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PubMedDate not supplied

[Plasma homocysteine measurement: a study of pre-analytical variation factors for conditions for total plasma homocysteine concentration].

An increase in homocysteine, a sulphur amino acid, is nowdays considered as a risk factor for cardiovascular diseases, and is independent of other risk factors. Reference range for total plasma homocysteine level in adults is usually 5-15 mmol/l. Hyperhomocysteinemia is defined as a fasting total plasma homocysteine level > 15 mmol/l. There may be also graded increased risks for subjects with homocysteinemia from 10 to 15 mmol/l. However, no threshold has been defined, partly because of the lack of standardization in pre-analytical and analytical steps. The aim of the present work was to evaluate three pre-analytical parameters on plasma homocysteine levels: i) the influence of three anticoagulants (EDTA, sodium citrate and lithium heparin); ii) the delay period of blood sample on ice before centrifugation; and iii) the advantages of strong acidic citrate at room temperature. The mean concentrations of total plasma homocysteine were different in function of the anticoagulant. These differences (EDTA minus lithium heparin or EDTA minus sodium citrate) were less than 10% however the used methods and could explain the good correlation between the results. However we recommend to keep the anticoagulant constant in the same study. When EDTA blood samples were immediately put on crushed ice, the maximum delay period before centrifugation could reach 4 hours. If ice is unavailable, strong acidic citrate at room temperature is a good alternative until for 4 hours.

Anticoagulants↗
PubMed2006

Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism?

Betaine homocysteine methyltransferase (BHMT), a Zn(2+)-dependent thiolmethyltransferase, contributes to the regulation of homocysteine levels, increases in which are considered a risk factor for cardiovascular diseases. Most plasma homocysteine is generated through the liver methionine cycle, in which BHMT metabolizes approximately 25% of this non-protein amino acid. This process allows recovery of one of the three methylation equivalents used in phosphatidylcholine synthesis through transmethylation, a major homocysteine-producing pathway. Although BHMT has been known for over 40 years, the difficulties encountered in its isolation precluded detailed studies until very recently. Thus, the last 10 years, since the sequence became available, have yielded extensive structural and functional data. Moreover, recent findings offer clues for potential new functions for BHMT. The purpose of this review is to provide an integrated view of the knowledge available on BHMT, and to analyze its putative roles in other processes through interactions uncover to date.

Animals↗
PubMed2001

Polymorphisms of key enzymes in homocysteine metabolism affect diet responsiveness of plasma homocysteine in healthy women.

High plasma total homocysteine (tHcy), low dietary intake of folate and other B vitamins, and genetic polymorphisms related to metabolism of homocysteine may interactively contribute to the risk of cardiovascular disease. We investigated whether known mutations in genes regulating homocysteine metabolism affect the responsiveness of serum folate and plasma tHcy to high intake of natural folate from food. Healthy females (n = 37) aged 22-57 y volunteered to participate in a crossover dietary intervention with two 5-wk diet periods (low and high folate diets). Concentrations of serum and RBC folate, serum vitamin B-12 and plasma tHcy were measured at baseline and at the end of each diet period. The prevalences of C677T transition of methylenetetrahydrofolate reductase (MTHFR) gene, 844ins68 of cystathionine beta-synthase (CBS) gene and A2756G mutation of methionine synthase (MS) gene were determined. Compared with the low folate diet, the high folate diet increased the serum folate concentration by 85% (P < 0.001), 77% (P < 0.001) and 55% (P < 0.05) in the subjects with the genotypes C/C (n = 19), C/T (n = 13) and T/T (n = 5), respectively, of the MTHFR gene. Also, the plasma tHcy of the subjects with the genotypes C/C, C/T and T/T was decreased by 11% (P < 0.001), 15% (P < 0.01) and 18% (P < 0.05), respectively, during the high folate diet period. The subjects carrying the G2756 allele of the MS gene (n = 15) had a more extensive reduction (P < 0.05) of plasma tHcy during the high folate diet period than the subjects with the genotype A/A (n = 22). The 844ins68 of CBS gene did not affect plasma tHcy concentrations or diet responsiveness. In conclusion, diet responsiveness of plasma homocysteine may be genetically regulated.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2003

Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study.

