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PubMed2001

Increasing levels of dietary homocystine with carotid endarterectomy produced proportionate increases in plasma homocysteine and intimal hyperplasia.

PURPOSE: The role that homocysteine may play in post-carotid endarterectomy (CEA) restenosis due to intimal hyperplasia is not well understood. This study was designed to investigate the effects of different levels of dietary homocystine on: (1) plasma homocysteine; (2) post-CEA intimal hyperplasia; and (3) levels of the methyl donor S-adenosylmethionine (SAM) and its counterpart S-adenosylhomocysteine (SAH) in the homocysteine pathway. METHODS: Male rats were fed specialized diets for 2 weeks pre- and post-CEA. Groups included control (0 homocystine added, n=9), 1.5 (1.5 g/kg homocystine added, n=10), 3.0 (3.0 g/kg homocystine added, n=9), and 4.5 (4.5 g/kg homocystine added, n=11). The rats underwent a surgical carotid endarterectomy. Endpoints included; plasma homocysteine, intimal hyperplasia, replicative index using with alpha-SM actin and BrdU, hepatic SAM levels, SAH levels, and the hepatic activities of methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS). RESULTS: Increasing dietary homocystine produced a proportionate increase in plasma homocysteine and an increase in intimal hyperplasia. Regression analysis of plasma homocysteine levels and intimal hyperplasia showed a significant correlation (r=0.71,P=0.003). Plasma homocysteine levels above 15 microM were associated with significant increases in intimal hyperplasia above 6.5% (P=0.04). Elevation of plasma homocysteine levels to moderate levels (5-25 microM) resulted in significant post-CEA intimal hyperplasia. Cellular analysis of the area of intimal hyperplasia in all diet groups showed comparable amounts of cells positive for alpha-SM actin. However, with increasing levels of dietary homocystine and plasma homocysteine there was an increase in replicative index (P<0.001) as determined by BrdU staining. Increasing dietary homocystine increased plasma homocysteine and was followed by increases in the replicative index thus producing increased intimal hyperplasia and lumenal stenosis. In hepatic measurements the 1.5 and 3.0 g/kg homocystine diets caused: increased liver activity of MTHFR (P=0.03) and decreased hepatic levels of SAM, SAH and SAM/SAH ratios compared to controls. Homocystine treatment did not cause significant alterations in CBS levels (P=0.992). These studies also showed no correlation of the MTHFR and CBS enzymes with plasma homocysteine levels or intimal hyperplasia. However, hepatic levels of SAM showed significant negative correlations with plasma homocysteine (r=-0.58; P=0.006) and with BrdU percentages of cellular proliferation (r=-0.69; P=0.06). CONCLUSION: The degree of post-CEA intimal hyperplasia in a rat model is directly related to the plasma level of homocysteine. The hyperplastic effects of homocysteine may be mediated in part by a physiological insufficiency of methyl donors as shown by decreases in SAM. Thus, increasing levels of plasma homocysteine enhanced and accelerated the smooth muscle cell response after CEA which led to increased intimal hyperplasia and lumenal stenosis.

Animals↗
PubMed2001

Levels of plasma homocysteine in persons with spinal cord injury.

BACKGROUND: Premature coronary vascular disease is a leading cause of morbidity and mortality in persons with chronic spinal cord injury (SCI). Evidence indicates that an elevated plasma homocysteine level is an independent risk factor for vascular disease. METHODS: Plasma homocysteine levels were collected in 845 subjects with SCI and compared to those in a reference population. Differences in plasma homocysteine were determined for sex, race/ethnicity, neurological deficit, and age, as well as for serum creatinine concentration. RESULTS: Plasma homocysteine was significantly higher in men than in women. Men were more likely to have moderately or severely elevated plasma homocysteine levels. Stratifying by male sex, greater percentages of whites and African Americans had severely elevated plasma homocysteine levels (>20 micromol/L) compared with Latinos (12% and 14% versus 8%; P > .01). For the total group with SCI, plasma homocysteine levels were not significantly different by race/ethnicity or neurological deficit subgroup. For the total group (P < .05) and within each sex (men, P < .05; women, P < .01), the older age group with SCI (>50 years) had significantly higher mean plasma homocysteine levels than the younger age group. Age was positively related to plasma homocysteine levels in men (P < .05) and women (P < .01). Plasma homocysteine levels were higher among men for any given age than among women (P < .0001) by an average of 3.19 +/- 0.51 micromol/L. Regardless of age or sex, persons with SCI tended to have higher levels of plasma homocysteine than able-bodied persons matched for age and sex. CONCLUSION: Because the risk of a vascular event increases with age, elevated levels of plasma homocysteine place older persons with SCI at further increased risk for a vaso-occlusive event. Of note, there was a stepwise increase in plasma homocysteine concentration for each quartile of higher serum creatinine concentration. Patients who have elevated levels of plasma homocysteine should receive a trial course of daily supplementation with oral folic acid and vitamin B12. If that is ineffective, they should receive vitamin B6 supplementation to lower their plasma homocysteine levels.

