The treatment of hyperhomocysteinemia

Abstract

The unique biochemical profile of homocysteine is characterized by chemical reactivity supporting a wide range of molecular effects and by a tendency to promote oxidant stress-induced cellular toxicity. Numerous epidemiological reports have established hyperhomocysteinemia as an independent risk factor for cardiovascular disease, cerebrovascular disease, dementia-type disorders, and osteoporosis-associated fractures. Although combined folic acid and B-vitamin therapy substantially reduces homocysteine levels, results from randomized placebo-controlled clinical trials testing the effect of vitamin therapy on outcome in these diseases have generally fallen short of expectations. These results have led some to abandon homocysteine monitoring in the management of patients with cardiovascular or cognitive disorders. These trials, however, have generally included patients with only mildly elevated homocysteine levels and have not addressed several clinical scenarios in which homocysteine reduction may be effective, including the primary prevention of atherothrombotic disease in individuals at low or intermediate risk, or those with severe hyperhomocysteinemia.

Figure 1. The homocysteine metabolic cycle

The sulfhydryl-containing amino acid homocysteine is an intermediate of normal methionine metabolism. Mutations in the 5,10 methyl-tetrahydrofolate reductase and cystathionine β-synthase genes impair homocysteine conversion to methionine and cystathionine, respectively. Alternatively, elevated levels of homocysteine may result from nutritional deficiencies of folic acid, vitamin B₆, and vitamin B₁₂ that are key enzyme cofactors required for normal homocysteine metabolism. Folic acid replenishes the tetrahydrofolate pool and is required for normal methionine synthase activity; however, folic acid also increases S-adenosylmethionine. This methyl donor is a precursor for asymmetrical dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, which leads to uncoupling of the enzyme, decreased bioavailable nitric oxide, and vascular endothelial dysfunction. Finally, the antioxidant glutathione is an end product of cysteine metabolism; aberrant transulfuration pathway activity has been implicated in decreased cellular antioxidant protection, which may represent one way by which elevated homocysteine levels serve as a surrogate for downstream processes that more specifically characterize the oxidative pathophysiology of various diseases linked to hyperhomocysteinemia. Adapted from Maron and Loscalzo (22).

Figure 2. Folate and asymmetrical dimethylarginine

Folic acid indirectly increases cellular stores of S-adenosylmethionine, which, in turn, facilitate the synthesis of asymmetrical dimethylarginine (ADMA). ADMA uncouples eNOS, resulting in increased oxidant stress, decreased bioavailable NO^•, and impaired vascular function. Dimethylarginine dimethylaminohydrolase degrades ADMA, although activity of this enzyme is decreased by various forms of oxidant stress, including directly by homocysteine. THF, tetrahydrofolate; SAM, S-adenosylmethionine; S-AdoHcy, S-adenosyl-homocysteine; DDAH, Dimethylarginine dimethylaminohydrolase; eNOS, endothelial nitric oxide synthase. Adapted from Palm F, et al. (85).

Figure 3. Homocysteine autoxidation

(A) Under oxidizing conditions, such as after exposure to plasma, homocysteine autoxidizes to form homocystine or homocysteine-mixed disulfides (upper pathway). Homocysteine may also cyclize under acidic conditions to form homoycysteine thiolactone (lower pathway). Hydroxyl radicals (OH⁻, OH^•) and superoxide anion (O₂^•−) are byproducts of these reactions; the latter can be converted to H₂O₂ in the presence of superoxide dismutases or spontaneously undergoes dismutation to H₂O₂. Homocysteine also promotes oxidant stress by directly impairing glutathione peroxidase expression (Gpx-1), an antioxidant enzyme that reduces H₂O₂ to water. (B) Homocysteine-induced reactive oxygen species formation decreases levels of bioavailable NO^• either by reducing the availability of key NOS cofactors, such as tetrahydrobiopterin (BH₄), or by inducing conversion of NO^• to peroxynitrite (ONOO⁻). SOD, superoxide dismutase; eNOS, endothelial nitric oxide synthase.