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2
*
Division of Human Nutrition and Epidemiology, Wageningen University, 6700 EV Wageningen, the Netherlands;
Wageningen Centre for Food Sciences, 6700 AN Wageningen, the Netherlands;
**
Department of Chronic Diseases Epidemiology, National Institute of Public Health and the Environment, 3720 BA Bilthoven, the Netherlands; and
Department of Pharmacology, University of Bergen, Bergen, N-5021, Norway
2To whom correspondence should be addressed. E-mail: petra.verhoef{at}staff.nutepi.wau.nl.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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20%) and meat (18%), whereas two thirds consisted of polyglutamates, derived mainly from vegetables (25%). The predictive power of the regression model with total folate intake as the independent variable adjusted for age, smoking and alcohol intake, did not increase when including the ratio of monoglutamate to polyglutamate folate intake. In addition, linear regression models showed that both monoglutamate and polyglutamate folate intake were associated positively with plasma folate levels. However, in men, the monoglutamate folate form appeared to be a threefold stronger determinant of plasma folate levels than polyglutamate folate, whereas in women, both folate forms were equally strong determinants. This might be explained by different food intake patterns of men and women, including alcohol intake. At present, it does not seem necessary to distinguish between food folate forms in advising an increase in folate intake from nonfortified foods.
KEY WORDS: • dietary folate intake • bioavailability • polyglutamate folate • monoglutamate folate • plasma folate • humans
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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,2
). More recently, the role of folic acid has been acknowledged in the prevention of neural tube defects (3
,4
). Folate has been associated with the risk of colon cancer (5
) and it is considered a major determinant of plasma homocysteine, a potential risk factor for cardiovascular disease (6
,7
). It is estimated that a 5 µmol/L increase of plasma homocysteine concentration is associated with a 20–30% higher risk of cardiovascular disease (8
).
Intake of supplemental folic acid effectively decreases plasma homocysteine concentrations (9
,10
). High dietary folate intake is also associated with lower homocysteine levels (11
–13
). However, debate exists concerning whether increased folate intake with nonfortified foods is effective in lowering homocysteine levels in the general population because dietary folate has a lower bioavailability than supplemental folic acid (14
–17
).
Bioavailablity is defined as the proportion of a nutrient ingested that becomes available to the body for metabolic processes or storage. The bioavailability of dietary folate may be hampered by the polyglutamate chain to which most of the natural folate is attached. This polyglutamate chain must be removed, except for the proximal glutamate moiety, by the enzyme glutamate carboxypeptidase II that is present in the human brush border. After that, folate can be absorbed and transported as a monoglutamate into the portal vein. Synthetic folic acid used for supplements and fortification consists of the monoglutamate form only. The relative bioavailability of dietary folate is estimated to be only 50% compared with synthetic folic acid (18
).
In the past decades, several attempts have been made to assess the bioavailability of folate polyglutamate compared with the monoglutamate form (19
–24
). The available data suggest that the polyglutamate form is 60–80% bioavailable compared with the monoglutamate form (25
). Definite conclusions cannot be made, however, due to study designs with single high doses, short periods of effect measurement, presaturation protocols and small groups of subjects, combined with a high between-person variation.
Until now, no data have been published on intake of monoglutamate and polyglutamate folate from nonfortified sources. Such figures are necessary to assess the need to include this particular bioavailability aspect in the dietary reference intake for the general population, especially for countries in which folate fortification is not allowed, such as the Netherlands.
With data from a Dutch survey, we calculated the intake of monoglutamate and polyglutamate folate from nonfortified foods and assessed the main food sources of both forms of the vitamin. Furthermore, we related monoglutamate and polyglutamate intake data to plasma folate concentrations. We hypothesized that the association between monoglutamate folate intake with plasma folate concentrations would be stronger than that of polyglutamate folate because of the assumed lower bioavailability of the polyglutamate form.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Subjects were randomly sampled from the population of the "Monitoring Project on Risk factors for Chronic Diseases" (MORGEN).3 The general purpose of that survey is to determine the prevalence of risk factors for chronic diseases in a representative sample of the Dutch population. The MORGEN study was approved according to the guidelines of the Helsinki Declaration by the external Medical Ethical Committee of the TNO Toxicology and Nutrition Institute.
