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PubMedDate not supplied

Homocysteine and risk of coronary artery disease: Folate is the important determinant of plasma homocysteine concentration.

OBJECTIVES: The purposes of this study were to study the effects of folate and vitamins B6 and B12 on plasma homocysteine concentration and to estimate the risks for coronary artery disease (CAD) according to quartiles of plasma homocysteine concentration. METHODS: The study was designed as a case-reference observational study. Case subjects (CAD group, n = 60) were identified by cardiac catheterization to have at least 70% stenosis of one major coronary artery; otherwise, patients were considered for a reference group (n = 60). Risk factors of cardiovascular disease were recorded, including age, sex, blood lipid profile, hypertension, smoking habits, and drinking habits. Plasma homocysteine, folate, pyridoxal 5'-phosphate, and vitamin B12 were measured. RESULTS: CAD subjects had significantly higher mean plasma homocysteine concentrations than did the reference subjects (13.9 +/- 4.9 versus 9.1 +/- 3.3 micromol/L). There were no significant differences between groups with regard to the three B vitamins; however, mean serum folate concentrations for subjects in the highest two quartiles of plasma homocysteine concentration (10.8-13.8 and >/=13.9 micromol/L) were significantly lower than those for subjects in the lowest two quartiles (</=8.0 and 8.1-10.7 micromol/L). Plasma homocysteine was strongly inversely associated with serum folate in the CAD (beta= -0.166, P < 0.05), reference (beta= -0.178, P < 0.001), and pooled (beta = -0.190, P < 0.001) groups. Age, sex, other confounding factors, and B-vitamin-adjusted odds ratios were significantly increased in the highest quartile of homocysteine concentration (odds ration, 5.54; 95% confidence interval, 0.38-81.41). The elevation of 1 ng/mL in serum folate concentration was found to decrease plasma homocysteine by 0.166 micromol/L. CONCLUSIONS: Serum folate, but not vitamin B6 or B12, was a strong predictor of plasma homocysteine; while all subjects had adequate B-vitamin status. Folate should be considered as a routine supplementation for individuals who have risk factors for CAD, even for individuals with adequate folate status.

Adult↗
PubMed2002

Postmethionine-load homocysteine determination for the diagnosis hyperhomocysteinaemia and efficacy of homocysteine lowering treatment regimens.

Substantial epidemiological evidence supports the vision that moderate hyperhomocysteinaemia is a graded and independent cardiovascular risk factor. The additional value of the methionine loading test for the assessment of hyperhomocysteinaemia continues to be disputed. This overview presents the historical background for the rationale of the methionine loading test and describes determinants and variability of the postmethionine-load homocysteine concentration. The association of postmethionine-load homocysteine concentrations and the risk of cardiovascular events is discussed. Furthermore, the results of homocysteine lowering treatment on postmethionine-load homocysteine are given. Up to 50% of subjects with hyperhomocysteinaemia can only be detected after performing a methionine loading test; these subjects have a normal fasting homocysteine. Both fasting and postmethionine-load homocysteine concentrations are influenced by serum folate and creatinine concentrations and by the methylenetetrahydrofolate reductase genotype, and may be subject to a wide intra-individual variability (approximately 20%). Cross-sectional studies suggest that cardiovascular risk may increase gradually from postmethionine-load homocysteine concentrations above 38 micromol/l. Supplementation with folic acid 0.5 mg daily adequately reduces postmethionine-load homocysteine; addition of pyridoxine appears to have no further homocysteine lowering effect. Prospective studies supporting the clinical significance of the methionine loading test for individual patient counselling are lacking; it seems, therefore, prudent to restrict this test for research purposes.

Cardiovascular Diseases↗
PubMed2005

Oral estradiol decreases plasma homocysteine, vitamin B6, and albumin in postmenopausal women but does not change the whole-body homocysteine remethylation and transmethylation flux.

