroke, peripheral atherosclerosis, and venous thromboembolism (the blockage of a blood vessel by a migrating clot). Furthermore, the risk associated with homocysteine appears to increase throughout the normal range of concentrations; each 1 micromolar rise in the concentration of homocysteine in the blood corresponds to an increase of about 10% in cardiovascular risk. This homocysteine-associated risk is strongly enhanced by smoking and hypertension. For reasons not yet clear, homocysteine levels tend to be higher in males, the elderly, smokers, and caffeine users. In light of evidence that homocysteine can be directly toxic to blood vessels—in particular, much like oxidized LDL cholesterol, it disrupts the healthful function of the cells lining the blood vessels—it seems likely that homocysteine is not merely a marker for some other pathogenic (disease causing) factor. It is therefore highly desirable to develop and implement safe measures for minimizing serum homocysteine levels. 

Metabolic Regulation of Homocysteine Levels 

In the body, dietary methionine is converted to homocysteine. In a series of metabolic steps, the enzyme cystathionine b-synthase (CBS) irreversibly generates a substance called cystathionine from homocysteine. The rate at which homocysteine is generated from methionine and then converted to cystathionine is evidently determined by the habitual dietary intake of methionine. If dietary methionine is fairly constant, the logical way to minimize homocysteine levels is to maximally activate CBS. 

Like many other enzymes that transform amino acids, CBS requires vitamin B6 to function properly. Inadequate levels of vitamin B6 can impair the activity of CBS, perhaps explaining why moderate B6 deficiency is pro-atherogenic in monkeys. Since daily supplementation with 100 mg or more of vitamin B6 often lowers homocysteine levels in people with homocystinuria as well as in patients with less dramatic elevations of homocysteine, it seems likely that normal tissue concentrations of vitamin B6 attained dietarily are frequently insufficient to maximally activate CBS. 

Another potential avenue for stimulating CBS activity and reducing homocysteine levels is to maximize tissue levels of S-adenosylmethionine (SAM), which is a strong activator of CBS. While dietary methionine is a source of homocysteine, it also accelerates the disposal of homocysteine by giving rise to SAM, a compound that contains methionine. 

One way to increase SAM levels in tissues is to accelerate the reactions that reconvert homocysteine to methionine. The best known of these reactions requires 5-methyltetrahydrofolate (MTHF; a substance derived from the vitamin folic acid) and vitamin B12. Dietary deficiencies (or malabsorption) of folic acid or vitamin B12, as well as genetic abnormalities which impair the efficiency of MTHF production, are linked to a reduction in tissue SAM levels and a consequent elevation of homocysteine. Genetic abnormalities in the enzyme whose product is MTHF have also been found to be a common cause of increased homocysteine. One particular genetic defect in this enzyme is quite common in the general population, affecting about 12% of us. These people have serum homocysteine levels approximately 25% higher than people who do not have the defectivegene. Fortunately, ample supplemental intakes of folic acid can compensate for the diminished activity of the enzyme and thus reduce homocysteine levels. However, this strategy will not work in those who have a severe deficiency of the enzyme that generates MTHF.


Controlling Homocysteine with Vitamins and Betaine

Several groups of investigators have reported the impact of supplementation with vitamins B6, B12, and folic acid, administered alone or jointly, in patients with homocystinuria, resulting from an excess of homocysteine. Folic acid appears to be useful in most subjects; very high doses of B6 (100 mg or more daily) also seem to have broad utility, whereas lower doses may benefit only those whose baseline B6 status is poor. The efficacy of supplemental B12 may likewise hinge on baseline B12 status. Not surprisingly, serum homocysteine levels tend to correlate inversely with serum levels or dietary intakes of these vitamins in the general population, indicating that vitamin nutriture is an important determinant of serum homocysteine in people who don't take B vitamin supplements. This may explain why low serum levels of folic acid or vitamin B6 have been shown to be cardiovascular disease risk factors. Among regular users of supplemental vitamins, average serum homocysteine is reported to be about 1.5 micromolar lower than in those who do not supplement, which should correspond to a 15% reduction in cardiovascular disease risk. Lower homocysteine levels in people who eat breakfast cerals may reflect the fact that such cereals are frequently enriched with B vitamins.

An additional mechanism for reconverting homocysteine to methionine is provided by the enzyme betaine homocysteine methyltransferase (BHMT). Human BHMT is found almost exclusively in the liver and kidney. High intakes of betaine (6 grams or more daily) have been used successfully to treat genetic homocystinuria in humans, and betaine fed to rats given alcohol or carbon tetrachloride has been shown to boost hepatic SAM levels. However, there has been relatively little interest in medical applications of betaine, and, in particular, only a few investigators have examined its potential utility for decreasing modestly elevated homocysteine levels. For example, Dr. K. Franken and colleagues used betaine (6 grams daily) and vitamins in several patients with mild hyperhomocysteinemia who were not optimally responsive to vitamins alone. The specific response to betaine was not reported, though. Dr. N. Dudman and colleagues gave 840 mg of betaine, twice daily, to patients with CBS deficiency. They reported reductions of homocysteine in the blood of about 30%. Since there are two mechanisms for reconverting homocysteine to methionine, one would expect that stimulation of both of these mechanisms should produce the most profound reductions in homocysteine. Supplementation with vitamins B6, B12, and folic acid, as well as betaine, may, through their influence on homocysteine levels, help reduce the risk of heart disease and other vascular diseases.

Last updated November, 1999

Honoring a Scientific Giant with Nutritional Research Toward Longer, Better Lives

Go back to the table of contents Go back to LPI home page Please send any comments, suggestions, or questions about The Linus Pauling Institute to