Adult↗
PubMed2002

Differential effects of homocysteine on porcine endothelial and vascular smooth muscle cells.

High concentrations of homocysteine damage endothelial cells and lower concentrations increase vascular smooth muscle cell (VSMC) growth. This study investigated the effects of various concentrations of homocysteine on endothelial cells (VECs) and VSMCs in terms of cell survival, proliferation, and function. VECs and VSMCs from porcine thoracic aorta were studied. These cells were exposed to homocysteine in concentrations of 20 microM, 400 microM, and 1 mM every 8 h for 24 h, and its effect on cell survival, proliferation, and function were studied using methylthiazoletetrazolium assay, [3H]-thymidine incorporation test, and 6-keto-prostaglandin F1alpha enzyme-linked immunosorbent assay for VECs, and platelet-derived growth factor (PDGF) enzyme-linked immunosorbent assay for VSMCs, respectively. In VECs, 20 microM of homocysteine reduced the viable cell count to 95 +/- 31%, 400 microM reduced it to 89 +/- 35%, 1,000 microM reduced it to *58 +/- 29% (control = 100 +/- 30%, n = 18, *p < 0.05). In VSMCs, 20 microM of homocysteine slightly increased the viable cell count to 106 +/- 30%, but there was no statistical significance; 400 microM of homocysteine reduced the viable cell count to *74 +/- 29%, 1,000 microM to *50 +/- 24% (control = 100 +/- 28%, n = 18, *p < 0.05). In VECs, 20 microM of homocysteine reduced [3H]-thymidine uptake by 98 +/- 14%, 400 microM reduced it by *82 +/- 17%, 1,000 microM reduced it by *66 +/- 17% (control = 100 +/- 12, n = 6, *p < 0.05), respectively. But in VSMCs, 20 microM of homocysteine significantly increased [3H]-thymidine uptake (*131 +/- 16%), and thereafter, homocysteine decreased VSMCs [3H]-thymidine uptake, 400 microM by *24 +/- 7%, 1,000 microM by *29 +/- 10% (control = 100 +/- 16, n = 6, *p < 0.05), respectively. Homocysteine decreased VEC prostacyclin secretion in a dose-dependent manner, 20 microM by 105 +/- 0.65 pg/100 microl, 400 microM by *100 +/- 2.37 pg/100 microl, 1,000 microM by *93 +/- 2.54 pg/100 microl (control = 107 +/- 1.26 pg/100 microl, n = 6, *p = 0.007). In VSMCs, 20 microM of homocysteine slightly increased PDGF secretion by 62.2 +/- 20.7 pg/100 microl, but there was little statistical significance (p = 0.13); 400 microM of homocysteine reduced PDGF secretion by *28.9 +/- 10.7 pg/100 microl, and 1,000 microM reduced it by *21.3 +/- 4.7 pg/100 microl (control = 54.5 +/- 9.3 pg/100 microl, n = 6, *p < 0.05). High concentrations of homocysteine damaged both VECs and VSMCs with respect to cell survival, proliferation, and function. By increasing exposure to homocysteine, it was shown that physiologic high concentrations of homocysteine enhanced VSMC proliferation.

Animals↗
PubMed1999

Fasting and post-methionine homocysteine levels in NIDDM. Determinants and correlations with retinopathy, albuminuria, and cardiovascular disease.

OBJECTIVE: The increased cardiovascular risk in subjects with NIDDM is partly explained by an association with established risk factors like hypertension, dyslipidemia, and obesity. Mild hyperhomocysteinemia has emerged as a new risk factor for cardiovascular disease. The purpose of this study was to assess its role in NIDDM. RESEARCH DESIGN AND METHODS: We studied predictors of homocysteine levels and correlations between homocysteine and (micro-)albuminuria, retinopathy, and history of cardiovascular disease in normotensive NIDDM subjects under stable metabolic control. This was done in 85 NIDDM subjects by measuring fasting and post-methionine-loading homocysteine levels together with blood pressure, BMI, serum cholesterol, triglyceride, HDL cholesterol, folate, vitamin B12, pyridoxal-5-phosphate, HbA1c, and (micro-)albuminuria and creatinine clearance in triplicate 24-h urine samples. The relationship between micro- and macrovascular complications and fasting homocysteine only was studied in an additional 65 subjects, giving a total of 150 subjects. RESULTS: In multiple regression analysis, significant (P < 0.05) predictors of fasting homocysteine were low-normal values of creatinine clearance (threshold effect at < 80 ml.min-1 .1.73 m-2), folate (< 20 nmol/l), and vitamin B12 (< 350 pmol/l), and postmenopausal status in women. Determinants of post-methionine homocysteine were pyridoxal-5-phosphate levels < 80 nmol/l, creatinine clearance, and sex (higher levels in women). Hyperhomocysteinemia did not cluster with other cardiovascular risk factors, like hypertension, obesity, or dyslipidemia. Regarding cardiovascular complications, fasting homocysteine, but not post-methionine homocysteine, was higher in subjects with a history of cardiovascular disease. There was a stepwise increase in the prevalence of subjects with cardiovascular disease with increasing fasting homocysteine. The prevalence of cardiovascular disease was 19.4% in the bottom quartile of fasting homocysteine, versus 55.0% in the top quartile (P for trend < 0.01). Neither fasting homocysteine nor post-methionine homocysteine correlated with (micro-)albuminuria or with retinopathy. CONCLUSIONS: The findings suggest that homocysteine levels in NIDDM rise even with modest deterioration of renal function and when vitamin status is in the low to low-normal range. Fasting homocysteine correlates with macrovascular disease, but we found no evidence of a correlation with retinopathy or (micro-)albuminuria. Post-methionine homocysteine levels do not show a correlation with micro- or macrovascular complications.