The MORGEN study population consists of men and women aged 20–65 y living in three Dutch towns (Amsterdam, Doetinchem and Maastricht). Data were collected from 1993 to 1997. Of the total number of 19,066 subjects that entered the MORGEN study until 1996, 14,356 persons were eligible for our analyses because we had completed questionnaires, enough blood available for all proposed biochemical analyses, such as plasma homocysteine and plasma folate, and recorded time of drawing and centrifugation of blood from these persons. Storage of whole blood at room temperature may increase plasma homocysteine concentrations artificially (26
,27
). Therefore, from the total of 14,356 subjects, 7992 were excluded because their blood had been stored at room temperature for >1 h. Of the 6364 subjects remaining, plasma homocysteine and plasma folate levels were determined for a random subsample of 3025 subjects, stratified for age and sex. This sample did not differ from the total study population with respect to established cardiovascular risk factors such as total and HDL cholesterol level, blood pressure, socioeconomic status, body mass index, and smoking. De Bree et al. recently described the relation between intake of B vitamins and the plasma homocysteine distribution in this population (11
).
Data collection.
Respondents filled out two questionnaires and underwent a medical examination. One of the questionnaires contained general questions on items such as age, sex, presence of (chronic) diseases and on risk factors for chronic diseases such as smoking habits and alcohol consumption. Food intake was determined by a semiquantitative food-frequency questionnaire (FFQ) [European Prospective Investigation into Cancer and Nutrition (EPIC) FFQ] on dietary habits over the last 12 mo, containing 178 food and supplement intake items with pictures of portion sizes. The FFQ and its reproducibility have been described in more detail by Ocké et al. (28
,29
).
Recently, the monoglutamate and polyglutamate folate content of 125 foods that account for 90% of folate intake in the Dutch population was determined by HPLC (30
). During food preparation, folate can be lost from foods by destruction or by leakage. Furthermore, enzymatic conversion of folate polyglutamate to the monoglutamate form may occur. Therefore, foods were prepared according to normal household practice before analysis (31
). With these figures, the monoglutamate and polyglutamate folate intake of our study population was calculated. For food items for which total folate content but not the monoglutamate proportion was known, we estimated this proportion making use of a closely comparable food item for which we did know the monoglutamate proportion (e.g., green and white cabbage). For a few food items, we could not find a comparable food item (e.g., mushrooms). These items, which accounted for only 3% of total folate intake, were excluded in the data analyses.
Alcohol intake was assessed with the FFQ by asking respondents how many glasses of beer, wine, liqueur and strong drinks per day, week, month or year they drank over the past 12 mo. One glass of alcoholic beverage was assumed to contain 10 g of alcohol.
Blood sampling.
Blood sampling took place in the morning between 0900 and 1400 h at the Municipal Health Centers in each of the three towns, after participants had signed an informed consent form. Venous blood (30 mL) was collected from nonfasting subjects. Blood samples were centrifuged for 10 minutes at 3000 x g and separated, and stored within 1 h at -20°C at the Health Centers. Samples were transported to the National Institute of Public Health (Bilthoven, the Netherlands) within 3 wk and stored at -80°C until further analysis.
Laboratory analysis.
Plasma folate concentrations were determined by a Lactobacillus casei microbiological assay according to the method described by Molloy and Scott (32
) in the laboratory of the Department of Pharmacology, University of Bergen, Norway. Intra- and interassay variability were 4.3 and 7.0%, respectively.
Data analysis.
Users of B-vitamins were excluded from all statistical analyses (n = 588), as well as two more persons with incomplete data; data of 2435 persons (1275 men and 1160 women) remained for analyses.
Plasma folate and folate intake data were all log-transformed to obtain normally distributed data. Residual energy adjustment was performed for nutrient intake according to the method described by Willett et al. (33
). To make the nutrient intake data interpretable, the individual residual nutrient intakes as calculated from the regression line of total energy intake on total nutrient intake were added to the nutrient intake at the mean energy intake (9391 kJ/d) in the study population.
The monoglutamate vs. polyglutamate folate content of the diet was expressed as a ratio calculated by dividing the monoglutamate folate intake by the polyglutamate folate intake (MP-ratio).
