Homocysteine Abstracts

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The following is a collection of homocysteine abstracts from published scientific research and papers. Integratedhealth.com has designed Homocysteine Calm with homocysteine research in mind. Readers might also be interested in Vitamin B-12, Folic Acid, and Folinic Acid.

(REFERENCE 1 OF 15)

Lewerin C, Nilsson-Ehle H, Matousek M, Lindstedt G, Steen B.

Reduction of plasma homocysteine and serum methylmalonate concentrations in apparently healthy elderly subjects after treatment with folic acid, vitamin B(12) and vitamin B(6): a randomised trial.

Eur J Clin Nutr. 2003 Nov;57(11):1426-36.

OBJECTIVES: To investigate, in an elderly population: (1) the effects of oral B-vitamin therapy on P-tHcys, S-MMA and Hb/MCV, (2) the appropriate decision limit for ‘high’ metabolite concentrations and (3) the estimated prevalence of vitamin B(12)/folate deficiency on the basis of different decision limits.

DESIGN: Double-blind placebo-controlled intervention study.

SETTING: Outpatient clinic. SUBJECTS: A total of 209 community-dwelling subjects, median age 76 y (range 70-93) y.

INTERVENTION: Four months of oral daily supplementation with 0.5 mg cyanocobalamin, 0.8 mg folic acid and 3 mg vitamin B(6).

RESULTS: High P- tHcys was found in 64% of men and 45% of women, high S-MMA in 11% of both. Vitamin B(12) deficiency was observed in 7.2% and folate deficiency in 11% of all subjects. Health-related upper reference limits for the metabolites at the start were higher than the laboratory’s upper reference limits. The latter were, however, similar to those of the vitamin replete group. There was a significant decrease in P-tHcys (P<0.001) and S-MMA (P=0.009) after 4 months of vitamin treatment. In a multivariate analysis, the P-Hcys change correlated positively with baseline P-tHcys and inversely with baseline P-folate and transferrin saturation (Fe/TIBC ratio). The S-MMA change correlated with baseline S-MMA and inversely with baseline vitamin B(12) and age.

CONCLUSIONS: Suboptimal vitamin status is an important cause of elevated P-tHcys and S-MMA in apparently healthy elderly subjects. Oral B-vitamin therapy is an effective and convenient way to normalise P-tHcys and S-MMA.

SPONSORSHIP: Support-Recip AB.European Journal of Clinical Nutrition (2003) 57, 1426-1436. doi:10.1038/sj.ejcn.1601707

Department of Haematology and Coagulation, Goteborg University, Goteborg, Sweden.

 

(REFERENCE 2 OF 15)

Colleran KM, Ratliff DM, Burge MR.

Potential association of thyrotoxicosis with vitamin B and folate deficiencies, resulting in risk for hyperhomocysteinemia and subsequent thromboembolic events.

Endocr Pract. 2003 Jul-Aug;9(4):290-5.

OBJECTIVE: To describe a patient with severe thyrotoxicosis attributable to Graves’ disease who had a thrombotic cerebrovascular accident and hyperhomocysteinuria, which resolved on correction of the thyrotoxicosis, and to present findings in a pilot study undertaken to investigate the relationship among thyrotoxicosis, homocysteine, folate, and vitamin B(12).

METHODS: We present a case report of the index case, with clinical and laboratory details. For the investigative analysis, 21 patients who were 18 to 50 years old and had newly diagnosed, untreated Graves’ disease and 10 age-and sex-matched euthyroid control subjects were studied. Of the patients with Graves’ disease, 11 underwent studies both at diagnosis and after treatment. Fasting blood tests were performed for thyrotropin, free thyroxine, homocys-teine, vitamin B(12), folate, and methylmalonic acid, a marker of vitamin B(12) deficiency. RESULTS: Vitamin B(12), folate, homocysteine, and methylmalonic acid levels were not significantly different between the thyrotoxic and control or posttreatment groups. In patients with thyrotoxicosis, however, free thyroxine was positively correlated with both homocysteine (r = 0.67; P = 0.03) and methylmalonic acid (r = 0.89; P = 0.003).