BACKGROUND: An association between depression and folate status has been demonstrated in clinical studies, whereas data are sparse on the relationship between depression and other components of 1-carbon metabolism such as vitamin B12, homocysteine, and the methylenetetrahydrofolate reductase 677C-->T polymorphism. The relationship between anxiety and these components is less well known. This study examined the associations between folate, total homocysteine, vitamin B12, and the methylenetetrahydrofolate reductase 677C-->T polymorphism, and anxiety and depression in a large population-based study. METHODS: Anxiety and depression, measured by the Hospital Anxiety and Depression Scale, were assessed in 5948 subjects aged 46 to 49 years (mean, 47.4 years) and 70 to 74 years (mean, 71.9 years) from the Hordaland Homocysteine Study cohort. By means of logistic regression models, anxiety and depression scores were examined in relation to the factors listed above. RESULTS: Overall, hyperhomocysteinemia (plasma total homocysteine level > or =15.0 micro mol/L [> or =2.02 mg/dL]) (odds ratio, 1.90; 95% confidence interval, 1.11-3.25) and T/T methylenetetrahydrofolate reductase genotype (odds ratio, 1.69; 95% confidence interval, 1.09-2.62), but not low plasma folate or vitamin B12 levels, were significantly related to depression without comorbid anxiety disorder. Plasma folate level was inversely associated with depression only in the subgroup of middle-aged women. None of the investigated parameters showed a significant relationship to anxiety. CONCLUSION: Our results provide further evidence of a role of impaired 1-carbon metabolism in depression.

Aged↗
PubMed1986

Possible involvement of the S-adenosyl-L-homocysteine metabolites, adenosine and L-homocysteine, in sleep in rats.

The effects of i.p. injections of adenosine (Ado) and homocysteine at 17.00 h were tested on the rat sleep-waking cycle. Administration of 7 and 50 mg/kg of Ado resulted in a significant increase in sleep in otherwise saline male rats during the environmental-dark period (18.00-06.00 h). Increments of paradoxical sleep were maximal with the smaller dose of Ado. The larger dose increased slow-wave sleep during the first 2 h. In contrast, administration of homocysteine (7 mg/kg) had no effect while a larger dose (50 mg/kg) induced a slight but significant long-lasting decrease of paradoxical sleep. These results were compared with those previously obtained with S-adenosyl-L-homocysteine (SAH), an intracellular precursor of Ado and L-homocysteine. It is proposed that the reported hypnotic action of exogenous SAH in rats could be mediated by Ado receptors.

Adenosine↗
PubMed2006

Homocysteine in assisted reproduction: does oestradiol influence homocysteine levels?

Steroid hormones including oestradiol have been identified as non-genetic factors that may influence plasma homocysteine. In advanced assisted reproduction, plasma oestradiol levels fluctuate markedly during the treatment cycle starting with normal followed by sub- and then supra-physiological levels. Because of the diverse harmful effects that hyperhomocysteinaemia has been associated with, it is imperative to understand how it may be manipulated during assisted reproduction. A total of 30 women undergoing treatment for infertility were recruited and followed through an advanced assisted reproduction cycle. Blood samples were analysed for oestradiol, homocysteine, vitamin B12, red cell folate and plasma folate during each phase. All patients had normal vitamin B12 and folate levels. Predictably, oestradiol showed marked changes as patients progressed through each treatment phase. However, there were no corresponding significant fluctuations in plasma homocysteine. Oestradiol concentration does not influence plasma homocysteine in women with normal vitamin B12 and folate levels undergoing advanced assisted reproduction.

Adult↗
PubMed1996

The Hordaland homocysteine study: the opposite tails odds ratios reveal differential effects of gender and intake of vitamin supplements at high and low plasma total homocysteine concentrations.

Both female sex and intake of vitamin supplements are known to be associated with a low mean plasma homocysteine level. In the present study, we used multiple logistic regression analyses to investigate the relation between these two variables and plasma homocysteine at the extreme ends of the plasma homocysteine distribution curve. We propose that the obtained set of odds ratios for hyper- and hypohomocysteinemia, referred to as the opposite tails odds ratios, may be an alternative approach to study determinants of plasma homocysteine.

Adult↗
PubMed1983

In vivo elevation of mouse brain S-adenosyl-L-homocysteine after treatment with L-homocysteine.

Intraperitoneal coadministration of adenosine and L-homocysteine markedly increased S-adenosyl-L-homocysteine in whole mouse brain, but further investigations showed that this elevation could also be produced following administration of L-homocysteine alone. The noted increase was maximal (+1325%) 10 min after treatment, remaining at about this level for 30-40 min before returning to control values after 180 min. Cerebral adenosine levels were decreased after treatment with L-homocysteine, adenosine, or these two substances in combination.