Linear regression models were used to describe trends in plasma folate levels (dependent variable) when associated with monoglutamate, polyglutamate or total folate intake (independent variables). Both monoglutamate and polyglutamate folate intakes were strongly correlated with total folate intake and could therefore not be fitted in the same model together with total folate. Total folate intake and the MP-ratio were noncollinear (Pearson correlation coefficient of 0.19 in men and 0.09 in women) and could therefore be fitted in the same model together. Monoglutamate and polyglutamate folate intakes were also considered to be noncollinear (r = 0.38 in men and 0.51 in women). Continuous models were used to compare the differences in plasma folate concentrations at a 50 µg higher intake of either monoglutamate or polyglutamate folate. Plasma folate levels were associated with folate intake by using the geometric means of quintiles of monoglutamate or polyglutamate folate intake as independent variables in the models to visualize trends. Multivariate models were adjusted for major explanatory factors of folate status such as age, smoking habits and alcohol intake (34
). Body mass index was not included in the models because it was not a confounder in the association between folate intake and plasma folate. Because we expected differences in dietary intake patterns, we carried out all analyses for men and women separately. All data analyses were performed with the Statistical Application Software for PC, version 6.12 (SAS Institute Inc., Cary, NC).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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, the dietary folate intake and plasma folate levels in the study population are shown. Total folate intake was 232 µg/d in men, of which 38% was provided by the monoglutamate form, and 186 µg/d in women, of which 33% was provided by the monoglutamate form. The MP-ratio was significantly higher for men [mean 0.60; 95% confidence interval (CI), 0.59–0.61] than for women (mean 0.48; 95% CI, 0.47–0.49).
|
). For men, alcoholic beverages also were an important source of monoglutamate folate intake, followed by eggs, milk, vegetables and fruits. For women, alcoholic beverages were a less important source of monoglutamate folate, whereas eggs, milk, vegetables and fruits were equally important sources. Vegetables were the most important source of polyglutamate folate for both men and women. Bread, potatoes and fruits delivered a substantial amount of polyglutamate folate to the diet as well, whereas meat and milk contributed less.
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, the univariate and multivariate linear regression models for the association between total folate and plasma folate are shown. When the MP-ratio was brought into the model as an explanatory variable, a significant coefficient was seen in men, but not in women. This indicates that in men, the MP-ratio of the dietary folate intake was an explanatory factor for plasma folate levels but not in women. However, addition of the MP-ratio to the models did not increase their explanatory capacity because the adjusted R2 remained 0.17 for men and 0.10 for women, respectively.
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. The multivariate model, in which both monoglutamate and polyglutamate folate intake were included as independent variables as well as the confounding variables age, smoking and alcohol intake, could explain 18% of plasma folate levels in men and 10% in women. The associations in men were stronger for the monoglutamate than for the polyglutamate form, whereas the reverse was true in women. The coefficients for monoglutamate folate intake in men and women differed significantly from each other (mean 0.38, 95% CI, 0.28–0.47 for men; mean 0.17, 95% CI, 0.06–0.27 for women). The results of the regression analyses are depicted in Figure 2
.
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|
). From the multivariate model, we calculated that in men, a 50 µg/d higher intake of monoglutamate folate was associated with 27% higher plasma folate levels, whereas a 50 µg/d higher intake of polyglutamate folate intake was associated with a higher plasma folate level of only 8%. This suggests that, in men, monoglutamate folate was a three times stronger determinant of plasma folate levels than polyglutamate folate. For women, a 50 µg higher intake of monoglutamate folate was associated with 11% higher levels of plasma folate, whereas this was 16% for a 50 µg higher polyglutamate folate intake.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Both monoglutamate and polyglutamate folate intakes were positively associated with plasma folate levels. In men, monoglutamate folate was a threefold stronger determinant of plasma folate levels than polyglutamate folate, which is in line with our prior hypothesis. In women, monoglutamate and polyglutamate folate appeared to be about equally strong determinants of plasma folate. In line with these findings, the coefficient for the MP-ratio in the multivariate models was significant only for men, although the variance explained by the model did not increase after addition of the MP-ratio to the model.
The present study can give only a rough estimate of real bioavailability issues for the following reasons: 1) bias in dietary data collection; 2) variation in the monoglutamate and polyglutamate folate content of foods; and 3) the assumption that one measurement of (nonfasting) plasma folate reflects folate status well enough to find valid associations. The bias in dietary data collection for the questionnaire used was studied using 12 monthly 24-h recalls as a reference to the EPIC FFQ (29
). For important folate sources such as bread, potatoes, fruit, meat, eggs and milk, relative validity figures of 0.41 to 0.78 were reported. For vegetable intake, a lower relative validity (0.25–0.36) was observed, leading to more measurement error in the estimation of vegetable intake than in that of other folate sources. Another issue is the estimation of monoglutamate and polyglutamate folate intakes. The food composition data we used, for which foods were prepared by standard household practice, approach actual intakes of monoglutamate and polyglutamate folate as closely as possible. Seasonal and regional variation in folate content of foods appeared to be low. However, analytical variance might have introduced some error (30
). RBC folate gives a better reflection of long-term folate status than plasma folate. Because RBC were not collected, we could not determine RBC folate from subjects. The percentages of variance in plasma folate levels explained by our models are in line with those found by other researchers (34
).
