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Research Communication

Availability of Food Folate in Humans

Institute of Nutritional Science, Department of Pathophysiology of Human Nutrition, University of Bonn, 53115 Bonn, Germany

¹To whom correspondence should be addressed.

	ABSTRACT

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The aim of our study was to determine whether the area-under-the-plasma-response-curve method with the positive area (AUC+) as primary analysis variable is suitable to evaluate the availability of food folate in humans. Healthy volunteers (n = 20) received four test meals in a randomized, four-period cross-over design as follows: meal A, 600 g spinach; meal B, 300 g spinach; meal C, 0.4 mg folic acid in water; meal D, folate-free control meal. Blood samples were drawn before administration of the test meals and up to 10 h postprandially. Plasma folate was significantly increased for up to 6 h after uptake of spinach and folic acid (P < 0.007), whereas the response curve after the control meal decreased slightly but significantly (P < 0.007). To calculate the net increase of plasma folate, the values were corrected by the individual predose concentrations. The AUC+ was calculated with these corrected values. The mean AUC+ was highest after consumption of meal A (71.2 ± 24.0 h x nmol/L) followed by meal C (61.8 ± 23.8 h x nmol/L) and meal B (41.4 ± 19.4 h x nmol/L). The AUC+ after meal B was significantly lower than after the other two meals (P < 0.05). The results suggest that the AUC method with multiple blood sampling is useful for assessing the availability of food folate in humans.

KEY WORDS: • folate • availability • spinach • AUC method • humans

	INTRODUCTION

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Intervention trials have clearly demonstrated a protective effect of periconceptional folic acid supplementation on the incidence of neural tube defects (NTD)² (British MRC Vitamin Study Research Group 1991 , Czeizel and Dudás 1992 ). Consequently, several health authorities in Europe and the United States advise all women of childbearing age to consume 0.4 mg folic acid per day to reduce their risk of having a NTD-affected pregnancy (CDC 1992 , Department of Health 1992 , Commission of the European Communities 1993 , Koletzko and von Kries 1994 , Société française de pédiatrie-Comité de nutrition 1995 , Tönz et al. 1996 ). To increase folate intake, three strategies may be considered, i.e., use of folic acid supplements, consumption of foods fortified with folic acid and selection of folate-rich foods (Department of Health 1992 ). However, the effectiveness of these interventions and especially the bioavailability of food folate are under discussion (Cuskelly et al. 1996 ).

A variety of experimental designs have been used to assess folate bioavailability in humans. These include bioassays with measurement of increases of plasma, red blood cell or urinary folate in response to a single or multiple test dose as well as isotopic techniques based on the recovery of labeled folate or metabolites in urine after a test dose (Gregory 1995 ). A technique used for assessing bioavailability of medicinal agents in pharmaceuticals is the area-under-the-plasma-response-curve method (AUC) (CPMP 1991 ). There are some important methodological problems associated with this method if used for endogenous compounds such as folate that occur naturally in the body. Other sources of folate have to be avoided during the measurement period, requiring either uptake of a folate-free diet or abstinence from food. However, fasting may affect plasma folate considerably. During fasting, the concentrations of plasma folate and bilirubin, an indicator of hepatic excretory activity, increase (Cahill et al. 1998 , Pietrzik et al. 1990 ). The nearly parallel changes in plasma folate and bilirubin suggest that fasting interrupts the enterohepatic circulation, leading to a block of an important elimination route (Pietrzik et al. 1990 ). The increasing plasma folate concentration during fasting could result in an overestimation of the AUC and thus the bioavailability of the substance under investigation.

The purpose of this study was to determine whether the AUC method, which is a generally accepted method to determine folic acid bioavailability from pharmaceuticals, can also be applied to assess the availability of food folate. Because of its relatively high folate content, commercially available leafy spinach was selected as the source of food folate and compared with a folic acid–containing aqueous reference dose.

	MATERIALS AND METHODS

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Subjects.