Adenosine↗
PubMed2002

Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease.

Cardiovascular diseases (CVD), especially coronary heart disease (CHD), are the most important causes of death in industrialized countries. Increased concentrations of total plasma homocysteine (tHcy) have been associated with an increased risk of CHD. Assuming that this relation is causal, a lower tHcy concentration will reduce the occurrence and recurrence of CHD. Therefore, it is important to know which factors determine the tHcy concentration. In the general population, the most important modifiable determinants of tHcy are folate intake and coffee consumption. Smoking and alcohol consumption are also associated with the tHcy concentration, but more research is necessary to elucidate whether these relations are not originating from residual confounding due to other lifestyle factors. The most important nonmodifiable determinant is the 677 C>T polymorphism in the gene that encodes methylenetetrahydrofolate reductase (MTHFR), a regulating enzyme in homocysteine metabolism. Especially subjects with the homozygous form of this polymorphism (i.e., 677TT genotype) and a low folate status have elevated tHcy concentrations. Specific clinical conditions like the use of antiepileptic drugs or methotrexate, renal failure, cancer, rheumatoid arthritis, and hypothyroidism may lead to elevated tHcy concentrations. The available epidemiological evidence indicates that an increased tHcy concentration is not an important risk factor for CHD in healthy subjects. However, prospective studies, which included subjects at high risk of CHD, and secondary prevention trials with intermediary endpoints consistently show that elevations in the tHcy concentration may be an important risk factor in these subjects for a (recurrent) CHD event. The induction of vascular endothelial dysfunction by homocysteine may underlie this increased risk. Ongoing intervention trials will indicate whether homocysteine-lowering through vitamin supplementation, prevents CHD in the treatment groups.

Adult↗
PubMed2006

Total plasma homocysteine, folate, and vitamin B12 status in healthy Iranian adults: the Tehran homocysteine survey (2003-2004)/a cross-sectional population based study.

BACKGROUND: Elevated plasma total homocysteine is an independent risk factor for cardiovascular disease and a sensitive marker of the inadequate vitamin B12 and folate insufficiency. Folate and vitamin B12 have a protective effect on cardiovascular disease. This population based study was conducted to evaluate the plasma total homocysteine, folate, and vitamin B12 in healthy Iranian individuals. METHODS: This study was a part of the Cardiovascular Risk Factors Survey in the Population Lab Region of Tehran University has been designed and conducted based on the methodology of MONICA/WHO Project. A total of 1214 people aged 25-64 years, were recruited and assessed regarding demographic characteristics, homocysteine, folate, and vitamin B12 levels with interview, questionnaires, examination and blood sampling. Blood samples were gathered and analyzed according to standard methods. RESULTS: The variables were assessed in 1214 participants including 428 men (35.3%) and 786 women (64.7%). Age-adjusted prevalence of hyperhomocysteinemia (Hcy > or = 15 micromol/L) was 73.1% in men and 41.07% in women (P < 0.0001). Geometric mean of plasma homocysteine was 19.02 +/- 1.46 micromol/l in men and 14.05 +/- 1.45 micromol/l in women (P < 0.004) which increased by ageing. Age-adjusted prevalence of low serum folate level was 98.67% in men and 97.92% in women. Age-adjusted prevalence of low serum vitamin B12 level was 26.32% in men and 27.2% in women. Correlation coefficients (Pearson's r) between log tHcy and serum folate, and vitamin B12 indicated an inverse correlation (r = -0.27, r = -0.19, P < 0.0001, respectively). CONCLUSION: These results revealed that the prevalence of hyperhomocysteinemia, low folate and vitamin B12 levels are considerably higher than other communities. Implementation of preventive interventions such as food fortification with folic acid is necessary.

Adult↗
PubMedDate not supplied

Chemical pathology of homocysteine. II. Carcinogenesis and homocysteine thiolactone metabolism.