Administration, Oral↗
PubMed2000

[Elevated levels of homocysteine in plasma as a risk factor for coronary artery disease].

This study was performed to assess the significance of association between coronary artery disease (CAD) and circulating homocysteine concentrations. 100 consecutive CAD patients (78 men and 22 women, aged 31 to 79 years) qualified for PTCA were investigated. At the time of PTCA, the risk factors for CAD and plasma for homocysteine and vitamins were obtained. The controls were without clinical evidence of coronary artery disease and hypertension (90 men and 30 women aged 32 to 81 years). Homocysteine was assayed using ELISA test. Red cell folate and plasma vitamin B12 were assayed by immunofluoroscency (Delphia test). Homocysteine concentrations were higher in patients than in controls (13.61 +/- 4.5 vs 10.99 +/- 4.49 mumol/L, p < 0.001, adjusted for age). Male patients had nonsignificantly higher homocysteine levels than females (13.94 +/- 5.21 vs 11.46 +/- 5.16 mumol/L, p = 0.05, adjusted for age). Elevated homocysteine level--defined as one in the top fifth of the control distribution > or = 12.83 mumol/L--was seen in 46% of the patients compared with 20% of the control group (p = 0.001). The odds ratio (OR) for CAD in persons with elevated homocysteine level was 3.1 (95% Cl 1.6-5.8, p < 0.001, adjusted for age). The OR for CAD of 5 mumol/L increment in homocysteine level was 2.1 (95% Cl 1.4-3.1 p < 0.001, adjusted for age). After adjustment for conventional risk factors (age, smoking, hypertension, family history of CAD, hyperlipidemia), elevated homocysteine level remained independent risk factor for CAD (OR 2.88, 95% Cl 1.1-7.8, p < 0.05). We observed inverse correlation between homocysteine and folate level (r = -0.32, p = 0.005) and between homocysteine and vitamin B12 concentrations (r = -0.24, p = 0.03), especially in men. Patients with elevated homocysteine level had lower levels of folate (629.6 +/- 241.2 nmol/L vs 735.1 +/- 252.4 nmol/L, p < 0.05), and vitamin B12 (213.6 +/- 64.4 pmol/L vs 246.6 +/- 62.3 pmol/L, p < 0.05) than patients with normal level of homocysteine. Elevated plasma homocysteine level is a strong risk factor for coronary artery disease. A 5 mumol/L increment in total homocysteine level may be associated with twofold increase of risk for the disease.

Adult↗
PubMed2001

Apoptotic cell death in the mouse retinal ganglion cell layer is induced in vivo by the excitatory amino acid homocysteine.

Homocysteine, an excitatory amino acid and a homolog of cysteine, induces neuronal cell death in brain via stimulation of N-methyl-D-aspartate (NMDA) receptors. It also selectively activates NMDA receptors of retinal ganglion cells, but it is not known if high levels of homocysteine are toxic to these cells. The purpose of this study was to determine whether increased levels of homocysteine caused death of neurons in the ganglion cell layer; if so whether this death occurred via an apoptotic mechanism and to determine the consequences of simultaneous elevation of homocysteine and glutamate, a known retinal excitotoxin, on the viability of neurons of the ganglion cell layer. C57BL/6 mice were injected intravitreally with either homocysteine or glutamate/homocysteine combined (final concentrations: 25, 75, and 200 microM); injection of glutamate (25 and 200 microM) served as a positive control. Eyes were harvested and cryosections prepared 5-6 days post-injection. Systematic morphometric analysis of retinas of mice injected with homocysteine indicated that the total number of cells in the ganglion cell layer decreased by about 23% following exposure to 200 microM homocysteine. To determine whether the neurons of the ganglion cell layer were dying by apoptosis, the TUNEL method was used and was confirmed by immunohistochemical studies of caspase-3, known to be expressed at high levels during retinal ganglion cell apoptosis. Microscopic analysis revealed significantly more TUNEL-positive cells in the ganglion cell layer in homocysteine-injected eyes than in contralateral PBS-injected eyes. Retinas injected with 75 and 200 microM homocysteine displayed significantly more TUNEL-positive neurons in the ganglion cell layer (2 and 2.9, respectively) than PBS-injected retinas (0.25). In eyes injected simultaneously with homocysteine/glutamate, the number of apoptotic cells in the ganglion cell layer almost doubled that for homocysteine or glutamate injections alone. Immunohistochemical analysis of activated caspase-3 revealed numerous positively labelled neurons in the ganglion cell layer in homocysteine and homocysteine/glutamate-injected eyes, but not in PBS-injected eyes. Quantification of this data revealed a significantly greater number of caspase-3-positive neurons in the ganglion cell layer of retinas injected with 75 and 200 microM homocysteine (2.9 and 4.4, respectively) than for PBS-injected retinas (0.5). This confirms that death of neurons in the ganglion cell layer is occurring by apoptosis. The present study provides the first evidence that homocysteine is toxic to neurons of the ganglion cell layer. In addition, it provides evidence that these retinal neurons are dying by apoptosis and it demonstrates for the first time that excitotoxic damage to neurons of the ganglion cell layer is potentiated by simultaneous elevation of homocysteine and glutamate. These findings are relevant to retinal ganglion cell death characteristic of diabetic retinopathy, which is thought to be mediated by overstimulation of the NMDA receptor.