Estrogens, both endogenous and exogenous, lower the fasting levels of the independent risk factor for cardiovascular disease homocysteine. The mechanism behind this observation remains unclear. In a randomized, placebo-controlled, double-blind study, 25 postmenopausal women with a screening homocysteine concentration above 10 micromol/liter were included. We investigated the influence on homocysteine levels of a 3-month treatment with a daily oral dose of 4 mg 17beta-estradiol (ET) or 4 mg ET combined with 10 mg dydrogesterone (EPT); the comparison group received placebo treatment. We performed primed continuous infusions of L-[2H3-methyl-13C]methionine to assess steady-state flux rates of transmethylation, remethylation, and transsulfuration. Homocysteine concentration relationships with S-adenosylmethionine, S-adenosylhomocysteine, creatinine, albumin, vitamins B6 and B12, and folate status were determined as well. The mean change from baseline in homocysteine concentration by both treatments compared with placebo (ET, -13%; EPT, -10%) was accompanied by a decrease in the concentration of vitamin B6 (ET, -25%; EPT, -38%) and albumin (ET, -7%; EPT, -11%). No significant changes in flux rates were observed. In a .multiltivariate analysis, changes in homocysteine concentration were related to changes in albumin concentration. No relation to other variables was observed. We conclude that the ET- and EPT-induced homocysteine changes in this study were not accompanied by a significant change in methionine-homocysteine flux rates and hypothesize that an estrogen-induced lowering of homocysteine levels is primarily part of a change in albumin metabolism.

Aged↗
PubMed1998

Protein binding of homocysteine and other thiols in HeLa cell cultures after addition of homocysteine and copper ions.

Homocysteine can be viewed as the first risk factor for atherosclerosis, believed to exert its effects through a mechanism involving oxidative damage. Oxygen radicals are known to interact with a variety of macromolecules leading to lipid peroxidation, DNA strand breakage and a variety of changes in proteins, including thiol oxidation. The present study deals with the protein-binding of homocysteine, cysteine and glutathione in a human cell line culture exposed to homocysteine and copper ions in order to elucidate the possible role of homocysteine in cell injury and atherogenesis. It is shown that homocysteine has the highest tendency of the thiols investigated to create disulfide bonds with proteins. The interaction with the protein cysteine thiol groups, which are involved in the function of many enzymes, structural proteins and receptors might disturb many metabolic functions in the cell. This finding might therefore be one reason for the cell-damaging effects of homocysteine. Addition of reduced homocysteine to cell cultures decreased the intra- and extracellular proportions of protein-bound thiols except that of intracellular glutathione. In agreement with the pro-oxidative effects of copper ions, the findings in the present study showed an increase of the protein-bound fractions of all thiols after the addition of copper ions. Another finding is that increased (in the presence of 100 mumol/l of copper ions) or decreased (in the presence of 100-2000 mumol/l of homocysteine) proportions of protein-bound fractions of the thiols in these short-term experiments did not seriously affect the cells since the cell growth was unchanged.

Copper↗
PubMed2002

Homocysteine is a protein amino acid in humans. Implications for homocysteine-linked disease.

Homocysteine is thought to be a non-protein amino acid. However, in vitro studies suggest that homocysteine is likely to be incorporated by indirect mechanisms into proteins in living organisms. Here I show that homocysteine is a protein amino acid in humans. Homocysteine bound by amide or peptide linkages (Hcy-N-protein) is present in human hemoglobin, serum albumin, and gamma-globulins. 1 molecule of homocysteine per 1000 or 1670 molecules of methionine was present in hemoglobin or albumin, respectively. Other proteins, such as low density lipoprotein, high density lipoprotein, transferrin, antitrypsin, and fibrinogen, contained lower amounts of Hcy-N-protein. In human plasma, levels of Hcy-N-protein represented from 0.3 to 23% of total homocysteine. Thus, Hcy-N-protein is a significant component of homocysteine metabolism in humans, possibly contributing to adverse effects of homocysteine on human cells.

Blood Proteins↗
PubMed2001

Total plasma homocysteine and related amino acids in end-stage renal disease (ESRD) patients measured by gas chromatography-mass spectrometry--comparison with the Abbott IMx homocysteine assay and the HPLC method.

