Abstract
Elevated circulating total homocysteine (tHcy) concentrations (hyperhomocysteinemia) have been regarded as an independent risk factor for cardiovascular disease (CVD). However, several large clinical trials to correct hyperhomocysteinemia using B-vitamin supplements (particularly folic acid) have largely failed to reduce the risk of CVD. There is no doubt that a large segment of patients with CVD have hyperhomocysteinemia; therefore, it is reasonable to postulate that circulating tHcy concentrations are in part a surrogate marker for another, yet-to-be-identified risk factor(s) for CVD. We found that iron catalyzes the formation of Hcy from methionine, S-adenosylhomocysteine and cystathionine. Based on these findings, we propose that an elevated amount of non-protein-bound iron (free Fe) increases circulating tHcy. Free Fe catalyzes the formation of oxygen free radicals, and oxidized low-density lipoprotein is a well-established risk factor for vascular damage. In this review, we discuss our findings on iron-catalyzed formation of Hcy from thioethers as well as recent findings by other investigators on this issue. Collectively, these support our hypothesis that circulating tHcy is in part a surrogate marker for free Fe, which is one of the independent risk factors for CVD.
Highlights
Homocysteine (Hcy) is exclusively formed from methionine (Met) through the transmethylation pathway [1]
We summarize results in the literature together with our investigations, which possibly indicate that circulating total Hcy (tHcy) is in part a surrogate for non-protein-bound iron, which is considered to be one of the independent risk factors for cardiovascular disease (CVD) [6]
Ubbink et al [19] later reported that the mean plasma tHcy increased by about 190% in EDTA-containing whole blood stored at room temperature for 24 h, whereas the increase was only 20% using sodium fluoride (NaF)-containing whole blood, and no such increase was observed when whole blood was stored at 4 °C
Summary
Homocysteine (Hcy) is exclusively formed from methionine (Met) through the transmethylation pathway [1]. Nutrients 2015, 7 extremely high circulating total Hcy (tHcy) concentrations (often >500 μmol/L) and suggested that it is detrimental to the integrity of the vascular wall This association received little attention until 1991, when Clarke et al [3] reported that hyperhomocysteinemia is an independent risk factor of cardiovascular disease (CVD); the “Hcy-CVD” hypothesis was born. These findings indicated that lowering tHcy is not effective in reducing the CVD-risk; circulating tHcy may be a surrogate marker of another, yet-to-be-identified, risk factor(s) for CVD. Iron catalyzes the formation of oxygen free radicals, especially when chelated by EDTA [7], and Sullivan [8] postulated that excess iron leads to atherosclerosis through oxygen free radical oxidation of LDL-C This hypothesis is controversial, it is supported by epidemiological data [9]. We believe that Met (or Met as a part of protein), S-adenosylhomocysteine and cystathionine are constantly exposed to free iron at acidic pHs during iron exchange, leading to Hcy formation
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