Analysis of Variance↗
PubMed1990

Reversion to a homocysteine-responsive phenotype in a human melanoma cell line is associated with diminished growth potential and increased methionine biosynthesis.

Our aim was to determine if the isolation of cells capable of proliferating in methionine-free homocysteine-containing medium, from the human MeWo-LC1 melanoma tumor cell line which is unable to proliferate or survive under such conditions, was associated with altered growth properties. Cells which were able to proliferate in methionine-free homocysteine-containing medium (homocysteine-responsive cells) were obtained from the homocysteine-nonresponsive MeWo-LC1 cell line after 8 months of continuous exposure to methionine-free homocysteine-containing medium. Unlike the parental MeWo-LC1 cell line, these homocysteine-responsive cells were also able to proliferate normally in methionine-free medium containing 5'-deoxy-5'-methylthioadenosine. In vitro growth rate, methionine requirement, and capacity to form colonies on soft agarose of these homocysteine-responsive cells were reduced compared to those of the homocysteine-nonresponsive parental MeWo-LC1 cell line. Unlike MeWo-LC1, these homocysteine-responsive cells were able to synthesize [3H]S-adenosylmethionine from [3H]adenine and homocysteine. The failure of the MeWo-LC1 cell line to proliferate in methionine-free homocysteine-containing medium may be due to a deficiency in the synthesis of methionine from homocysteine and 5-methyltetrahydrofolic acid. These results indicate that acquisition of a homocysteine-responsive phenotype in homocysteine-nonresponsive malignant human tumor cells is associated with a reduction in the autonomous growth potential of such cells.

Adenosine↗
PubMed2005

Homocysteine promotes p38-dependent chemotaxis in bovine aortic smooth muscle cells.

OBJECTIVE: Increased levels of homocysteine in the blood are a risk factor for atherosclerosis. The purpose of this study was to examine the effects of homocysteine on smooth muscle cell (SMC) migration and to determine whether p38 was involved in this process. METHODS: The effect of 0.5 to 2.0 mmol/L d , l -homocysteine as a chemoattractant for SMCs was assayed with a modified Boyden chamber. To determine the functional role of p38 in SMC chemotaxis induced by d , l -homocysteine, we treated SMCs with a p38 inhibitor, SB203580, before the assay. RESULTS: The number of migrated cells was increased 7.0 +/- 1.2-fold (n = 15; P < .001) by 2.0 mmol/L d , l -homocysteine. SB203580 partially prevented the migration of SMCs toward homocysteine. Preconditioning SMCs with 2.0 mmol/L d , l -homocysteine significantly enhanced chemotaxis toward 10% fetal bovine serum compared with nonconditioned control SMCs (28.9 +/- 3.3-fold vs 15.6 +/- 2.8-fold; P < .05). There was a fourfold p38 activation after exposure of SMCs to 2.0 mmol/L d , l -homocysteine by immunoblot. CONCLUSIONS: These results suggest that homocysteine not only is a chemoattractant for SMC but can also enhance SMC chemotactic potential. The mechanism of these effects may involve p38 activation. CLINICAL RELEVANCE: This study demonstrates that homocysteine can promote chemotaxis of SMCs through a p38-dependent pathway. To our knowledge, this is the first report that homocysteine may influence SMC chemotaxis. It may be an important mechanism for homocysteine-induced atherogenesis, because the migration of SMCs from the media is believed to play a critical role in progressive intimal thickening. Although homocysteine promotes atherogenesis and thrombosis by a variety of mechanisms, the effects of homocysteine on SMC proliferation and migration might be critical elements that may have potential therapeutic implications, because selective blockade of the p38 pathway is feasible.

Animals↗
PubMed2006

Ginkgolide A attenuates homocysteine-induced endothelial dysfunction in porcine coronary arteries.