Increased concentrations of homocysteine probably contribute to the high cardiovascular morbidity and mortality in hemodialysed end-stage renal disease (ESRD) patients and are determined by a variety of factors such as age, residual renal function, and vitamin status. Fasting plasma concentrations of total homocysteine, methionine, cysteine, and cystathionine were determined by gas chromatography-mass spectrometry (GC-MS) in 131 ESRD patients receiving daily oral folate (160-320 microg) and vitamin B6 (10-20 mg) supplements. Concentrations of homocysteine determined by GC-MS were compared with those measured by high-performance liquid chromatography (HPLC) and an immunofluorescence method (IMx analyzer) using Passing-Bablok regression analysis. Mean plasma concentration of total homocysteine determined by GC-MS (28.7+/-11.9 micromol/l [mean+/-SD]) was significantly lower than that determined by HPLC (34.0+/-14.5 micromol/l; p<0.001) or IMx (32.4+/-13.9 micromol/l; p<0.001). A close correlation existed between GC-MS and HPLC (r=0.931; y=1.203 x+0.279) and GC-MS and IMx (r=0.896; y=1.105 x+0.766). Linear regression analysis showed positive correlations between plasma concentrations of homocysteine and cysteine (r=0.434; p<0.001) and homocysteine and cystathionine (r=0.187; p=0.032). Plasma concentrations of homocysteine correlated negatively with folate (r=-0.281; p=0.001) and vitamin B12 (r=-0.229; p=0.009). GC-MS proved to be a sensitive and reliable method for the determination of total plasma homocysteine and related amino acids. Despite vitamin supplementation, ESRD patients requiring chronic maintenance hemodialysis, have high plasma concentrations of homocyst(e)ine which seems to be metabolized mainly within the transsulfuration pathway, while remethylation to methionine seems to be disturbed.

Adult↗
PubMed2005

Effects of homocysteine on vascular and tissue adenosine: a stake in homocysteine pathogenicity?

Homocysteine may have deleterious effects on the cardiovascular system. It has been hypothesized that these effects may be brought about by a decrease in the adenosine concentration via the S-adenosylhomocysteine hydrolase reaction. A requirement for this causal relationship is proof of a reduction in vascular adenosine concentration during conditions of elevated homocysteine concentrations. In the present communication we summarize published data obtained during systematic variation of the arterial homocysteine concentration. Most of the results reported show that an increase in homocysteine concentration to 100 microM is associated with a 20-50% decrease in vascular adenosine concentration and an increase in tissue S-adenosylhomocysteine level. Homocysteine effects on the adenosine concentration seem to be more pronounced under conditions of impaired oxygenation. Further experiments, in particular on organs and tissue that release high amounts of homocysteine, i.e., the liver, are warranted to study the potential effects of homocysteine on vascular and tissue adenosine concentrations and consequent effects on organ function. The evidence obtained may be relevant for future assessment of risk indicators in conjunction with homocysteine pathogenicity, which might potentially be extended to measurements of adenosine or S-adenosylhomocysteine levels.

Adenosine↗
PubMed2003

Homocysteine, cysteine, and glutathione in human colonic mucosa: elevated levels of homocysteine in patients with inflammatory bowel disease.

The present study was performed to evaluate the levels of the amino thiols cysteine, homocysteine, and glutathione in the colonic mucosa of patients with various intestinal diseases, especially chronic inflammatory bowel disease. Colonic biopsies of macroscopically normal mucosa out of a proximal and distal segment were collected from 187 patients with various intestinal diseases. Protein was assayed in duplicate by the method of Lowry et al (1951), using bovine serum albumin as standard. Total glutathione, cysteine, and homocysteine were quantified by high performance liquid chromatography (HPLC) with fluorescent detection. Only in patients with inflammatory bowel disease were the homocysteine levels in the large bowel mucosa significantly elevated compared with the concentrations in patients with normal mucosa. No significant differences were seen for glutathione and cysteine concentrations in colonic mucosa among the different groups of diseases. No correlation was found between the age of the patients and levels of the amino thiols investigated. GSH content and concentrations of cysteine and homocysteine were similar in male and female subjects. In our study markedly elevated concentrations of homocysteine in the colonic mucosa were observed in patients suffering from ulcerative colitis and Crohn's disease. This finding has been reported already in the literature for plasma homocysteine levels. Increased homocysteine levels in the colonic mucosa and plasma of patients with inflammatory bowel disease may play a role in the pathogenesis of Crohn's disease and ulcerative colitis.