CONCLUSION: The positive correlation between free thyroxine levels and both homocysteine and methylmalonic acid suggests that thyrotoxicosis may be associated with functional vitamin B(12) deficiency. Such a deficiency may result in clinically important hyperhomocysteine-mia.

Department of Internal Medicine, University of New Mexico, School of Medicine, Albuquerque, New Mexico.

 

(REFERENCE 3 OF 15)

Kadziela J, Janas J, Dzielinska Z, Szperl M, Gazdzik D, Chotkowska E, Piotrowski W, Ruzyllo W.

The C677T mutation in methylenetetrahydrofolate reductase gene, plasma homocysteine concentration and the risk of coronary artery disease.

Kardiol Pol. 2003 Jul;59(7):17-26; discussion 26.

BACKGROUND: The C677T mutation in methylenetetrahydrofolate reductase (MTHFR) gene is one of the causes of an elevated homocysteine plasma concentration and is probably one of the atherosclerotic risk factors. AIM. To assess the relationship between the presence of the MTHFR gene mutation, plasma homocysteine concentration and the risk of coronary artery disease (CAD).

METHODS: The study group consisted of 120 consecutive patients (78% were male, mean age 59.2+/-9.6 years) with angiographically confirmed CAD and 106 healthy volunteers (76% were male, mean age 47.4+ or -6.0 years). The MTHFR gene mutation was detected based on the polymerase chain reaction and digestion with restrictive endonuclease HinfI. Total homocysteine plasma concentration was measured using HPLC. Folic acid and vitamin B12 plasma levels were assessed using the chemiluminescence method. Hyperhomocysteinemia was defined as homocysteine concentration > or =90 percentile of the control group which was > or =12.4 micro mol/L.

RESULTS: The incidence of the mutation of allele T and the genotype TT was similar in patients and controls (51.7% vs 56.6%, and 9.2% vs 10.4%, NS, respectively). The folic acid and vitamin B12 levels were not related to the MTHFR genotype (folic acid: 8.1 ng/L in homozygotes TT vs 8.6 in heterozygotes CT and 8.3 in homozygotes CC; and vitamin B12: 273 pg/L vs 303.3 vs 314.3, respectively). Although homozygotes TT had significantly higher homocysteine concentration than heterozygotes and homozygotes CT or CC (15.4 vs 11.0 vs 11.2 micro mol/L, p<0.001), the odds ratio for CAD in genotype TT was 0.87 (95% CI 0.5-2.1, NS). The odds ratio in subjects with at least one mutated T allele was 0.82 (95%CI 0.5-1.4, NS). Homocysteine plasma concentration was significantly higher in patients with CAD than controls (12.8+/-5.1 vs 10.0+/-5.0 micro mol/L, p<0.001) and correlated significantly with folic acid (r= -0.28, p=0.0001), vitamin B12 (r= -0.19, p<0.005), age (r=0.35, p=0.0001) and creatinine (r=0.26, p=0.0001). The odds ratio for CAD in subjects with hyperhomocysteinemia was 7.1 (95%CI 3.4-14.9, p=0.001) and was 2.6 (95%CI 1.6-4.1, p=0.0001) with a homocysteine increase of 5 micro mol/L. Multivariate analysis showed that hyperhomocysteinemia was an independent risk factor of CAD (OR 2.7, 95%CI 1-7.2, p<0.05).

CONCLUSIONS: Hyperhomocysteinemia rather than a mutation in the methylenetetrahydrofolate reductase gene, is an independent risk factor of coronary artery disease.

1st Department of Coronary Artery Disease, National Institute of Cardiology, Warsaw, Poland.

 

(REFERENCE 4 OF 15)

van den Bosch MA, Bloemenkamp DG, Mali WP, Kemmeren JM, Tanis BC, Algra A, Rosendaal FR, van der Graaf Y.

Hyperhomocysteinemia and risk for peripheral arterial occlusive disease in young women.

J Vasc Surg. 2003 Oct;38(4):772-8.