The volunteers (10 women, 10 men, all Caucasians, mean age 27 ± 2.8 y, mean body mass index 21.2 ± 2.2 kg/m²) were recruited from university students and laboratory staff. Subjects were eligible if they were apparently healthy without history of an organic or psychotic disease. None of the female subjects had any prior history of an infant with a NTD. The volunteers did not take folic acid supplements or drugs known to interact with folate metabolism. Subjects were screened for fasting folate concentrations above a certain cut-off value (plasma folate >6.8 nmol/L, red blood cell folate >317 nmol/L) to avoid inclusion of subjects with a low folate status (Sauberlich 1995 ). The volunteers were instructed to continue their normal dietary habits for the duration of the study. The study protocol was reviewed and approved by the Ethics Committee of the General Medical Council Hamburg (Germany). Informed written consent was obtained from all volunteers before participation in the study.

Study design.

In a randomized cross-over design, the volunteers received four different test meals with a wash-out period of 1 wk between the test days. Meal A consisted of two packages of commercially available leafy spinach (600 g). The spinach contained 80 µg folate/100 g wet weight according to the imprint of the package (leafy spinach, Langnese-Iglo, Hamburg, Germany). Meal B was composed of one package of spinach (300 g) plus a folate-free formula diet³ (12 g powder mixed with 100 mL water) to account for the energy difference from meal A and water (177 mL) to account for volume difference. Meal C consisted of an aqueous solution containing 0.4 mg folic acid (pteroylmonoglutamic acid, Synopharm, Barsbüttel, Germany) in 5 mL water, formula diet (24 g powder mixed with 200 mL water) and water (350 mL). The reference dose of 0.4 mg folic acid was selected because this amount is recommended by different health authorities for prevention of the occurrence of NTD. Meal D was made up of formula diet (24 g powder mixed with 200 mL water) and water (355 mL) and served as a control to evaluate possible changes of the plasma folate concentration during the test day without intake of folate. All meals contained 402 kJ and 555 mL water. The content of macronutrients was similar (fat: A 1.8 g, B, C, D 1.7 g; carbohydrate: A 2.4 g, B 7.7g, C, D 13 g; protein: A 13.8 g, B 10.4 g, C, D 7 g). The nutrient composition was estimated according to the nutrient composition database Bundeslebensmittelschlüssel (1996) and the package label of the formula.

The meals were prepared directly before consumption. Frozen spinach was thawed overnight at 4°C and heated in a microwave without additional water at 600 W for 8 min with stirring after 4 min (600 g spinach) or 6 min with stirring after 3 min (300 g spinach), respectively. The volunteers consumed the test meals at 0800 h after an overnight fast.

Basal diet during the test days.

The subjects consumed the folate-free formula diet described above (35 g powder in 200 mL water) together with milk chocolate as source of energy (770 kJ/35 g containing < 1 µg folate) and 200 mL of mineral water, coffee or tea without sugar and milk at 1000, 1200, 1400 and 1600 h. Additional drinks or food were not allowed during the test day.

Analytical methods.

Blood samples were obtained by venipuncture using vacutainers with sodium heparin as anticoagulant (Becton Dickinson, Rutherford, NJ). A fasting blood sample was drawn directly before consumption of the test meals, which was followed by seven postprandial samples (1, 2, 3, 4, 6, 8 and 10 h). Plasma was separated by centrifugation (3000 x g, 10 min) and stored at -20°C until analysis. Plasma folate was determined with a chemiluminescence assay (Magic Lite Folic Acid Immunoassay, Chiron Diagnostics, Fernwald, Germany) after dilution of all samples with folate diluent (1:2). All samples of each volunteer were analyzed in one assay to reduce measurement variability.

Statistical analysis.