Adolescent↗
PubMed2001

Taurine prevents the decrease in expression and secretion of extracellular superoxide dismutase induced by homocysteine: amelioration of homocysteine-induced endoplasmic reticulum stress by taurine.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for atherosclerosis. Homocysteine has been shown to induce endoplasmic reticulum (ER) stress in vascular endothelial cells. ER stress is a condition in which glycoprotein trafficking is disrupted and unfolded proteins accumulate in the ER. ER molecular chaperons, such as GRP78, are induced and an ER resident kinase, PERK, is activated when cells are subjected to ER stress. Conversely, taurine is reported to have antiatherogenic effects by unknown mechanisms. To elucidate the mechanisms by which homocysteine induces atherosclerosis and taurine prevents it, we examined whether homocysteine and taurine affect the expression and secretion of extracellular superoxide dismutase (EC-SOD), a glycoprotein secreted from vascular smooth muscle cells (VSMCs) that protects the vascular wall from oxidative stress. METHODS AND RESULTS: We assessed the expression of EC-SOD and GRP78 mRNA in cultured rat VSMCs by Northern blot analysis. The EC-SOD protein secreted into the culture medium was examined by Western blot analysis. Homocysteine (5 mmol/L) and other ER stress inducers, including A23187, were found to decrease EC-SOD mRNA expression and protein secretion. Furthermore, they upregulated GRP78 mRNA expression and activated PERK. Taurine (0.5 to 10 mmol/L), conversely, prevented these actions induced by homocysteine. CONCLUSIONS: Homocysteine induces ER stress and reduces the secretion and expression of EC-SOD in VSMCs, leading to increased oxidative stress in the vascular wall. Taurine restores the secretion and expression of EC-SOD by ameliorating ER stress induced by homocysteine.

Animals↗
PubMed1987

Homocysteine thiolactone, N-homocysteine thiolactonyl retinamide, and platelet aggregation.

Because of platelet abnormalities, thrombosis and arteriosclerosis observed in human and experimental homocysteinemia, the effects of several chemical forms of homocysteine were studied in human platelets in vitro. The free base of homocysteine thiolactone caused primary platelet aggregation over a wide range of concentration (4 X 10(-8) to 10 micrograms/ml), but polar salts of homocysteine thiolactone, homocystine, homocysteine, and homocysteic acid were inactive. N-homocysteine thiolactonyl retinamide and trans retinoic acid caused aggregation at 100 micrograms/ml. Homocysteine thiolactone caused thromboxane TXB2 and prostacyclin 6-keto-PGF1 alpha formation during aggregation, but there was no release of ATP. This finding demonstrates dissociation between aggregation and release of dense granule content. Accumulation of the free base of homocysteine thiolactone may explain abnormal platelet function and thrombosis in human and experimental homocysteinemia.

Adenosine Triphosphate↗
PubMed1993

Kinetics of plasma homocysteine in healthy subjects after peroral homocysteine loading.

The kinetics of plasma homocysteine were determined in 13 healthy subjects after peroral administration and in one person after intravenous injection. Various forms of homocysteine completely dissolved in an aqueous solution were rapidly absorbed after peroral administration, and the bioavailability was estimated to be 0.53. The volume of distribution was 0.66 L/kg. The area under the plasma concentration curve (AUC0-48 h) was proportional to the administered dose (33.5-134 mumol/kg body wt), and showed small interindividual variations. Plasma homocysteine showed first-order elimination kinetics for at least 6 h. The half-life (t1/2) was 223 +/- 45 min, and there was a significant correlation between t1/2 values determined on two different occasions in the same individual. The transient hyperhomocysteinemia was associated with an increase in plasma methionine, which probably reflects intracellular remethylation of homocysteine. Less than 2% of the administered homocysteine dose was recovered in the urine. These findings may form the basis for future studies on the regulation of plasma homocysteine in health and disease, and should motivate the evaluation of a homocysteine loading test as a diagnostic tool.

Absorption↗
PubMed1993

Methionine synthase inactivation by nitrous oxide during methionine loading of normal human fibroblasts. Homocysteine remethylation as determinant of enzyme inactivation and homocysteine export.