OBJECTIVE: Few studies to date have examined the relationship between hyperhomocysteinemia and peripheral arterial occlusive disease (PAOD) in young women. In this study we assessed hyperhomocysteinemia as a risk factor for PAOD in young women. In addition, we evaluated the effect of joint exposure to hyperhomocysteinemia and traditional risk factors.

METHODS: Two hundred twenty women, ages 18 to 49 years, with PAOD and 629 healthy women (control group) from a population-based case-control study filled out the same structured questionnaire and donated venous blood samples for determination of plasma homocysteine levels. Hyperhomocysteinemia was defined as nonfasting total plasma homocysteine level above the 90th percentile of the control range.

RESULTS: Young women with hyperhomocysteinemia had a 2.5-fold (95% confidence interval [CI], 1.7-3.9) increased risk for PAOD. When presence of hyperhomocysteinemia was combined with presence of a traditional risk factor, relative risk strongly increased in smokers (odds ratio [OR], 18.9; 95% CI, 8.3-42.9) and in women with hypertension (OR, 10.3; 95% CI, 5.4-19.8), hypercholesterolemia (OR, 8.5; 95% CI, 4.2-17.1), and diabetes (OR, 8.9; 95% CI, 1.7-46.9).

CONCLUSIONS: Hyperhomocysteinemia is a risk factor for PAOD in young women. There is a strong synergistic effect between hyperhomocysteinemia and all traditional vascular risk factors. Our findings may have implications for risk management in these young women.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.

 

(REFERENCE 5 OF 15)

Earnest CP, Wood KA, Church TS.

Complex multivitamin supplementation improves homocysteine and resistance to LDL-C oxidation.

J Am Coll Nutr. 2003 Oct;22(5):400-7.

OBJECTIVE: We previously reported in an open-label pilot trial that a 24-ingredient multivitamin formula favorably influenced homocysteine concentration and LDL-C oxidation indices following 24 weeks of supplementation. Our current aim was to more thoroughly examine this same formula in a randomized, placebo-controlled, clinical study.

METHODS: We examined 182 participants for selected plasma vitamin concentrations and clinically relevant variables including homocysteine, lipids and LDL-C oxidation indices at baseline and six months.

RESULTS: We found no significant differences between groups for any parameter at baseline. Following six months of vitamin supplementation, we observed elevations in plasma concentrations of vitamin B6 (as pyridoxal 5′-phosphate; PLP), vitamin B12, folate, vitamin C, vitamin E and beta-carotene (p < 0.0001), all of which were significantly greater than respective placebo group changes (p < 0.0001). Homocysteine decreased in the treatment (8.38 +/- 2.9 vs. 6.93 +/- 2.5 micro mol/L; p < 0.0001) and placebo group (8.17 +/- 3.0 vs. 7.42 +/- 2.2 micro mol/L; p < 0.0001) from baseline to six months, respectively, with reductions in the treatment group being greater than placebo (p < 0.008). LDL-C oxidation indices were also improved as LDL-C oxidation rate was decreased (-0.39 micro mol/min/g protein; p < 0.0003) and LDL-C lag time increased (11.3 min; p < 0.003) in supplemented participants. Further analysis also showed that LDL-C oxidation rate was lower (p < 0.0007) and LDL-C lag time longer (p < 0.0001) for the vitamin group than placebo treatment after six months.

CONCLUSION: We conclude that a multi-ingredient vitamin formula with antioxidant properties has measurable effects on homocysteine and LDL-C oxidation indices.

The Cooper Institute, Dallas Texas 75230, USA. cearnest@cooperinst.org

 

(REFERENCE 6 OF 15)

Schofield RS, Wessel TR, Walker TC, Cleeton TS, Hill JA, Aranda JM Jr.

Hyperhomocysteinemia in patients with heart failure referred for cardiac transplantation: preliminary observations.

Clin Cardiol. 2003 Sep;26(9):407-10.

BACKGROUND: Hyperhomocysteinemia is becoming recognized as a risk factor for cardiovascular disease, yet there are limited data on the prevalence of hyperhomocysteinemia in patients with heart failure.