Abnormalities of methionine metabolism in malignancy include carcinogenicity of methionine deficiency, methionine auxotrophy of cultured malignant cells, deficient methylation of DNA, and aerobic glycolysis that is reversed by methionine. Cells from children with homocystinuria form an aggregated sulfated extracellular matrix and grow in a pattern similar to cultured malignant cells. Normal cells metabolize homocysteine thiolactone to sulfate, but malignant cells accumulate homocysteine thiolactone, which thiolates proteins and other cellular macromolecules. Thioretinamide, the amide of retinoic acid homocysteine thiolactone, and its cobalamin complex, thioretinaco, are antineoplastic and chemopreventive against carcinogenesis. Deficiency of these compounds in malignant cells is believed to increase conversion of methionine to homocysteine thiolactone and thioco, its cobalamin complex. These compounds are believed to participate in oxidative phosphorylation by formation of thioretinaco ozonide disulfonium complexes that are the active sites of adenosine triphosphate (ATP) binding in mitochondrial membranes. Hypothetical deficiency of thioretinaco may explain important metabolic abnormalities of malignant cells.

Anticarcinogenic Agents↗
PubMed2006

S-alkylated homocysteine derivatives: new inhibitors of human betaine-homocysteine S-methyltransferase.

A series of S-alkylated derivatives of homocysteine were synthesized and characterized as inhibitors of human recombinant betaine-homocysteine S-methyltransferase (BHMT). Some of these compounds inhibit BHMT with IC50 values in the nanomolar range. BHMT is very sensitive to the structure of substituents on the sulfur atom of homocysteine. The S-carboxybutyl and S-carboxypentyl derivatives make the most potent inhibitors, and an additional sulfur atom in the alkyl chain is well tolerated. The respective (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic, (R,S)-6-(3-amino-3-carboxy-propylsulfanyl)-hexanoic, and (R,S)-2-amino-4-(2-carboxymethylsulfanyl-ethylsulfanyl)-butyric acids are very potent inhibitors and are the strongest ever reported. We determined that (R,S)-5-(3-amino-3-carboxy-propylsulfanyl)-pentanoic acid displays competitive inhibition with respect to betaine binding with a Kappi of 12 nM. Some of these compounds are currently being tested in mice to study the influence of BHMT on the metabolism of sulfur amino acids in vivo.

Betaine-Homocysteine S-Methyltransferase↗
PubMed2003

Low diagnostic value of fasting and post-methionine load homocysteine tests. A study in Dutch subjects with homocysteine test indications.

BACKGROUND: Homocysteine is a cardiovascular disease risk factor. We investigated, both in subjects with past plasma total homocysteine (tHcy) test indications and healthy adults, the diagnostic value of a fasting (tHcy) (f-tHcy) and the added value of a post-methionine-load tHcy (postload-tHcy). METHODS: Plasma homocysteine cut-off values were retrospectively used for hyperhomocysteinemia assessment in 3477 subjects with past tHcy test indications and 177 apparently healthy subjects. Cut-off values were based on reference limits (f-tHcy < or = 15.0; postload-tHcy < or = 50.0 micro mol/l), relative risk (f-tHcy < or = 12.0, postload-tHcy < or = 38.0; or f-tHcy < or = 10.0 micro mol/l) and vitamin-optimized reference limits (f-tHcy < or = 9.3; postload-tHcy < or = 35.1 micro mol/l). RESULTS: Use of the American Heart Association 10 micro mol/l f-tHcy cut-off value gave hyperhomocysteinemia prevalences of 65% in subjects with past tHcy test indications and 50% in healthy subjects. The combination of the vitamin-optimized reference limits for f-tHcy and postload-tHcy gave a hyperhomocysteinemia prevalence of 79% in subjects with tHcy test indications, of which only 5% was on account of increased postload-tHcy. Corresponding values for healthy subjects were 68% and 3%, respectively. CONCLUSIONS: Employment of a 10 micro mol/l (American Heart Association) or 9.3 micro mol/l (vitamin-optimized reference) cut-off value leaves no indications for tHcy testing from an evidence-based point-of-view.

Adult↗
PubMed2002

S-homoadenosyl-L-cysteine and S-homoadenosyl-L-homocysteine. Synthesis and binding studies of hon-hydrolyzed substrate analogues with S-adenosyl-L-homocysteine hydrolase.

Treatment of homoadenosine [9-(5-deoxy-beta-D-ribo-hexofuranosyl)adenine] with thionyl chloride and pyridine in acetonitrile gave 6'-chloro-6'-deoxyhomoadenosine, which underwent nucleophilic displacement with L-cysteine or L-homocysteine to give homologated analogues of S-adenosyl-L-homocysteine. Each amino acid in aqueous sodium hydroxide at 60 degrees C gave excellent conversion from the chloronucleoside, and adsorption on Amberlite XAD-4 resin provided more convenient isolation than prior methods. Weak binding of these non-hydrolyzed analogues to S-adenosyl-L-homocysteine hydrolase was observed.