BACKGROUND: Homocysteine is an independent risk factor for atherosclerosis. The objective of this study was to investigate whether ginkgolide A (GA), a major constituent of Ginkgo biloba, could block homocysteine-induced endothelial dysfunction in porcine coronary arteries. METHODS: Porcine coronary artery rings were assigned to six treatment groups: control; homocysteine (50 micromol/L); low-dose (50 micromol/L) or high-dose (100 micromol/L) GA; and homocysteine plus low-dose or high-dose GA. After 24 hours' incubation, the rings were analyzed for vasomotor function in response to a thromboxane A2 analogue (U46619), bradykinin, and sodium nitroprusside. Endothelial nitric oxide synthase (eNOS) was studied by using real-time polymerase chain reaction and immunohistochemistry analysis. Superoxide anion production was assessed by chemoluminescence analysis. RESULTS: Endothelium-dependent relaxation (bradykinin) was significantly reduced in ring segments treated with homocysteine as compared with the control (P < .05). When homocysteine was combined with either low-dose or high-dose GA, endothelium-dependent relaxation was markedly recovered. There was no significant difference in maximal contraction (U46619) or endothelium-independent relaxation (sodium nitroprusside) among all groups. In addition, superoxide anion production was increased by 113% in the homocysteine-treated group, whereas there was no statistically significant difference between the control and GA/homocysteine groups. Furthermore, eNOS messenger RNA and protein levels were substantially reduced in the homocysteine-treated group (P < .05), but not in the GA/homocysteine combined groups. CONCLUSIONS: Homocysteine significantly impairs endothelium-dependent vasorelaxation through oxidative stress and downregulation of eNOS in porcine coronary arteries. GA effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores the potential clinical benefits and applications of GA in controlling homocysteine-associated vascular injury and cardiovascular disease. CLINICAL RELEVANCE: Homocysteine is an independent risk factor for atherosclerosis. This study showed that ginkgolide A, a major constituent of Ginkgo biloba, effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores potential clinical benefits and applications of ginkgolide A in controlling homocysteine-associated vascular injury and cardiovascular disease.

Animals↗
PubMed2005

High homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model.

Elevated plasma homocysteine has been found to be a risk factor for Alzheimer's disease as well as cerebral vascular disease, suggesting that some risk factors can accelerate or increase the severity of several CNS disease processes. We screened plasma total homocysteine levels of 193 schizophrenic patients vs. 762 controls for plasma homocysteine levels. The effect of schizophrenia was marked (p<0.0001) and mean homocysteine level was 16.3+/-12 (S.D.) microM in schizophrenic patients vs. 10.6+/-3.6 (S.D.) microM in healthy controls. The increase was almost entirely in young male schizophrenic patients. It seemed important to determine if this finding is already present in newly admitted schizophrenic patients. Serum homocysteine levels were studied in 184 consecutively admitted schizophrenic patients and 305 control subjects. Homocysteine levels were markedly increased in this population of newly admitted schizophrenic patients, especially in young males. However, no difference was found for CSF homocysteine levels between schizophrenia patients and controls. We also examined homocysteine levels in 41 euthymic outpatients with bipolar disorder. Functional deterioration in patients was rated as 'present' or 'absent' by consensus of two treating clinicians. Young male bipolar patients were found to have higher homocysteine levels than controls. Among the male subjects, bipolar patients showing deterioration had homocysteine levels which were significantly higher than other patients. We attempted to develop a model of homocysteine neurotoxicity in mice. Mice were fed homocysteine in water at a dose of 200 mg/kg per mouse per day. Independent samples of animals were studied at 2 to 6 months with behavioral tests including apomorphine-induced stereotypy and spatial learning and memory in the Morris Water Maze. Homocysteine levels were elevated up to 800% at months 5 and 6 by this procedure. No homocysteine-induced defects were found in any behavioral test until month 5 when mild but statistically significant abnormalities in the Morris Water Maze were detected.

Adolescent↗
PubMed2006

Effects of common anti-epileptic drug monotherapy on serum levels of homocysteine, vitamin B12, folic acid and vitamin B6.

There is emerging evidence to support the unfavorable effects of some anti-epileptic drugs on the plasma homocysteine concentrations. Elevated homocysteine levels induced by anti-epileptic drug administration can theoretically increase not only the risk of vascular occlusive diseases, but also the risk of resistance to anti-epileptics and development of refractory epilepsy. To investigate the effect of common anti-epileptic drugs on the homocysteine metabolism, a total of 75 epileptic patients receiving phenytoin (n=16), carbamazepine (n=19), or valproic acid (n=22) and no anti-epileptic drug (n=18) were enrolled. Eleven age- and sex-matched healthy subjects served as the control group. Blood concentrations of homocysteine, folic acid, Vitamin B12 and pyridoxal 5'-phosphate (active circulating form of Vitamin B6) were measured. Compared to the control group, epileptic patients on anti-epileptic drug had higher blood levels of homocysteine. No difference in homocysteine concentrations was observed among epileptic patients in terms of the anti-epileptic drug used. Patients receiving phenytoin had significantly lower folic acid levels and those receiving carbamazepine had marginally lower pyridoxal 5'-phosphate levels in comparison with those using other anti-epileptic drugs. A negative correlation between homocysteine and folic acid concentrations was detected in epileptic patients on anti-epileptic drug. The duration of anti-epileptic drug use was correlated to the decrease of folic acid levels, but not with changes observed in homocysteine, Vitamin B12 and pyridoxal 5'-phosphate levels. No relationship between seizure frequency and homocysteine levels was observed in epileptic patients. Our results confirm that common anti-epileptic drugs has disadvantageous effects on homocysteine status. Because there was no significant change in homocysteine concentrations in epileptic patients who were not receiving an anti-epileptic drug, and no positive correlation between seizure frequency and homocysteine levels, we suggest that increase of homocysteine levels may be due to anti-epileptic drug use, rather than being epileptic in origin. Additionally, the underlying mechanism for homocysteine increase seems to be a decrease of cofactor molecules in patients using carbamazepine and phenytoin (pyridoxal 5'-phosphate and folic acid, respectively). However, changes observed are not related to the alteration in the levels of cofactors and remain unclear in the patients using valproic acid.

