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,4
* Wageningen Centre for Food Sciences, Nutrition and Health Programme, Wageningen, the Netherlands;
Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, the Netherlands; and
** Department of Nutritional Physiology, TNO Nutrition and Food Research, Zeist, the Netherlands
4To whom correspondence should be addressed. E-mail: petra.verhoef{at}wur.nl.
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ABSTRACT |
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 TOP ABSTRACT SUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • homocysteine metabolism • betaine • folic acid • methionine-loading test • intervention study
Nutritional strategies aimed at lowering plasma homocysteine concentration are of interest because elevated plasma homocysteine levels are considered to be a risk factor for cardiovascular disease (1 –4 ). This relationship has been reported both for plasma homocysteine concentrations in the fasting state and for the increment after an oral methionine load independently of fasting levels (5 ,6 ). Homocysteine is a breakdown product of methionine, and it can be further degraded to cysteine via vitamin B-6–dependent reactions. Alternatively, it can be remethylated into methionine and the required methyl group is then obtained from betaine or from 5-methyltetrahydrofolate (Fig. 1 ).
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The influence of betaine supplementation on circulating homocysteine concentration has been studied mainly in clinical settings. Betaine treatment combined with folic acid normalized fasting plasma homocysteine concentrations in patients with severe hyperhomocysteinemia due to inborn errors in homocysteine metabolism [e.g., cystathionine ß-synthase deficiency (16
–18
)]. In addition, betaine treatment corrected the abnormal homocysteine response after methionine loading in patients with inborn hyperhomocysteinemia (16
). Currently, little published information is available concerning the effect of betaine on plasma homocysteine concentration in persons with normal to mildly elevated homocysteine levels. Brouwer et al. (19
) reported that the daily ingestion of 6 g betaine for 2 wk lowered fasting plasma homocysteine by 
8%, but this was not a placebo-controlled study. More recently, it was shown that betaine supplementation (6 g/d for 12 wk) decreased fasting plasma homocysteine by 9% in obese men and women (20
). Homocysteine levels after an oral methionine load were not measured in any study. We investigated the effect of more prolonged betaine supplementation on plasma homocysteine concentration in the fasting state and after methionine loading in men and women with mild elevations of homocysteine compared with placebo and folic acid.
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SUBJECTS AND METHODS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Subjects and design.
Of the 86 subjects who met our criteria, the 36 subjects (15 men and 21 women) with the highest plasma total homocysteine concentrations were included in the study (range 8.9–21.0 µmol/L). They were stratified by gender and plasma homocysteine concentration and then randomly assigned to one of three treatment groups. Treatment consisted of the ingestion of 3 g of anhydrous betaine, 400 µg of folic acid with 3 g of placebo (lactose) or 3 g of placebo, dissolved in a glass of water twice a day (i.e., after breakfast and the evening meal) for 6 wk. Thus, the daily dose was 6 g of betaine, 800 µg of folic acid with 6 g of placebo or 6 g of placebo. During a run-in period of 8 d, all subjects ingested 3 g of placebo twice a day to familiarize themselves with the study procedures. Betaine has a bitter taste, whereas lactose is sweet. To avoid distinct differences in taste between study substances of run-in and treatment periods, 1 mg of quinine was added to study substances supplied during the run-in period.
On the last day of the run-in period and on the last day of the treatment period, a methionine-loading test was performed. After a blood sample was collected from fasting subjects, they ingested 100 mg L-methionine/kg body mass (range 4.4–9.5 g) dissolved in a glass of orange juice with breakfast. During the methionine-loading tests, dietary intake was controlled to ensure consistent nutrient (i.e., methionine) intake across tests. Breakfast and lunch consisted of several slices of protein-free bread with diet margarine, jam, honey, or slices of cucumber and tomato. Dinner consisted of a vegetarian meal and an apple. Black coffee and tea intake was unlimited. Throughout the study, subjects were asked to refrain from products based on animal liver and to consume no more than 2 eggs per week.
Blood collection.
Venous blood was taken from an anticubital vein in the forearm after an overnight fast on study d 5, 8, 47 and 50. In addition, blood samples were obtained 3, 6, 9 and 24 h after methionine loading. For plasma collection, blood was collected in tubes containing EDTA. For serum collection, blood was placed in tubes containing clot activator and a gel to separate serum and packed cells after centrifugation. Immediately after collection, blood was mixed well and put on ice. Within 30 min, samples were centrifuged for 10 min at 2000 x g at 4°C. Aliquots were stored frozen at -20°C. Samples were coded so that laboratory technicians were unaware of the identity and treatment of subjects. All samples obtained from one subject were analyzed in the same run.
