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Elevated plasma homocysteine level promotes atherosclerosis in blood vessels due to, among others, generation of reactive oxygen species and reduction of nitric oxide bioavailability. The aim of this study was to investigate whether melatonin administration reduces plasma homocysteine level in rats consuming increased doses of methionine in the diet. The trial lasted for two months. The rats were divided into a few groups - 2 groups consisted of animals fed a standard diet, 2 groups consisted of animals fed a diet rich in methionine for one and two months, a group which had methionine removed from the diet in the second month, a group which had methionine removed from the diet and melatonin administered in the second month, a group still fed a diet rich in methonine in the second month and also given melatonin, and a group of animals on a diet rich in methionine for two months and given melatonin at the same time. Hcy, lipid peroxidation markers (MDA+4HNE) and nitric oxide metabolite (NO(2)(-)/NO(3)(-)) concentrations were determined in the plasma of all the rats. As a result of the tests it was found that plasma Hcy concentration increases in the first month of a methionine-rich diet but then decreases in the second month. MDA+4HNE changes are similar. Melatonin significantly intensifies the effects. The changes of NO(2)(-)/NO(3)(-) concentrations were noticed especially in the groups receiving melatonin. Elimination of methionine from the feed does not change the value of NO(2)(-)/NO(3)(-). NO production increases only after administration of melatonin. On the basis of received results it might be stated that melatonin administration together with a methionine-rich diet significantly decreases Hcy concentration, the level of oxidative stress and increases NO production. It might have some practical implications, especially when the level of endogenous melatonin decreases e.g. in elderly people or people with hyperhomocysteinemia.

The effects of dietary manipulation of folate and methionine on plasma homocysteine (Hcy) and high-density lipoprotein cholesterol (HDL-C) levels in wild-type and apolipoprotein-E-deficient mice were determined. A low-folate diet with or without folate and/or methionine supplementation in drinking water was administered for 7 weeks. Fasted Hcy rose to 23 microM on a low-folate/high-methionine diet, but high folate ameliorated the effect of high methionine on fasted plasma Hcy to approximately 10 microM. Determination of nonfasted plasma Hcy levels at 6-h intervals revealed a large diurnal variation in Hcy consistent with a nocturnal lifestyle. The daily average of nonfasted Hcy levels was higher than fasted values for high-methionine diets but lower than fasted values for low-methionine diets. An acute methionine load by gavage of fasted mice increased plasma Hcy 2.5 h later, but mice that had been on high-methionine diets had a lower fold induction. Mice fed high-methionine diets weighed less than mice fed low-methionine diets. Based on these results, two solid-food diets were developed: one containing 2% added methionine and the other containing 2% added glycine. The methionine diet led to fasted plasma Hcy levels of >60 microM, higher than those with methionine supplementation in drinking water. Mice on methionine diets had >20% decreased body weights and decreased HDL-C levels. An HDL turnover study demonstrated that the HDL-C production rate was significantly reduced in mice fed the methionine diet.

The effects of chronic betaine ingestion were investigated in rats. Rats were fed an experimental diet containing 5% betaine for 4 wk and methionine was intravenously administered. The elevations of plasma homocysteine were assessed by comparing the increments to the initial measured value and the positive incremental area under the plasma homocysteine concentration curve over the 240-min post-methionine-loading period (deltaAUC0-240). In the betaine-ingesting rats, deltaAUC0-240 was significantly lower than in the control group (48% of the control), and the increments of plasma homocysteine were also lower compared with the control, especially 15-30 min after methionine loading. Choline, a precursor of betaine, did not alter the plasma homocysteine elevation. In a definite period immediately after methionine loading, carnitine, a methyl-group-rich amino acid, induced a significant increase of plasma homocysteine, compared to the control. Moreover, plasma homocysteine concentration was significantly decreased by 4 wk of betaine ingestion. Betaine enhanced liver BHMT activity whereas choline and carnitine did not show any effects on BHMT activity. These results suggest that betaine contributes to both the decrease in the plasma homocysteine concentration and the suppression of plasma homocysteine elevation through the activation of liver BHMT.