The different results obtained in men and women may be explained by distinct patterns of food intake. Although men obtain 12% of their monoglutamate folate from fruits and vegetables, women obtain 21% from these sources. The food matrix of fruits and vegetables might reduce folate bioavailability. The food matrix can be described as the cell structure that encapsulates a nutrient and complexes it to proteins and fiber.
Little is known about the role of food matrix and its interaction with different chemical folate forms in folate bioavailability. Van het Hof et al. (36
) and Castenmiller et al. (37
) compared the effects of consumption of whole-leaf spinach with that of chopped spinach on plasma folate levels. Both authors concluded that disruption of the vegetable matrix resulted in higher folate bioavailability.
Another explanation for the better bioavailability of monoglutamate folate in men than in women might be differences in alcohol intake. Brussaard et al. (34
) also reported a consistent positive relationship between alcohol consumption in the general (nonalcoholic) Dutch population and serum folate concentrations independent of folate intake, such as we found in the present study. Monoglutamate folate intake from beer may partially explain this association, although it remained after adjustment for total folate intake. A direct positive effect of low doses of ethanol on plasma folate concentrations cannot be excluded. To date, research has focused on the effect of high doses of alcohol. An inverse relationship between alcohol intake and folate status was shown in alcoholics. (38
,39
). In vitro studies showed that alcohol could cleave folate, thereby destroying its vitamin activity (40
). Also, alcohol was shown to decrease glutamate carboxypeptidase II activity, thereby affecting the absorption of polyglutamate folate (41
,42
). Until now, only one intervention study examined the effects of lower alcohol doses on folate levels (43
). In that study, no effect was found of red wine, beer or spirits on plasma folate concentrations compared with water. However, the dosage of alcohol in this study might still have been too high (40 g/d).
In conclusion, intake of polyglutamate folate was twice that of monoglutamate folate in this Dutch population. The positive trends in plasma folate levels found for both monoglutamate and polyglutamate folate intakes prove that both folate forms contribute favorably to plasma folate levels of both men and women. The present study suggests that folate bioavailability in men is reduced by the polyglutamate chain, which supports our initial hypothesis, but not in women. This discrepancy might be due to differences in dietary patterns leading to differences in folate bioavailability caused by the food matrix in which the folate is contained. Therefore, it may not be the polyglutamate chain that reduces dietary folate biavailability but rather the matrix in which dietary folate is incorporated. Alcohol intake appeared to be a strong determinant of folate status and might explain the different findings in men and women as well. Because of possible uncontrollable bias, data must be interpreted with some caution. To study the specific factors involved in folate bioavailability more thoroughly, properly designed intervention studies are required. At present, it does not seem necessary to distinguish between food folate forms in advising an increase in folate intake from the diet.
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FOOTNOTES |
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3 Abbreviations used: CI, confidence interval; EPIC, European Prospective Investigation into Cancer and Nutrition; FFQ, food-frequency questionnaire; MORGEN, Monitoring Project on Risk Factors for Chronic Diseases; MP-ratio, monoglutamate to polyglutamate ratio.
Manuscript received 11 October 2001. Initial review completed 16 November 2001. Revision accepted 23 February 2002.
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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D. J McKillop, H. McNulty, J. M Scott, J. M McPartlin, J. Strain, I. Bradbury, J. Girvan, L. Hoey, R. McCreedy, J. Alexander, et al. The rate of intestinal absorption of natural food folates is not related to the extent of folate conjugation Am. J. Clinical Nutrition, July 1, 2006; 84(1): 167 - 173. [Abstract] [Full Text] [PDF]
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M. P Hannon-Fletcher, N. C Armstrong, J. M Scott, K. Pentieva, I. Bradbury, M. Ward, J. Strain, A. A Dunn, A. M Molloy, M. A Kerr, et al. Determining bioavailability of food folates in a controlled intervention study Am. J. Clinical Nutrition, October 1, 2004; 80(4): 911 - 918. [Abstract] [Full Text] [PDF]
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A. Melse-Boonstra, K. J. Lievers, H. J Blom, and P. Verhoef Bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid in subjects with different genotypes of the glutamate carboxypeptidase II gene Am. J. Clinical Nutrition, September 1, 2004; 80(3): 700 - 704. [Abstract] [Full Text] [PDF]
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A. Melse-Boonstra, C. E West, M. B Katan, F. J Kok, and P. Verhoef Bioavailability of heptaglutamyl relative to monoglutamyl folic acid in healthy adults Am. J. Clinical Nutrition, March 1, 2004; 79(3): 424 - 429. [Abstract] [Full Text] [PDF]
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