A high plasma concentration of homocysteine is a risk factor for cardiovascular disease, and studies have shown that 0.5 to 5 mg of folic acid as a dietary supplement can lower homocysteine by 25%. Cellular S-adenosylmethionine (SAMe) is an intermediate metabolite in the methionine to homocysteine pathway, and serves as a methyl donor for methyl acceptors such as DNA, RNA and proteins. Transfer of methyl groups from SAMe to acceptors results in the formation of S-adenosylhomocysteine (SAH). The ratio of SAMe to SAH is therefore a biomarker for methylation capacity, with higher values indicating an increased capacity to undergo methylation reactions. Under cellular conditions equilibrium strongly favours conversion of homocysteine to SAH (via addition of adenosine by the SAH hydrolase enzyme), and therefore high cellular levels of homocysteine cause a concomitant increase in SAH formation. The latter binds to methyltransferases with a higher affinity that SAMe and inhibits DNA methylation.
The mechanisms by which elevated homocysteine increases the risk of cardiovascular disease is not known, and various mechanisms have been suggested that include oxidative and non-oxidative modification of the endothelial lining of the arteries. However, it is possible that the inhibition of methylation caused by elevated homocysteine plays a mechanistic role in the development of cardiovascular disease. The most frequent cause of hyperhomocysteinaemia is a mutation on the gene coding for 5,10-methyltetrahydrofolatereductase (MTHFR) which leads to decreased MTHFR activity and a reduction in the conversion of homocysteine to methionine. Individuals with a reduced capacity for 1-carbon metabolism show elevated homocysteine plasma concentrations and have an increased risk for cardiovascular disease. An interaction therefore exists between MTHFR and DNA methylation, through folate, homocysteine and SAH that suggests there might be a therapeutic response to vitamin treatment. However, studies on folic acid supplementation in patients with hyperhomocysteinaemia are limited and controversial.
For example, researchers1 have investigated the effects of 5 mg of folic acid supplementation on 7 hyperhomocysteinaemic individuals with MTHFR mutations causing a reduction in 1-carbon metabolism. Following an 8 week supplemental period, folic acid caused a decrease in plasma homocysteine compared to baseline levels (51.2 to 26.1 µmol/L). Concomitantly, a significant increase in the plasma SAMe concentrations and the SAMe to SAH ratio was also observed. This suggests that folic acid supplementation in individuals with a MTHFR mutation results in altered 1-carbon metabolism. However, the folic acid supplementation had no effect on DNA methylation. Therefore, although folic acid is able to reverse one of the metabolic abnormalities associated with hyperhomocysteinaemia, it appears that the epigenetic influence of folic acid in DNA methylation status in not convincing. However, the authors focussed on genome-wide DNA methylation, and it is therefore possible that selective genes methylation may have occurred.
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