Biochemical analyses.
Total homocysteine (sum of all oxidized and reduced forms of homocysteine) was determined in plasma using HPLC (21 ). Within- and between-run CV were 3.6 and 6.4%, respectively. Vitamin B-6 (pyridoxal 5-phosphate) was measured in plasma according to the method of Schrijver et al. (22 ). Folate and vitamin B-12 were measured in serum samples with the SimulTRAC Radioassay Kit (ICN Pharmaceuticals, Orangeburg, NY). Intra- and interassay CV for B-vitamins were <8%. Serum glucose was analyzed by the hexokinase method, i.e., enzymatic phosphorylation and oxidation. The reaction is determined photometrically (commercially available Gluco-quant; Roche Diagnostics, Mannheim, Germany). Serum triacylglycerols were analyzed by enzymatic hydrolysis with subsequent enzymatic determination of the liberated glycerol by colorimetry (commercially available kit; Roche Diagnostics). Serum total cholesterol was analyzed by enzymatic conversion to a stable chromogen, which can be easily detected by colorimetry. HDL cholesterol was analyzed by a homogeneous enzymatic colorimetric test using polyethylene glycol–modified enzymes and dextran sulfate (commercially available kit; Roche Diagnostics).
Statistics.
All subjects completed the study. However, two subjects of the placebo group participated in one rather than two methionine-loading tests. One man failed to attend the initial loading test due to nontreatment-related illness. A woman experienced nausea and light-headedness after the first methionine load test and therefore refrained from the second. Data of these subjects were not used in the analyses related to postload plasma homocysteine response. For each individual, changes in fasting homocysteine, folate, vitamin B-6 and vitamin B-12 were calculated by subtracting the mean of baseline values (i.e., samples collected on d 5 and 8) from the mean of treatment values (i.e., samples collected on d 47 and 50). For each volunteer, the plasma homocysteine response after methionine loading was quantified by calculating the total area under the plasma homocysteine-time curve (AUC). In addition, the increment after 6 h was determined by subtracting the value obtained immediately before methionine intake from the value obtained 6 h after methionine intake. Changes in AUC and in the increment after 6 h were calculated by subtracting the values obtained after 6 wk of treatment (d 50) from that after the run-in placebo treatment (d 8). Changes were averaged per treatment group, and these means were compared with ANOVA (SAS Software version 6.12, SAS Institute Inc, Cary, NC). If the ANOVA indicated an overall treatment effect (P 
0.05), t tests were used to compare two treatment means. Furthermore, for the betaine treatment group and folic acid treatment group, the mean changes and 95% CI relative to the change in the placebo group are reported. Values are presented as means ± SD, unless indicated differently.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The mean homocysteine concentration at screening was 12.7 µmol/L, which in our laboratory corresponds to the 75th percentile of homocysteine values in healthy middle-aged Dutch volunteers (J. Durga, Wageningen University, personal communication). Before supplementation, treatment groups did not differ (Table 1). Randomization was thus successful. After 6 wk of intervention, plasma homocysteine had increased by 4% in the placebo group, whereas it had decreased by 11% (P = 0.05 compared with placebo) in the betaine group and by 18% (P = 0.004 compared with placebo) in the folic acid group (Table 2). Thus, the change in fasting homocysteine tended to be less in the betaine group than in the folic acid group (P = 0.32).