Adolescent↗
PubMed1999

Genetic and nongenetic factors influencing plasma homocysteine levels in patients with ischemic cerebrovascular disease and in healthy control subjects.

Moderately elevated plasma homocysteine levels have been established as an independent risk factor for atherosclerosis and its complications, including cerebrovascular disease. A common mutation (C677T) in the gene encoding for the enzyme methylenetetrahydrofolate reductase (MTHFR) has been linked to increased plasma homocysteine levels in homozygous carriers, particularly in the presence of low folate levels. However, the results of most of the previous studies suggest that the C677T MTHFR mutation is not a significant risk factor for arterial disease. This discrepancy might, at least partly, be due to the fact that plasma homocysteine levels are influenced by several other factors, including age, gender, renal function, and vitamin status. We investigated the relation between plasma homocysteine levels, the C677T MTHFR mutation, and these other factors in a population of 96 patients with transient ischemic attacks or minor strokes and in 96 age- and sex-matched healthy control subjects. We further tested the value of a multivariate model for the prediction of plasma homocysteine levels under particular consideration of the MTHFR mutation status. In the patients, plasma homocysteine levels were significantly higher than in the healthy control subjects. With regard to the MTHFR mutation, the distribution of the C/C, C/T, and T/T genotypes was not significantly different between patients and healthy control subjects. Univariate (linear regression) analysis revealed significant (positive) correlations between plasma homocysteine levels on the one hand and age and creatinine on the other, the latter particularly in subjects with creatinine levels in the upper quartile. Significant (negative) correlations were found between plasma homocysteine levels, vitamin B12, and folate levels. However, these relations could much better be expressed by means of a multiplicative regression model. T/T subjects exhibited slightly higher homocysteine levels than C/C and C/T subjects; however, the differences between the 3 genotypes were not significant. Multivariate (stepwise regression) analysis revealed age, vitamin B12 levels, folate levels, and creatinine levels as significant independent variables influencing plasma homocysteine levels, whereas the MTHFR mutation status and gender were removed from the model. Considering all 192 subjects, only 28.8% of the variance of plasma homocysteine levels could be accounted for by the model. However, in homozygous carriers of the MTHFR mutation, the predictive power of the model is very high, explaining 76.1% of the variance of plasma homocysteine levels. According to our results, the C677T mutation does not constitute a major risk factor for transient ischemic attack or minor stroke, even under consideration of other possibly confounding factors that are known to affect plasma homocysteine levels. However, it is possible to predict plasma homocysteine levels in homozygous carriers of the mutation with high accuracy. The knowledge of the MTHFR mutation status may therefore help to identify subjects at high risk for hyperhomocysteinemia.

Adult↗
PubMed1999

Folic acid inhibits homocysteine-induced proliferation of human arterial smooth muscle cells.

PURPOSE: An elevated plasma homocysteine level has been identified as an independent risk factor for atherosclerosis. Whether this represents a marker for vascular disease or a direct effect on the vasculature remains unclear. Because vascular smooth muscle cells (VSMCs) play an integral role in the atherosclerotic process, we studied the effect of homocysteine on human infragenicular VSMC proliferation and the role of folic acid in reversing the homocysteine effect. METHODS: Human infragenicular VSMCs harvested from amputation specimens were studied. Various cell groups were exposed to physiologic (6.25 micromol/L and 12.5 micromol/L) and pathologic (25 micromol/L to 500 micromol/L) concentrations of homocysteine. Similar groups were simultaneously exposed to 20 nmol/L of folic acid. Cell counts and DNA synthesis, as reflected by [methyl-(3)H]-thymidine incorporation, were performed at 6 days and 24 hours, respectively. Additional groups were exposed to various combinations of folic acid (20 nmol/L), vitamin B(6) (145 nmol/L), and vitamin B(12) (0.45 nmol/L) in the presence of homocysteine (25, 50, and 250 micromol/L). RESULTS: Homocysteine resulted in a dose-dependent increase in DNA synthesis and cell proliferation. Cell counts increased significantly at homocysteine concentrations ranging from 25 micromol/L to 500 micromol/L (P <.05), with a maximal increase of 98% at 500 micromol/L of homocysteine. The addition of 20 nmol/L folic acid resulted in significant inhibition of cell proliferation at all homocysteine concentrations studied (P <.001). Maximal inhibition of 70% occurred in the cells exposed to 50 micromol/L of homocysteine. The increases in [methyl-(3)H]-thymidine incorporation ranged from 36% at 6 micromol/L homocysteine to a maximum of 247% at 500 micromol/L homocysteine. All increases were statistically significant (P <.05). The addition of 20 nmol/L folic acid resulted in significant inhibition of DNA synthesis (P <.002). Vitamins B(6) and B(12) did not demonstrate significant antiproliferative properties. CONCLUSION: A possible role of homocysteine in the formation of atherosclerotic lesions is through a direct proliferative effect on VSMCs in a dose-dependent fashion. Folic acid intake at levels available in dietary supplements may prove protective in hyperhomocysteinemia-induced atherosclerosis. Vitamins B(6) and B(12) alone do not appear to exhibit a substantial inhibitory effect in the setting of elevated homocysteine levels.

