The metabolism and significance of homocysteine in nutrition and health
Review Open Access
The metabolism and significance of homocysteine in nutrition and health
Avinash Kumar1, Henry A. Palfrey1, Rashmi Pathak1, Philip J. Kadowitz2, Thomas W. Gettys3 and Subramanyam N. Murthy1Email authorView ORCID ID profile
Nutrition & Metabolism201714:78
https://doi.org/10.1186/s12986-017-0233-z
© The Author(s). 2017
Received: 10 November 2017Accepted: 7 December 2017Published: 22 December 2017
Abstract
An association between arteriosclerosis and homocysteine (Hcy) was first demonstrated in 1969. Hcy is a sulfur containing amino acid derived from the essential amino acid methionine (Met). Hyperhomocysteinemia (HHcy) was subsequently shown in several age-related pathologies such as osteoporosis, Alzheimer’s disease, Parkinson’s disease, stroke, and cardiovascular disease (CVD). Also, Hcy is associated with (but not limited to) cancer, aortic aneurysm, hypothyroidism and end renal stage disease to mention some. The circulating levels of Hcy can be increased by defects in enzymes of the metabolism of Met, deficiencies of vitamins B6, B12 and folate or by feeding Met enriched diets. Additionally, some of the pharmaceuticals currently in clinical practice such as lipid lowering, and anti-Parkinsonian drugs are known to elevate Hcy levels. Studies on supplementation with folate, vitamins B6 and B12 have shown reduction in Hcy levels but concomitant reduction in certain associated pathologies have not been definitive. The enormous importance of Hcy in health and disease is illustrated by its prevalence in the medical literature (e.g. > 22,000 publications). Although there are compelling data in favor of Hcy as a modifiable risk factor, the debate regarding the significance of Hcy mediated health effects is still ongoing. Despite associations between increased levels of Hcy with several pathologies being well documented, whether it is a causative factor, or an effect remains inconclusive. The present review though not exhaustive, is focused on several important aspects of Hcy metabolism and their relevance to health.
Keywords
HomocysteineMethionineHyperhomocysteinemiaInflammationDietaryCardiovascular disease
Background
Homocysteine (Hcy) is a sulfur containing amino acid formed during the metabolism of methionine (Met) to cysteine (Cys). Hyperhomocysteinemia (HHcy), or increased circulating levels of Hcy, is generally recognized as an independent risk factor for coronary, cerebral, and peripheral atherosclerosis [1–3]. The levels of Hcy can be increased by defective metabolism of Met, resulting from either mutation in genes coding for the enzymes of Hcy metabolism [4, 5], or deficiencies of certain vitamin cofactors [6, 7]. In addition to genetic alterations, vitamin deficiencies, and several other environmental factors such as increased intake of Met, certain medications, disease state, pregnancy, and lactation are known to contribute to variations in Hcy levels [8–11]. Altered cellular export mechanisms have also been known to increase Hcy levels [12]. In general the dietary contribution of Hcy alone is insignificant given its low levels in most foods [13]; mainly derived from Met.
Serum or plasma Hcy is a well-known risk factor for cardiovascular disease (CVD) [14, 15] and this has been demonstrated among others in subjects with significant carotid stenosis particularly [16, 17]. It has been shown that HHcy following a Met load was significantly more in non-insulin dependent diabetes mellitus patients with vascular disease and also in patients with reduced cystathionine-β-synthase (CβS) activity [18, 19]. Studies have shown total-Hcy (tHcy) levels as a strong predictor of mortality in patients with angiographically confirmed coronary artery disease [20]. Association of elevated serum Hcy with sudden unexpected death, especially in patients with diabetes, has been reported [21]. In the absence of other known risk factors, HHcy was shown to stimulate the expression of monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin. This leads to increased monocyte adhesion to the arterial endothelium, and may significantly contribute to the development of atherosclerosis by facilitating monocyte/macrophage infiltration into the arterial wall [22].
Apart from defects in the enzymes of Hcy metabolism that are inherited, HHcy can also be induced experimentally by dietary manipulations. These include enrichment of diets with Met or depleting diets with vitamins folate or B6 or B12 [23]. Further, studies have shown that consumption of meat and dairy based products can also bring about an increase in circulating levels of Hcy [24, 25]. In a cross over study using an isocaloric diet but varying in protein concentrations, Verhoef and coworkers have shown increases in postprandial Hcy following the consumption of a high protein diet; 4–4.5 g protein bound methionine/d [26].
Hcy damages cells and tissues of arteries by eliciting the release of cytokines, cyclins, and other mediators of inflammation and cell division [27]. Additionally, Hcy causes oxidative stress by affecting cellular respiration, leading to oxidation of low density lipoproteins (LDL) and other constituents of plaques [28]. Stamler and colleagues reported that Hcy also antagonizes the vasodilatory properties of nitric oxide (NO) by forming S-nitrosohomocysteine, leading to endothelial dysfunction, the forerunner for atherogenesis [29].
Although Hcy has been associated with CVD and other age-related pathologies, whether it is a consequence or causative factor is subject of intense debate. The negative findings of interventional studies with vitamin B therapy have cast doubts on the role of Hcy in CVD pathogenesis resulting in Hcy controversy. To complicate this further, some interventional studies with folic acid and B vitamins have shown a reduction in Hcy levels but not the pathology, however these have met with criticisms in the design of the study that include duration and inadequate number of subjects [30]. It is argued that the Hcy lowering trials have been underpowered and also the duration of follow-up not being long enough; a consideration largely ignored. Interestingly, in a meta-analysis of the effect of B vitamins on stroke Wang and coworkers investigated the difference in outcome of follow-up for less than 36 months and more than 36 months. They demonstrated a statistically significant 29% reduction in the studies with at least 36 months of follow-up which could not be seen in the short-term studies [31]. Several studies on supplementation of folic acid to lower Hcy have not considered the possible adverse effects of unmetabolized folic acid (especially when given in large doses). Folic acid used for supplementation has to be reduced to tetrahydrofolate which requires 1-carbon substitution to initiate the methylation process. Further, it is argued that the beneficial effects of lowering of Hcy by B vitamins could depend (...truncated)