Nitrous oxide inactivates the enzyme methionine synthase by oxidation of enzyme bound cobalamin, which is formed from the cofactor methylcobalamin during the catalytic cycle. The resulting inhibition of homocysteine remethylation increases the homocysteine efflux and thereby the level of extracellular homocysteine, both in patients and cultured cells. In the present work we measured the kinetics of enzyme inactivation and homocysteine export rate in two human fibroblast cell lines exposed to nitrous oxide and cultured in the presence of low to supraphysiological concentrations (15-100 microM) of methionine. Both the rate and extent of methionine synthase inactivation were reduced by increasing methionine concentration in the culture medium. In cells not exposed to nitrous oxide, methionine increased the homocysteine export rate in a dose-dependent manner. Nitrous oxide increased the export at low methionine concentrations, so that for treated cells the export was high and essentially independent of the extracellular methionine level. Neither methionine nor nitrous oxide significantly affected the amount of S-adenosylmethionine or folate in these cells. These data agree with methionine synthase as a low Km and methionine conserving enzyme, highlight the importance of methionine synthase activity as a determinant of homocysteine export and point to the possibility of protecting the enzyme by reducing catalytic turnover through product inhibition.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2003

L-homocysteine sulfinic acid and other acidic homocysteine derivatives are potent and selective metabotropic glutamate receptor agonists.

Moderate hyperhomocysteinemia is associated with several diseases, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, and spina bifida. However, the mechanisms for their pathogenesis are unknown but could involve the interaction of homocysteine or its metabolites with molecular targets such as neurotransmitter receptors, channels, or transporters. We discovered that L-homocysteine sulfinic acid (L-HCSA), L-homocysteic acid, L-cysteine sulfinic acid, and L-cysteic acid are potent and effective agonists at several rat metabotropic glutamate receptors (mGluRs). These acidic homocysteine derivatives 1) stimulated phosphoinositide hydrolysis in the cells stably expressing the mGluR1, mGluR5, or mGluR8 (plus Galpha(qi9)) and 2) inhibited the forskolin-induced cAMP accumulation in the cells stably expressing mGluR2, mGluR4, or mGluR6, with different potencies and efficacies depending on receptor subtypes. Of the four compounds, L-HCSA is the most potent agonist at mGluR1, mGluR2, mGluR4, mGluR5, mGluR6, and mGluR8. The effects of the four agonists were selective for mGluRs because activity was not discovered when L-HCSA and several other homocysteine derivatives were screened against a large panel of cloned neurotransmitter receptors, channels, and transporters. These findings imply that mGluRs are candidate G-protein-coupled receptors for mediating the intracellular signaling events induced by acidic homocysteine derivatives. The relevance of these findings for the role of mGluRs in the pathogenesis of homocysteine-mediated phenomena is discussed.

Animals↗
PubMed2004

Homocysteine thiolactone induces apoptosis in cultured human trophoblasts: a mechanism for homocysteine-mediated placental dysfunction?

OBJECTIVE: Hyperhomocystinemia is a thrombophilic condition associated with placental dysfunction. We tested the hypothesis that homocysteine-thiolactone, a metabolite of homocysteine, induces apoptosis in cultured trophoblasts. STUDY DESIGN: Cytotrophoblasts from term human placentas were cultured for 72 hours or less in the presence or absence of 50 to 400 micromol/L homocysteine-thiolactone or 400 micromol/L cysteine (control), with or without vitamin C, vitamin E, folate, or N-acetylcysteine. Cell death was assessed by cellular adenosine triphosphate concentration, medium lactate dehydrogenase level, and immunocytochemical staining for the cleavage products of cytokeratin 18 and poly(adenosine diphosphate ribose) polymerase. Changes in expression of p53, Bcl-2, Bax, and Bak were quantified by Western immunoblotting. RESULTS: Homocysteine-thiolactone induced a concentration dependent increase in total cell death and death by apoptosis, compared with control. Vitamin C ameliorated apoptosis in cytotrophoblasts, whereas N-acetylcysteine mitigated cell death in syncytiotrophoblasts. Apoptosis in both phenotypes occurred with increased expression of p53 and Bak, but no change in Bcl-2 or Bax. CONCLUSION: Homocysteine-thiolactone enhances apoptosis in cultured human trophoblast, and the effect can be limited by antioxidants.