HYPOTHESIS: The purpose of this study was to examine the prevalence of hyperhomocysteinemia in patients with severe heart failure and to correlate serum homocysteine levels with factors that may affect homocysteine metabolism.

METHODS: Serum homocysteine levels were measured at the time of cardiac transplant evaluation in 89 consecutive patients with severe heart failure. Homocysteine levels for patients with ischemic cardiomyopathy (ICM) were compared with levels obtained in patients with nonischemic cardiomyopathy (NICM), and homocysteine levels were correlated with demographic and hemodynamic parameters as well as functional status.

RESULTS: The mean plasma homocysteine level was increased (14.3 +/- 5.3 micromol/l, normal <9.0 micromol/l) and was equivalent between patients with ICM versus NICM (14.7 +/- 5.8 micromol/l vs. 13.8 +/- 4.5 micromol/l, p = 0.44). Elevated homocysteine levels were seen in a large proportion (89%) of patients and were equally common to patients with NICM (94%) and ICM (85%). Serum homocysteine levels correlated with serum creatinine (r = 0.51, p < 0.001), with a history of diabetes (p = 0.028), and with a history of peripheral vascular disease (p = 0.045). Only 6% of patients were receiving folic acid therapy at the time of transplant referral.

CONCLUSION: Hyperhomocysteinemia is common in patients with severe heart failure, and plasma homocysteine levels are uniformly elevated regardless of the etiology of heart failure. Elevated plasma homocysteine levels are likely a consequence of heart failure-related renal insufficiency.

Division of Cardiovascular Medicine and Shands Transplant Center, University of Florida College of Medicine, Gainesville, Florida, USA. schofrs@medicine.ufl.edu

 

(REFERENCE 7 OF 15)

Wolters M, Hermann S, Hahn A.

B vitamin status and concentrations of homocysteine and methylmalonic acid in elderly German women.

Am J Clin Nutr. 2003 Oct;78(4):765-72.

BACKGROUND: Prior investigations found that elderly persons are at higher risk than are younger persons for B vitamin deficiency, which leads to elevated plasma total homocysteine (tHcy) concentrations that are associated with an increased risk for certain diseases such as coronary artery disease. To date, published data have shown decreased vitamin status and elevated tHcy among the elderly.

OBJECTIVE: We evaluated the dietary intake and the blood status of various B vitamins and tHcy and methylmalonic acid (MMA) concentrations in 178 younger (60-70-y-old) female seniors.

DESIGN: Dietary intake was assessed with a 3-d diet record. Thiamine, riboflavin, and vitamin B-6 activity coefficients of erythrocyte transketolase (EC 2.2.1.1), erythrocyte glutathione reductase (EC 1.6.4.2), and erythrocyte alpha-aspartic aminotransferase (EC 2.6.1.1) were used as functional indexes for the status of the 3 vitamins, respectively. Concentrations of serum and red blood cell folate, serum cobalamin and MMA, and plasma tHcy were measured.

RESULTS: Indexes of thiamine, pyridoxine, and cobalamin indicated insufficient status in one-third of the women, whereas tHcy and MMA concentrations were elevated in 17.4% and 9.6% of the women, respectively. An association between vitamin intake and vitamin concentration in the blood was found only for folate. The mean tHcy concentration in subjects in the lowest quartile of serum folate concentration was 23% higher than that in subjects in the highest quartile. There was no association between riboflavin and tHcy concentrations. MMA was positively correlated with age and inversely correlated with serum cobalamin concentration.

CONCLUSIONS: Even in younger, well-educated, female seniors, the prevalence of low B vitamin status and elevated plasma tHcy concentration is high. Thiamine, pyridoxine, folate, and cobalamin supplementation should be considered.

Institute of Food Science, Department of Applied Chemistry, University of Hanover, Hanover, Germany. maike.wolters@lw.uni-hannover.de

 

(REFERENCE 8 OF 15)

Cotter AM, Molloy AM, Scott JM, Daly SF.