Cell Division↗
PubMed1999

Plasma homocysteine concentration related to diet, endothelial function and mononuclear cell gene expression among male hyperlipidaemic smokers.

BACKGROUND: Elevated plasma concentration of homocysteine is an independent risk factor for development of cardiovascular diseases. MATERIALS AND METHODS: We evaluated potential links between homocysteine and atherothrombogenesis by relating the plasma concentration of homocysteine to (i) dietary antioxidants and omega-3 fatty acids (and determined influence of intervention with antioxidants or omega-3 fatty acids); (ii) markers of endothelial cell function; and (iii) peripheral blood mononuclear cell mRNA levels. RESULTS: We observed an inverse relationship between the plasma homocysteine concentration and dietary intake of vegetables, vitamin C and beta-carotene and between homocysteine and the serum concentration of folate, vitamin B12 and omega-3 fatty acids. Intervention with antioxidants or omega-3 fatty acids did not affect plasma homocysteine concentration. The plasma levels of cysteinylglycine and vitamin B12 correlated positively with circulating E-selectin and VCAM-1, respectively, whereas folate in serum and blood correlated negatively with P-selectin. A negative correlation was found between the concentrations of homocysteine and von Willebrand factor. Negative and positive correlations were found between plasma homocysteine and the mononuclear cell mRNA levels of peroxisome proliferator activated receptor delta (PPAR delta) and c-myc respectively. A negative correlation was also found between plasma homocysteine and mononuclear cell mRNA levels of the proteoglycan serglycin. Homocysteine was not correlated with serum activity of glutathione peroxidase or with the mRNA level of glutathione peroxidase in mononuclear cells. CONCLUSION: The plasma homocysteine level was negatively correlated with dietary intake of vegetables, including vitamins C and E, and serum omega-3 fatty acids, whereas supplementation with antioxidants or omega-3 fatty acids did not affect plasma homocysteine concentration. Homocysteine was not associated with circulating adhesion molecules or increased procoagulant activity, but homocysteine may alter mononuclear cell gene expression. Cysteine showed no significant correlation with these parameters.

Adult↗
PubMed2001

Albumin thiolate anion is an intermediate in the formation of albumin-S-S-homocysteine.

An elevated concentration of plasma total homocysteine is an independent risk factor for cardiovascular disease. Greater than 80% of circulating homocysteine is covalently bound to plasma protein by disulfide bonds. It is known that albumin combines with cysteine in circulation to form albumin-Cys(34)-S-S-Cys. Studies are now presented to show that the formation of albumin-bound homocysteine proceeds through the generation of an albumin thiolate anion. Incubation of human plasma with l-(35)S-homocysteine results in the association of >90% of the protein-bound (35)S-homocysteine with albumin as shown by nonreduced SDS-polyacrylamide gel electrophoresis. Treatment of the complex with beta-mercaptoethanol results in near quantitative release of the bound l-(35)S-homocysteine, demonstrating that the binding of homocysteine to albumin is through a disulfide bond. Furthermore, using an in vitro model system to study the mechanisms of this disulfide bond formation, we show that homocysteine binds to albumin in two steps. In the first step homocysteine rapidly displaces cysteine from albumin-Cys(34)-S-S-Cys, forming albumin-Cys(34) thiolate anion and homocysteine-cysteine mixed disulfide. In the second step, albumin thiolate anion attacks homocysteine-cysteine mixed disulfide to yield primarily albumin-Cys(34)-S-S-Hcy and to a much lesser extent albumin-Cys(34)-S-S-Cys. The results clearly suggest that when reduced homocysteine enters circulation, it attacks albumin-Cys(34)-S-S-Cys to form albumin-Cys(34) thiolate anion, which in turn, reacts with homocysteine-cysteine mixed disulfide or homocystine to form albumin-bound homocysteine.

Albumins↗
PubMed2001

Relative roles of albumin and ceruloplasmin in the formation of homocystine, homocysteine-cysteine-mixed disulfide, and cystine in circulation.