Apoptosis↗
PubMed2004

Folate, homocysteine levels, methylenetetrahydrofolate reductase (MTHFR) 677C --> T variant, and the risk of myocardial infarction in young women: effect of female hormones on homocysteine levels.

In young women data are limited about the association between myocardial infarction (MI) and hyperhomocysteinemia, low folate or methylenetetrahydrofolate reductase (MTHFR) genotypes. The effect of oral contraceptive (OC) use on plasma homocysteine levels is not clear. We assessed the association between hyperhomocysteinemia, low folate, MTHFR 677TT mutation and risk of MI, and we investigated the effect of OC use on homocysteine levels in controls. In 181 patients with a first MI and 601 controls 18-49 years of age from a population-based case-control study, non-fasting blood samples were available. The homozygote mutant allele (TT) was detected in 12% of the patients and in 10% of controls. The odds ratio (OR) for MI in TT patients compared with the wild-type (CC) controls was 1.3 [95% confidence interval (CI) 0.8, 2.3]. For all MTHFR genotypes combined, the OR for MI in the lowest quartile of folate (<5.4 nmol L-1) compared with the highest quartile (>10.4 nmol L-1) was 3.0 (95% CI 1.7, 5.1). A 2-fold increased risk of MI was found in women with the TT genotype who had folate levels below the median of 7.4 nmol L-1 compared with CC genotype and folate levels above the median (OR = 2.0; 95% CI 1.0, 3.7). Mean homocysteine levels were 12.2 micromol L-1 in OC users and 12.3 micromol L-1 in non-users. Only at the 97.5 percentile (cut-off 21.0 micromol L-1) was the adjusted OR for higher vs. lower homocysteine levels increased by 2.8-fold (95% CI 1.2, 6.8). Low folate is a risk factor for MI, particularly in women with the MTHFR 677TT genotype. Homocysteine levels were not influenced by OC use.

Adolescent↗
PubMed2004

Maternal homocysteine before conception and throughout pregnancy predicts fetal homocysteine and birth weight.

BACKGROUND: Increased homocysteine has been associated with pregnancy complications. METHODS: We investigated prospectively the effect of maternal homocysteine on normal pregnancy outcome. The study included 93 women and their offspring; 39 of the women took folic acid during the second and/or third trimesters of pregnancy. We measured homocysteine at preconception; at weeks 8, 20, and 32 of pregnancy; during labor; and in the fetal cord; we also recorded birth weight. RESULTS: Geometric mean (SE) maternal total homocysteine (tHcy) increased between 32 weeks of pregnancy and labor [7.98 (1.05) micromol/L in unsupplemented women and 6.26 (1.07) micromol/L in supplemented women; P <0.0001 for both]. Fetal tHcy was lower than maternal tHcy [6.39 (1.06) micromol/L in unsupplemented pregnancies (P <0.0001), and 5.18 (1.06) micromol/L in supplemented pregnancies (P <0.05)]. Maternal tHcy was correlated from preconception throughout pregnancy (8 weeks, r = 0.708; 20 weeks, r = 0.637; 32 weeks, r = 0.537; labor, r = 0.502; P <0.0001 for all time points) and with fetal tHcy [preconception, r = 0.255 (P <0.05); 8 weeks, r = 0.321 (P <0.01); 20 weeks, r = 0.469; 32 weeks, r = 0.550; labor, r = 0.624 (P <0.0001)]. Mothers in the highest tHcy tertile at 8 weeks of pregnancy were three times [odds ratio, 3.26 (95% confidence interval, 1.05-10.13); P <0.05] and at labor were four times [3.65 (1.15-11.56); P <0.05] more likely to give birth to a neonate in the lowest birth weight tertile. Neonates of mothers in the highest tHcy tertile at labor weighed, on average, 227.98 g less than those of mothers in the low and medium tertiles (P = 0.014). CONCLUSIONS: Supplemented mothers had lower tHcy at labor than unsupplemented mothers, as did their neonates. Maternal and fetal tHcy was significantly correlated throughout the study. Neonates of mothers in the highest tertile of homocysteine weighed less.

Adolescent↗