Elevated plasma homocysteine in early pregnancy: a risk factor for the development of nonsevere preeclampsia.

Am J Obstet Gynecol. 2003 Aug;189(2):391-4; discussion 394-6.

OBJECTIVE: We have recently demonstrated that an elevated plasma homocysteine in early pregnancy is associated with the development of severe preeclampsia. The aim of this study was to determine whether an elevated plasma homocysteine in early pregnancy is also associated with the development of nonsevere preeclampsia.

STUDY DESIGN: Blood was obtained from patients attending for a first antenatal visit. Subjects were asymptomatic women who subsequently developed nonsevere preeclampsia. Controls were matched for parity, gestational age, and date of sample collection. Plasma homocysteine was measured using fluorescence polarization immunoassay.

RESULTS: There were 71 cases of nonsevere preeclampsia sampled at a mean gestational age (+/-SD) of 15.9+/-3.6 weeks and 142 controls at 15.6+/-3.4 weeks. The preeclampsia cases had a mean (+/-SD) homocysteine level of 8.4+/-2.4 micromol/L, whereas controls had a mean homocysteine of 7.07+/-1.5 micromol/L (P</=.0001).

CONCLUSION: Women who develop nonsevere preeclampsia have higher plasma homocysteine levels in early pregnancy compared with women who remain normotensive throughout pregnancy. An elevated plasma homocysteine value in early pregnancy may be associated with a 4-fold increased risk for development of nonsevere preeclampsia.

Department of Biochemistry, Trinity College Dublin and Coombe Women’s Hospital, Dublin, Ireland. acotter@med.miami.edu

 

(REFERENCE 9 OF 15)

Aronow WS.

Homocysteine. The association with atherosclerotic vascular disease in older persons.

Geriatrics. 2003 Sep;58(9):22-4, 27-8.

Plasma homocysteine is a risk factor for coronary artery disease, stroke, peripheral arterial disease, extracranial carotid arterial disease, aortic atherosclerosis, deep vein thrombosis, and possibly dementia and Alzheimer’s disease in older persons. Randomized trials are in progress investigating whether multivitamin therapy with folic acid, vitamin B12, and vitamin B6 to reduce plasma homocysteine levels will reduce the risk for atherosclerotic vascular disease.

Department of Medicine, Divisions of Cardiology and Geriatrics, New York Medical College, Valhalla, NY, USA.

 

(REFERENCE 10 OF 15)

Nagga K, Rajani R, Mardh E, Borch K, Mardh S, Marcusson J.

Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia.

Dement Geriatr Cogn Disord. 2003;16(4):269-75.

The prevalence of dementia disorders, cobalamin and/or folate deficiency as well as gastritis increases with age. To investigate whether there is an association between these conditions, plasma homocysteine (Hcy), serum methylmalonic acid, serum cobalamin and blood folate concentrations were measured. Gastritis was indirectly diagnosed by measuring serum antibodies against H,K-ATPase, HELICOBACTER PYLORI and intrinsic factor, using enzyme-linked immunosorbent assays. The studied groups consisted of 47 patients with Alzheimer’s disease (AD), 9 with AD pathology in combination with additive vascular lesions, 59 with vascular dementia, 8 who were cognitively impaired, and 101 control cases. Plasma Hcy concentrations were significantly elevated in the dementia groups, with the highest levels in patients with vascular pathology. We conclude that hyperhomocysteinemia is a common finding in patients with dementia disorders of different etiologies. The markers for gastritis did not contribute to an elucidation of a possible connection between this condition, dementia disorders, or cobalamin/folate deficiency. Copyright 2003 S. Karger AG, Basel

Department of Geriatrics, University Hospital of Linkoping, Linkoping, Sweden. Katarina.Nagga@lio.se

 

(REFERENCE 11 OF 15)

Ho PI, Ashline D, Dhitavat S, Ortiz D, Collins SC, Shea TB, Rogers E.

Folate deprivation induces neurodegeneration: roles of oxidative stress and increased homocysteine.

Neurobiol Dis. 2003 Oct;14(1):32-42.