Background and Aims: Dietary methionine affects cholesterol metabolism in growing rats. Methionine effects on adult rats and mechanisms by which methionine alters the lipid metabolism are not fully elucidated. We investigated possible mechanisms by which dietary methionine acts on lipid metabolism of adult rats., Methods: Male adult rats were divided into three groups (n=10) and were fed casein-based diets differing in methionine concentration (low-methionine diet: 0.96 g/kg; adequate-methionine diet: 2.22 g/kg, high-methionine diet: 6.82 g/kg) for 4 weeks. Concentrations of triacylglycerols and cholesterol in plasma and lipoproteins, concentration of homocysteine in plasma, concentration of cholesterol in liver, fecal lipid excretion, expression of hepatic HMG-CoA reductase, phosphatidylethanolamine N-methyltransferase 2 (PEMT-2) and of LDL receptor were measured., Results: Rats fed the high-methionine diet had higher plasma homocysteine concentrations than rats fed the low-methionine diet (p<0.05). Although concentrations of cholesterol in plasma and lipoproteins were not different between the groups, there was a distinct positive correlation between circulating plasma homocysteine and plasma cholesterol (R(2)=0.55, p<0.001). The fecal excretion of cholesterol and bile acids was not altered by dietary methionine. The relative mRNA concentration of HMG-CoA reductase and of LDL receptor remained unaffected by dietary methionine. Gene expression of PEMT-2 was higher in rats fed the high-methionine diet than in rats fed the other diets (p<0.05)., Conclusion: The results demonstrate that dietary methionine contributes to a rise in circulating homocysteine concentration which positively correlates with the concentration of plasma cholesterol. However, the effects of methionine on cholesterol metabolism of adult rats were relatively weak., (Copyright (c) 2006 S. Karger AG, Basel.)

Recent studies have focused on establishing a link between the pathogenesis of ethanol and the disruption of metabolic pathways in the liver. Ethanol alters hepatic methionine metabolism, leading to perturbation of S-adenosylmethionine-dependent transmethylation. Therefore, the supply of metabolically related nutrients such as folate may play a role in the hepatotoxic effects of ethanol.

Folic acid treatment decreases plasma total homocysteine concentrations in healthy subjects, but the effects on homocysteine metabolism are unknown. In the present study, we investigated the effect of 3 weeks of oral treatment with 5 mg of folic acid on one-carbon flux rates in 12 healthy subjects, using in vivo stable isotope methods. In addition, we determined the effect of folic acid on blood concentrations of amino acids which may have regulatory roles in homocysteine metabolism, i.e. homocysteine, AdoMet (S-adenosylmethionine), AdoHcy (S-adenosylhomocysteine), serine and glycine. Primed, continuous infusions with [2H3-methyl-1-13C]methionine were used to determine flux rates of methionine transmethylation, homocysteine remethylation and homocysteine trans-sulphuration. Metabolic homocysteine clearance was defined as the ratio of trans-sulphuration and plasma homocysteine level. Folic acid treatment increased the homocysteine remethylation rate by 59% [95% CI (confidence interval), 13-97%; P = 0.02] and methionine transmethylation rate by 20% (95% CI, 3-41%; P=0.03). Plasma total homocysteine concentration (-18%; 95% CI, -28 to -9%; P<0.01) and the serine/glycine ratio (-20%; 95% CI, -63 to -6%; P<0.01) decreased significantly, and the AdoMet/AdoHcy ratio (11%; 95% CI, 1-20%; P = 0.02) increased significantly. Changes in one-carbon flux rates did not correlate significantly with changes in plasma concentration of these amino acids. In conclusion, folic acid treatment lowered plasma homocysteine concentration and increased whole-body remethylation and transmethylation flux in healthy subjects.

Objective: We examined whether amino acid-based peritoneal dialysate that contains 85 mg/dL L-methionine affects homocysteine (Hcy) metabolism., Design: The study enrolled 17 adult CAPD patients (11 men, 6 women) who had been receiving CAPD for at least 6 months and who had low serum albumin levels (<3.7 g/dL). Diet was not specifically changed. All of the study patients received daily 4-exchange CAPD treatment, and they used Nutrineal (Baxter Healthcare, Deerfield, IL, U.S.A.) as one of their daily exchanges (first or second exchange). Blood samples were collected every 2 weeks, and Hcy was measured., Results: After use of Nutrineal, serum albumin was unchanged, but blood urea nitrogen (BUN) and total protein were increased. Before the study began, 1 patient had a very high Hcy level (256 micromol/L); his data were excluded from the analysis. In the remaining 16 patients, baseline Hcy was 24.4 +/- 7.0 micromol/L. Levels of Hcy progressively increased with the use of Nutrineal: 28.1 +/- 6.2 micromol/L in week 2, 28.4 +/- 7.1 micromol/L in week 4, 29.1 +/- 7.6 micromol/L in week 6, 29.3 +/- 9.0 micromol/L in week 8, 27.5+/-9.7 micromol/L in week 10, and 30.3 +/- 8.2 micromol/L in week 12., Conclusions: Nutrineal might help to replenish daily protein loss, but it also increased formation of Hcy and, therefore, the potential risk of cardiovascular illness. Further studies will be needed to examine the effect of folic acid and vitamin B(12) supplementation in the rescue of that Hcy increase, and also a possible correlation with methylenetetrahydrofolate reductase gene polymorphism.