Adenosylhomocysteinase↗
PubMed2001

Elevated homocysteine levels with weight loss after Lap-Band surgery: higher folate and vitamin B12 levels required to maintain homocysteine level.

OBJECTIVE: To investigate homocysteine levels and their relationship with serum folate and vitamin B12 concentrations with weight loss after the Lap-Band form of gastric restrictive surgery, with the view to minimizing risk. METHODS: We measured levels of fasting plasma homocysteine (tHcy), folate (serum and RBC) and vitamin B12 in two groups. The study group was 293 consecutive patients at 12 (n=192) or 24 (n=101) months review after surgery. The controls were 244 consecutive patients presenting for this surgery. RESULTS: The group losing weight had higher geometric mean tHcy levels: 10.4 (95% CI, 9.8-10.8) micromol/l compared with 9.2 (95% CI, 8.9-9.7) in controls (P<0.001). This occurred with higher folate levels and unchanged vitamin B12 levels. Levels of folate and B12 together explained 35% (r (2)) of the homocysteine variance in the weight loss group compared with only 9% (r (2)) in controls (P<0.001). Those taking regular multivitamin supplements had lower tHcy levels: 9.6 (9.1-10.0) micromol/l vs 12.3 (11.4-13.3) in those not taking supplements (P<0.001). A low normal plateau of tHcy levels occurred at levels of folate >15 ng/l and B12)600 ng/ml. A curvilinear relationship exists between these cofactors and tHcy levels, with the dose-response relationship shifted to the right in the weight loss group. CONCLUSION: This study shows elevated tHcy levels with weight loss, without lower serum folate or vitamin B(12) levels. There is an altered dose-response relationship with higher serum B(12) and folate levels required to maintain recommended tHcy levels. Patients losing weight have significant health benefits; however, they may be at greater risk of vascular events or fetal abnormality in association with raised tHcy levels. Multivitamin supplementation is effective in lowering tHcy levels.

Adult↗
PubMed2001

Supplemental creatine may decrease serum homocysteine and abolish the homocysteine 'gender gap' by suppressing endogenous creatine synthesis.

Creatine synthesis is responsible for the large majority of the methyl group transfers in normal hepatic metabolism, and is significantly greater in men than in women. Since methyl group depletion impairs the efficiency of homocysteine disposal, it is believed that the comparatively high rate of creatine synthesis in men is primarily responsible for the 'gender gap' in homocysteine levels. Adequate supplemental intakes of creatine can suppress creatine synthesis by inhibiting expression of the enzyme arginine-glycine transamidase. Thus, it is proposed that creatine supplementation may represent a practical strategy for decreasing plasma homocysteine levels.

Animals↗
PubMed2002

Vitamin supplementation normalizes total plasma homocysteine concentration but not plasma homocysteine redox status in patients with acute coronary syndromes and hyperhomocysteinemia.

Despite the growing evidence that elevated total homocysteine (tHcy) in plasma is a cardiovascular risk factor, the mechanism underlying the vascular injury is still unknown. Studies are difficult due to the fact that little is known about the formation of different homocysteine species in vivo. In the present study we have investigated the different fractions of tHcy in 21 patients with acute coronary syndromes and elevated concentration of plasma tHcy. A subgroup of the patients (n=16) was investigated before and after a 3 months study period with or without vitamin supplementation (folic acid 5 mg, pyridoxine 40 mg and cyanocobalamin 1 mg once daily). A major finding is that these patients had a lowered ratio (0.95%) between the concentration of reduced homocysteine (HcyH) and tHcy compared to controls (1.38%). A low ratio HcyH/tHcy in plasma in combination with elevated plasma tHcy concentrations might reflect increased oxidative activity or decreased reducing capacity in plasma from the patients. Another main finding in the present study is that, although vitamin supplementation of these patients normalized plasma tHcy, the ratio between HcyH and tHcy did not normalize. Since substantial evidence indicates that progression of arteriosclerosis is related to enhanced oxidant activity, the premature vascular disease associated with increased plasma tHcy concentration might be due to increased oxidative activity and the elevated plasma tHcy concentration may only reflect the increased oxidative stress.

Acute Disease↗