Clinical studies suggest a relationship between folate deficiency and neurological and disorders including Alzheimer’s disease (AD). To investigate mechanisms underlying this association, we examined the consequences of folate deprivation on neuronal cultures. Culturing embryonic cortical neurons and differentiated SH-SY-5Y human neuroblastoma cells in folate-free medium induced neurodegenerative changes characteristic of those observed in AD, including increased cytosolic calcium, reactive oxygen species (ROS), phospho-tau and apoptosis. In accord with clinical studies, generation of the neurotoxic amino acid homocysteine (HC) was likely to contribute to these phenomena, since (1) a significant increase in HC was detected following folate deprivation, (2) addition of the inhibitor of HC formation, 3-deazaadenosine, both prevented HC formation and eliminated the increase in ROS that normally accompanied folate deprivation, (3) direct addition of HC in the presence of folate induced the neurotoxic effects that accompanied folate deprivation, and (4) an antagonist of NMDA channels that blocks HC-induced calcium influx also blocked calcium influx following folate deprivation. Folate deprivation decreased the reduced form of glutathione, indicating a depletion of oxidative buffering capacity. This line of reasoning was supported by an increase in glutathione and reduction in ROS following supplementation of folate-deprived cultures with the cell-permeant glutathione precursor, N-acetyl-L-cysteine, or vitamin E. Folate deprivation potentiated ROS and apoptosis induced by amyloid-beta, while folate supplementation at higher concentrations prevented generation of ROS by amyloid-beta, suggesting that folate levels modulate the extent of amyloid-beta neurotoxicity. These findings underscore the importance of folate metabolism in neuronal homeostasis and suggest that folate deficiency may augment AD neuropathology by increasing ROS and excitotoxicity via HC generation.

Center for Cellular Neurobiology and Neurodegeneration Research, University of Massachusetts-Lowell, Lowell, MA 01854, USA.

 

(REFERENCE 12 OF 15)

Taylor LM Jr.

Elevated plasma homocysteine as risk factor for peripheral arterial disease–what is the evidence?

Semin Vasc Surg. 2003 Sep;16(3):215-22.

There is abundant evidence that elevated plasma homocysteine (HC) is independently associated with presence of atherosclerotic disease. There is credible evidence from a number of prospective studies that elevated HC is independently associated with progression of atherosclerotic disease. All studies to date agree that vitamin therapy, primarily folate, results in reliable decreases in HC, without recognized toxicity or side effects. Two small, randomized clinical trials have demonstrated clinically relevant benefit from folate treatment, which reduced HC in patients, compared to placebo. The results of multiple large scale clinical trials will be available within 2 to 5 years, and these have sufficient power to determine whether vitamin therapy intended to lower plasma HC will be established as the first effective therapy for atherosclerosis that does not involve expensive medication with toxic side effects and/or difficult changes in habits or lifestyle.

Oregon Health and Sciences University, Portland, OR 97201, USA.

 

(REFERENCE 13 OF 15)

Matetzky S, Freimark D, Ben-Ami S, Goldenberg I, Leor J, Doolman R, Novikov I, Eldar M, Hod H.

Association of elevated homocysteine levels with a higher risk of recurrent coronary events and mortality in patients with acute myocardial infarction.

Arch Intern Med. 2003 Sep 8;163(16):1933-7.

BACKGROUND: Despite the prothrombotic and proinflammatory effects associated with elevated homocysteine levels, only limited data exist regarding the effect of homocysteine levels on outcome of patients with acute myocardial infarction.

METHODS: Homocysteine levels were determined within 24 hours of presentation in 157 consecutive patients with acute myocardial infarction. Patients were allocated to 2 groups: those with homocysteine levels of 2.7 mg/L (20 micro mol/L) or more (n = 22 [14%]) and those with homocysteine levels of less than 2.7 mg/L (n = 135 [86%]).