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

Hyperhomocystinemia is a risk factor for cardiovascular disease, and acute elevation of plasma homocysteine after methionine loading impairs endothelial function in healthy subjects. Interestingly, pretreatment with vitamin C can ameliorate this effect. We have already shown that acute oral vitamin C administration reduces arterial stiffness in healthy subjects, and the aim of the present study was to investigate the effect of methionine loading on arterial stiffness with and without concomitant vitamin C using the noninvasive technique of pulse wave analysis. Eight healthy male subjects (mean age, 29 years; range, 20-42 years) were studied on three occasions at weekly intervals. In a double-blind, double-dummy, randomized order they received orally either 100 mg/kg methionine, 100 mg/kg methionine plus 2 g of vitamin C, or matching placebos. Peripheral and central blood pressure, heart rate, cardiac index, arterial stiffness, and plasma homocysteine levels were assessed at baseline and 6 hours after dosing. Compared with placebo, there was no significant change in any of the hemodynamic parameters, including arterial stiffness, after oral methionine, although plasma homocysteine did increase from 11.5 +/- 1.6 to 28.7 +/- 4.4 microM (mean +/- SEM; p < 0.001). Combined methionine and vitamin C led to a similar increase in plasma homocysteine but significantly reduced augmentation index by 10.5 +/- 3.2% (p = 0.02). Acute hyperhomocystinemia does not significantly alter arterial stiffness, as assessed by pulse wave analysis, whereas a combination of methionine and vitamin C leads to a similar reduction in augmentation index to that previously described after vitamin C alone. These data reinforce evidence that vitamin C reduces arterial stiffness but do not indicate any important interaction with oral methionine.

Objectives: A few reports have shown elevated fasting total plasma homocysteine (tHcy) in patients taking antiepileptic drugs (AEDs). In this study we determined the influence of AEDs on plasma tHcy levels prior to and following methionine loading., Material and Methods: Thirty-four patients on different AEDs and 34 matched controls were recruited. Blood samples were drawn prior to and 6 h post-methionine loading (6h-PML)., Results: The patients on AEDs inducing the cytochrome P450 (carbamazepine, phenytoin, phenobarbital, primidone), had higher fasting and 6h-PML plasma tHcy concentrations than the controls (P = 0.01 and P<0.001). Patients on AED inhibiting the cytochrome P450 (valproate [VPA]), had lower 6h-PML p-tHcy concentrations than controls (P = 0.01)., Conclusions: Our data indicate that not only fasting but also 6h-PML tHcy levels should be determined in order to identify hyperhomocysteinemia among patients on AEDs. Inducer AEDs seem to have an opposite effect than the inhibitor VPA on plasma tHcy, erythrocyte folate and serum folate levels.

Introduction and Objectives: We have already proved that basal and after load homocysteinemia are risk factors for vascular disease and it is also known that premenopausal women are relatively protected against this disease. The objective of this paper was the assess whether there are any differences in the plasma levels of homocystein which might contribute to explain the differences in the incidence of vascular diseases found in both sexes., Patients and Methods: Two hundred and four patients (153 males) without previous vascular disease were enrolled in the study. These patients were participating in a screening program for cardiovascular risk factors in a central hospital in Lisbon. We evaluated the basal homocysteinemia and homocysteinemia 6 hours after an oral load with methionine (0.1 g/kg body weight). Basal and after load homocysteinemia in men and women, as well as in women before and after menopause, was compared. Because homocysteinemia does not have a normal distribution, we used non-parametric statistical tests, namely the Mann-Whitney test., Results: Men had higher values for basal homocysteinemia than women (mean and standard deviation)--9.64 +/- 3.15 versus 8.56 +/- 2.82 mumol/l, (p = 0.0018)--as well as for after load homocysteinemia--24.40 +/- 7.84 versus 23.71 +/- 10.16 mumol/L, non significant difference. Premenopausal women (n = 42) had lower basal homocysteinemia values than post menopausal women (n = 9)--8.41 +/- 3.02 versus 9.23 +/- 1.38 mumol/L, p < 0.05--and similarly after load homocysteinemia values--23.86 +/- 10.65 versus 23.01 +/- 7.47 mumol/L., Conclusions: Basal homocysteinemia is significantly higher in men than in women. After menopause, basal homocysteinemia levels increase significantly in women, approaching those in men. The levels of after load homocystein are not dependent on sex or pre- or postmenopausal condition. Homocysteinemia might explain, at least partly, the differences in the incidence of vascular disease in both sexes and the increased vascular risk in postmenopausal women.