Homocyst(e)ine, Diet, and Cardiovascular Diseases

Homocysteine is a sulfur-containing amino acid, rapidly oxidized in plasma to the disulfides homocystine and cysteine-homocysteine (Figure 1⇓). Plasma/serum total homocysteine, also termed homocyst(e)ine, is the sum of homocysteine in all 3 components. Figure 2⇓ displays factors involved in the metabolism of homocysteine, including its metabolic relationship to methionine. Although dietary intake of total protein and methionine does not correlate significantly with blood homocyst(e)ine,1 a single dose of oral methionine (100 mg/kg body weight) can elevate homocyst(e)ine levels, and as described further below, this has been used as a diagnostic test to detect disordered homocyst(e)ine metabolism. Because variable changes in homocyst(e)ine levels have been observed postprandially,2 it is customary to obtain measurements in the fasting state. Normal levels of fasting plasma homocyst(e)ine are considered to be between 5 and 15 μmol/L. Moderate, intermediate, and severe hyperhomocyst(e)inemia refer to concentrations between 16 and 30, between 31 and 100, and >100 μmol/L, respectively.3 Figure 1. Molecular species of homocysteine. Figure 2. Simplified outline of methionine/homocysteine metabolism. Vitamin coenzymes and substrates: THF, tetrahydrofolate; B2, riboflavin; B6, vitamin B6 as its biological active form, ie, pyridoxal 5′-phosphate; and B12, methyl cobalamin. Intermediate metabolite: DMG, dimethylglycine.Several vitamins function as cofactors and substrates in the metabolism of methionine and homocysteine (Figure 2⇑). Folic acid and cyanocobalamin (vitamin B12) regulate metabolic pathways catalyzed by the enzymes methylenetetrahydrofolate reductase (MTHFR) and methionine synthase, respectively, whereas pyridoxine (vitamin B6) is a cofactor for cystathionine β-synthase. A number of studies have shown inverse relationships of blood homocyst(e)ine concentrations with plasma/serum levels of folic acid, vitamin B6, and vitamin B12.4 5 6 Administration of supplemental folic acid in doses between 0.2 and 15 mg/d can lower plasma homocyst(e)ine levels without apparent toxicity.7 8 …