RESULTS: Female and diabetic patients had significantly lower homocysteine levels than males (P<.01) and nondiabetic patients (P =.005), respectively, with no significant correlation with age (r = 0.07, P =.42) or other risk factors. Patients with homocysteine levels greater than or equal to 2.7 mg/L and less than 2.7 mg/L did not differ significantly regarding extent of coronary artery disease as reflected by prevalence of multivessel disease (54% vs 61%; P =.87), and their in-hospital course. However, in a mean +/-SD follow-up of 30 +/- 10 months, patients with homocysteine levels greater than or equal to 2.7 mg/L had a higher incidence of recurrent coronary events (36% vs 17%; P =.04) and death (18% vs 5%; P<.05). Homocysteine levels greater than or equal to 2.7 mg/L remain a significant determinant of recurrent coronary event and/or death after controlling for potential cofounders by multivariate analysis (odds ratio, 3.8; 95% confidence interval, 1.3-11.0).

CONCLUSIONS: In patients with acute myocardial infarction, elevated homocysteine levels are associated with a higher risk of recurrent coronary events and death, independent of other risk factors and the extent of coronary artery disease.

Heart Institute, Sheba Medical Center, Tel Hashomer, Israel.

 

(REFERENCE 14 OF 15)

Maeda M, Yamamoto I, Fujio Y, Azuma J.

Homocysteine induces vascular endothelial growth factor expression in differentiated THP-1 macrophages.

Biochim Biophys Acta. 2003 Sep 8;1623(1):41-6.

Hyperhomocysteinemia has been reported to be an independent risk factor for atherosclerosis and atherothrombosis. However, the molecular mechanism by which hyperhomocysteinemia can lead to atherosclerosis and atherothrombosis has not been completely described. Vascular endothelial growth factor (VEGF) has been proposed to play an important role in the progression of atherosclerosis. In the present study, we hypothesized that hyperhomocysteinemia might be associated with VEGF expression in atherosclerotic lesions. We investigated VEGF mRNA expression and VEGF secretion by homocysteine (Hcy) in differentiated THP-1 macrophages. As a result, it has been revealed that VEGF mRNA was upregulated by Hcy in a dose- and time-dependent manner in THP-1 macrophages with the increase in VEGF secretion. Importantly, other sulfur compounds, such as methionine and cysteine, showed no effect on VEGF expression, indicating that homocysteine specifically induced VEGF. Our findings suggest that hyperhomocysteinemia could promote the development of atherosclerotic lesions through VEGF induction in macrophages.

Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.

 

(REFERENCE 15 OF 15)

Barak AJ, Beckenhauer HC, Mailliard ME, Kharbanda KK, Tuma DJ.

Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats.

J Nutr. 2003 Sep;133(9):2845-8.

Previous studies showed that chronic ethanol administration inhibits methionine synthase activity, resulting in impaired homocysteine remethylation to form methionine. This defect in homocysteine remethylation was shown to increase plasma homocysteine and to interfere with the production of hepatic S-adenosylmethionine (SAM) in ethanol-fed rats. These changes were shown to be reversed by the administration of betaine, an alternative methylating agent. This study was undertaken to determine additional effects of ethanol on methionine metabolism and their functional consequences. The influences of methionine loading and betaine supplementation were also evaluated. Adult Wistar rats were fed ethanol or a control Lieber-DeCarli liquid diet for 4 wk, and metabolites of the methionine cycle were measured in vitro in isolated hepatocytes under basal and methionine-supplemented conditions. S-Adenosylhomocysteine (SAH) concentrations were elevated in hepatocytes isolated from ethanol-fed rats compared with controls and in hepatocytes from both groups when supplemented with methionine. The addition of betaine to the methionine-supplemented incubation media reduced the elevated SAH levels. The decrease in the intracellular SAH:SAM ratio due to ethanol consumption inhibited the activity of the liver-specific SAM-dependent methyltransferase, phosphatidylethanolamine methyltransferase. Our data indicate that betaine, by remethylating homocysteine and removing SAH, overcomes the detrimental effects of ethanol consumption on methionine metabolism and may be effective in correcting methylation defects and treating liver diseases.

VA Alcohol Research Center, Department of Veterans Affairs Medical Center, Omaha, NE 68105, USA. ajbarak@yahoo.com