Disulfide forms of homocysteine account for >98% of total homocysteine in plasma from healthy individuals. We recently reported that homocysteine reacts with albumin-Cys(34)-S-S-cysteine to form homocysteine-cysteine mixed disulfide and albumin-Cys(34) thiolate anion. The latter then reacts with homocystine or homocysteine-cysteine mixed disulfide to form albumin-bound homocysteine (Sengupta, S., Chen, H., Togawa, T., DiBello, P. M., Majors, A. K., Büdy, B., Ketterer, M. E., and Jacobsen, D. W. (2001) J. Biol. Chem. 276, 30111-30117). We now extend these studies to show that human albumin, but not ceruloplasmin, mediates the conversion of homocysteine to its low molecular weight disulfide forms (homocystine and homocysteine-cysteine mixed disulfide) by thiol/disulfide exchange reactions. Only a small fraction of homocystine is formed by an oxidative process in which copper bound to albumin, but not ceruloplasmin, mediates the reaction. When copper is removed from albumin by chelation, the overall conversion of homocysteine to its disulfide forms is reduced by only 20%. Ceruloplasmin was an ineffective catalyst of homocysteine oxidation, and immunoprecipitation of ceruloplasmin from human plasma did not inhibit the capacity of plasma to mediate the conversion of homocysteine to its disulfide forms. In contrast, ceruloplasmin was a highly efficient catalyst for the oxidation of cysteine and cysteinylglycine to cystine and bis(-S-cysteinylglycine), respectively. However, when thiols (cysteine and homocysteine) that are disulfide-bonded to albumin-Cys(34) are removed by treatment with dithiothreitol to form albumin-Cys(34)-SH (mercaptalbumin), the conversion of homocysteine to its disulfide forms is completely blocked. In conclusion, albumin mediates the formation of disulfide forms of homocysteine by thiol/disulfide exchange, whereas ceruloplasmin converts cysteine to cystine by copper-dependent autooxidation.

Ceruloplasmin↗
PubMed2004

The dose-response relation between serum homocysteine and cardiovascular disease: implications for treatment and screening.

BACKGROUND: With the recognition that serum homocysteine may cause cardiovascular disease there is clinical interest in homocysteine measurement to guide treatment with folic acid. It is uncertain whether treatment is best directed at those with high homocysteine or those at high risk irrespective of initial homocysteine. DESIGN AND METHODS: Dose-response plots of the associations between serum homocysteine and ischaemic heart disease and deep vein thrombosis were determined from retrospective (case-control) studies (a meta-analysis of 12 age-matched studies) prospective studies and studies of the C677T MTHFR polymorphism (a comparison of risk in three genotypes in a meta-analysis of 72 studies). The value of serum homocysteine as a screening test was assessed from distributions of serum homocysteine in men who did and did not die from ischaemic heart disease in a large prospective study. RESULTS: There were straight-line relationships between serum homocysteine and disease events in the three types of study; a given decrease in homocysteine would produce a similar proportional risk reduction from any pre-treatment level. There was substantial overlap between the distributions of serum homocysteine in men who did and did not die of ischaemic heart disease, indicating poor screening performance; there was no serum homocysteine cut-off that concentrated the majority of disease events into a small minority of the population. CONCLUSION: Interventions to lower serum homocysteine, if judged to be worthwhile, should not be limited to people with a high homocysteine but should be offered to everyone at high risk, regardless of pre-treatment homocysteine.

Adult↗
PubMed2005

Effect of folic acid on methionine and homocysteine metabolism in end-stage renal disease.

BACKGROUND: The pathogenesis of hyperhomocysteinemia in end-stage renal disease (ESRD) is unclear. Folic acid lowers, but does not normalize, the plasma homocysteine level in patients with ESRD, but its effect on whole body metabolism of homocysteine is unknown. METHODS: We studied the effect of 3 weeks of oral treatment with 5 mg folic acid per day on homocysteine metabolism in six chronic hemodialysis patients and six healthy controls. Primed, continuous infusions with [(2)H(3)-methyl-1-(13)C] methionine were used to determine flux rates of methionine transmethylation, homocysteine remethylation, and homocysteine transsulfuration. Metabolic homocysteine clearance was defined as the ratio of transsulfuration and plasma homocysteine level. RESULTS: Folic acid treatment lowered plasma homocysteine significantly by 39% (95% CI 5 to 73) in the ESRD group, but plasma homocysteine remained higher than baseline values in the control group. In ESRD patients, homocysteine remethylation and methionine transmethylation rate increased by 34% (95% CI 5 to 62) and 22% (95% CI 5 to 39), respectively (i.e., levels that were similar to the baseline values of the control group). Transsulfuration rate and metabolic homocysteine clearance were not significantly altered by folic acid treatment in both the ESRD and the control group. CONCLUSION: In ESRD patients, folic acid treatment lowers, but does not normalize plasma homocysteine, whereas homocysteine remethylation and methionine transmethylation increase to levels found in untreated healthy controls. These findings indicate a persistent, folate-independent, defect in metabolic homocysteine clearance in ESRD.

Administration, Oral↗