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At the end of the run-in period, the homocysteine response to methionine loading was not different among treatment groups (Fig. 2 ). Plasma homocysteine peaked within 6–9 h and declined thereafter, but had not returned to baseline values after 24 h. One subject in the placebo group had an increase in plasma homocysteine after the second methionine challenge that was far greater than expected on the basis of his first methionine loading test (AUC, 2453 µmol · 24 h/L and increment after 6 h, 132 µmol/L). It is likely that the relatively low concentrations of vitamin B-6 (7 nmol/L) and folate (3.7 nmol/L) in the plasma of this person caused the abnormal response. This explains why the mean AUC and increment after 6 h increased by 201 ± 648 µmol · 24 h/L and 10.4 ± 33.2 µmol/L in the placebo group. When this subject was removed from the data set, the recalculated changes in AUC and in the increment after 6 h for the placebo group were -0 ± 134 µmol · 24 h/L and 0.3 ± 9.0 µmol/L, respectively (see Table 2). After 6 wk betaine intervention, the AUC was 40% lower (P = 0.02 compared with placebo; P = 0.006 compared with folic acid) and the increment after 6 h was 49% lower (P = 0.04 compared with placebo; P = 0.008 compared with folic acid) than before treatment (Table 2). Folic acid treatment did not affect the postmethionine AUC and the increment after 6 h, and the changes in the folic acid and placebo groups did not differ.
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As expected, after 6 wk of intervention the folate concentration had increased in the folic acid group, but not in the other two groups. The change in folate concentration in the folic acid group was greater than the change in the betaine and placebo groups. Furthermore, the negative change in vitamin B-12 concentration in the placebo group was greater than the changes in the betaine and folic acid groups (Table 3).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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11% and reduced the increase in plasma homocysteine 6 h after methionine loading by 40% in middle-aged volunteers with mildly elevated homocysteine levels. A high fasting plasma homocysteine concentration and an elevated response after methionine loading are considered to be independent risk factors for cardiovascular disease. In fact, an increase in fasting plasma homocysteine of 5 µmol/L (1 SD) has been estimated to increase the risk of cardiovascular disease by 20% (4
). The strength of the association between the increase in plasma homocysteine after methionine loading and disease risk has been quantified in only a few studies. The relationship is gradual and of similar strength as observed for fasting homocysteine (23
). Our results suggest that betaine supplementation could be successful in maintaining circulating homocysteine concentrations at a low level throughout the day. The homocysteine-lowering effects of betaine can most likely be ascribed to an increase in betaine-dependent remethylation due to increased betaine availability and enhanced activity of the enzyme betaine methyltransferase in both the liver and kidney. We did not measure betaine levels in the liver, but studies with rats (24 ) and chickens (25 ) showed that betaine feeding elevates hepatic betaine pools. It has also been demonstrated in rats that betaine supplementation increases the expression and activity of betaine methyltransferase (26 ,27 ). Finkelstein et al. reported that excessive intake of methionine also enhanced betaine methyltransferase activity (28 ), and methionine and homocysteine infusion reduced hepatic betaine concentration (29 ) in rats. This may explain why betaine was highly effective in reducing the increase in plasma homocysteine after methionine loading.
Folic acid supplementation had no influence on the plasma homocysteine response after methionine loading. This may be accounted for in part by the rise in S-adenosylmethionine after methionine loading. High levels of S-adenosylmethionine inhibit 5-methyltetrahydrofolate production by suppressing methylenetetrahydrofolatereductase activity (30 ). Another reason for the lack of an effect of folic acid is that the Michaelis constant (Km) for methionine synthase, the enzyme required for the conversion of homocysteine to methionine via 5-methyltetrahydrofolate, is much lower than for betaine methyltransferase (31 ). This means that the folate-dependent remethylation of homocysteine is at maximum capacity at much lower circulating S-adenosylmethionine concentrations than the betaine-dependent remethylation. However, folic acid supplementation did lower the increase in plasma homocysteine after methionine loading in patients with severe hyperhomocysteinemia (10 ,12 ,15 ). Combined with our findings, this indicates that folic acid may suppress plasma homocysteine accumulation after methionine loading in patients with monogenetic defects of homocysteine metabolism, but not in subjects with mild elevations of plasma homocysteine caused by multiple environmental and genetic factors.
The daily intake of 800 µg folic acid decreased fasting plasma homocysteine concentration somewhat more than 6 g of betaine, although the difference was not significant. This may be related to the fact that the betaine-dependent remethylation of homocysteine is restricted to the liver and kidney, whereas the folate-dependent remethylation of homocysteine occurs in most cells. The fasting homocysteine concentration may represent the movement of unmetabolized homocysteine from extrahepatic sites of synthesis to the liver. If this is true, then supplementation with folic acid would decrease the "supply" of homocysteine to the liver, and betaine would reduce the liver "output" of homocysteine. This implies that combined ingestion of folic acid and betaine may be most effective in lowering fasting homocysteine concentration.
The dose of folic acid used in the present study was less than what has been used in the studies with hyperhomocysteinemic patients. Therefore, it is possible that the daily dose of folic acid was too low to achieve an optimal response. However, 5 mg of folic acid was no more effective in lowering the postload plasma homocysteine response in chronic hemodialysis patients than 1 mg of folic acid (10 ). This suggests that in our subjects, higher doses of folic acid would have been no more effective in lowering postload plasma homocysteine than the 800 µg that we used. The dose of betaine ingested by the subjects was well above the average daily intake of betaine and its precursor, choline (32 ). Unexpectedly, vitamin B-12 levels decreased more in the placebo group than in the betaine and folic acid groups. When we examined the individual data, it became clear that this was due mainly to one subject having a drop in vitamin B-12 from 426 pmol/L before treatment to 261 pmol/L after 6 wk of treatment. Folic acid and vitamin B-6 concentrations remained constant in this person and it is not known why vitamin B-12 concentration decreased.
Even though elevated levels of plasma homocysteine are linked to vascular disease, there is currently much debate concerning whether the relationship is causal (4 ,33 ). For example, it has been proposed that folic acid supplementation may modify endothelial function independent of its effect on homocysteine (34 ). We have shown that betaine can decrease plasma homocysteine levels without affecting folate status. Lowering of plasma homocysteine via betaine supplementation may therefore provide an answer to the question(s) whether homocysteine and/or folate are causally related to cardiovascular disease.
In conclusion, our results suggest that betaine could be used effectively to lower fasting plasma homocysteine levels and to prevent plasma homocysteine levels from rising after methionine intake. Whether this stabilization of homocysteine may reduce the risk of cardiovascular disease is unknown.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Funded by the Wageningen Centre for Food Sciences, an alliance of major Dutch food industries, TNO Nutrition and Food Research and Wageningen University and Research Centre, with financial support by the Dutch government.
3 Present address: Netherlands Olympic Committee, Netherlands Sports Confederation, Arnhem, the Netherlands.
Manuscript received 9 October 2002. Initial review completed 6 November 2002. Revision accepted 9 February 2003.
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LITERATURE CITED |
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A. Melse-Boonstra, P. I Holm, P. M Ueland, M. Olthof, R. Clarke, and P. Verhoef Betaine concentration as a determinant of fasting total homocysteine concentrations and the effect of folic acid supplementation on betaine concentrations Am. J. Clinical Nutrition, June 1, 2005; 81(6): 1378 - 1382. [Abstract] [Full Text] [PDF]
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K.-A. da Costa, C. E Gaffney, L. M Fischer, and S. H Zeisel Choline deficiency in mice and humans is associated with increased plasma homocysteine concentration after a methionine load Am. J. Clinical Nutrition, February 1, 2005; 81(2): 440 - 444. [Abstract] [Full Text] [PDF]
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 P. I. Holm, P. M. Ueland, S. E. Vollset, O. Midttun, H. J. Blom, M. B.A.J. Keijzer, and M. den Heijer Betaine and Folate Status as Cooperative Determinants of Plasma Homocysteine in Humans Arterioscler. Thromb. Vasc. Biol., February 1, 2005; 25(2): 379 - 385. [Abstract] [Full Text] [PDF]
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S. A. Craig Betaine in human nutrition Am. J. Clinical Nutrition, September 1, 2004; 80(3): 539 - 549. [Abstract] [Full Text] [PDF]
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P. Verhoef and M. B Katan A healthy lifestyle lowers homocysteine, but should we care? Am. J. Clinical Nutrition, May 1, 2004; 79(5): 713 - 714. [Full Text] [PDF]
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P. I. Holm, O. Bleie, P. M. Ueland, E. A. Lien, H. Refsum, J. E. Nordrehaug, and O. Nygard Betaine as a Determinant of Postmethionine Load Total Plasma Homocysteine Before and After B-Vitamin Supplementation Arterioscler. Thromb. Vasc. Biol., February 1, 2004; 24(2): 301 - 307. [Abstract] [Full Text]
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M. R. Olthof, T. van Vliet, E. Boelsma, and P. Verhoef Low Dose Betaine Supplementation Leads to Immediate and Long Term Lowering of Plasma Homocysteine in Healthy Men and Women J. Nutr., December 1, 2003; 133(12): 4135 - 4138. [Abstract] [Full Text] [PDF]
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