The data from all volunteers (n = 20) admitted to the study were included in the statistical analysis (intention-to-treat analysis). The AUC _{(0–10 h)} were calculated according to the trapezoidal method (Pfeifer et al. 1984 ). Individual predose plasma folate concentrations of each test day were used as baseline for the calculation of AUC. To avoid negative AUC values, which can result in some cases if plasma folate concentration falls below baseline, the positive area-under-the-plasma-response-curve (AUC+) was used, neglecting all values falling below the individual predose level. Peak plasma folate concentration (C_max) was determined from the corrected plasma response curve. The test meals were compared with respect to plasma folate at subsequent time points, AUC+ and C_max by means of parametric models (Student's t test for within-subject comparisons and ANOVA with post-hoc Student-Newman-Keuls test for between-subject comparisons). Differences were considered significant at P < 0.05. To reduce the possibility of type I error when conducting multiple comparisons of means for dependent variables, a Bonferroni-corrected P-value of 0.007 was used (Wassertheil-Smoller 1990 ). All P-values are two-tailed. Because the variables were normally distributed according to the Shapiro-Wilk test, the statistical analyses were performed with untransformed variables. Values are reported as means ± SD. The pharmacokinetic parameters were calculated using the software TOPFIT, version 2.0 (Heinzel et al. 1993 ). For statistical analysis, the software SPSS for Windows (Version 7.5.2, SPSS, Chicago, IL) was used.

	RESULTS

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Plasma folate.

The predose plasma folate concentrations did not differ on the four test days (P = 0.53), indicating that there were no carry-over effects from the preceding test days. Table 1 presents the mean plasma folate values before and after consumption of the four test meals. The plasma responses after consumption of a folate-containing meal exhibited a similar pattern for all three groups. The mean increase in plasma folate significantly exceeded the predose level for up to 4 h (meal B) and 6 h (meals A and C) (P < 0.007). Consumption of the folate-containing meals resulted in C_max of 19.1 ± 6.5 nmol/L (meal A), 12.1 ± 4.4 nmol/L (meal B) and 17.8 ± 5.8 nmol/L (meal C) and occurred between 1 and 2 h postprandially (Table 2 ). The C_max obtained after subjects consumed 300 g spinach was significantly lower than that after consumption of 600 g spinach or folic acid, (P < 0.05). A slight decrease in the mean plasma folate concentration was observed after consumption of the folate-free control meal (meal D), which reached a minimum after 10 h. The mean concentration was significantly lower than the fasting value (0 h) after 1, 4, 6, 8 and 10 h (P < 0.007).

To calculate AUC+, the individual predose plasma folate concentration for each meal was subtracted from the measured plasma folate values. The AUC+ was higher after consumption of 600 g spinach or 0.4 mg folic acid than after consumption of 300 g spinach (P < 0.05, Table 2 ).

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study was conducted to determine whether the AUC method developed for assessment of the bioavailability of medicinal agents in pharmaceuticals is suitable for evaluation of availability of food folate in humans. Assessment of the availability of physiologic substances such as vitamins is more complex than the determination of the availability of xenobiotics. The amount of folate absorbed by individual subjects can vary considerably depending on several factors, i.e, in subjects with low folate status, folate is transported from plasma to the cells more rapidly and lower amounts of folate are excreted with the urine. The altered plasma clearance rate has a direct effect on the plasma response curve (Pietrzik et al. 1990 ). The absorption rate might be influenced by pathologic conditions (e.g., malabsorption) or physiologic conditions such as growth, pregnancy and lactation. Other factors with an effect on absorption may include food matrix, pH value at the jejunal mucosal surface, intestinal transit time or inhibition of pteroyl-polyglutamate hydrolase activity by unknown food components (Gregory 1995 ). Moreover, the discrimination between physiologic nutrient levels and postabsorption concentrations is difficult without labeling of the nutrient. Fasting also affects plasma folate, resulting in increased concentrations. Pietrzik et al. (1990) observed a more than 100% increase in serum folate from a mean of 8 ng/mL (18 nmol/L) to 18 ng/mL (40.7 nmol/L) during a 24-h fast. Similar findings were reported by Cahill et al. (1998) . During a 36-h fast, serum folate increased from a mean of 14.8 ng/mL (33.5 nmol/L) to 29.3 ng/mL (66.3 nmol/L).

To minimize these influences, only healthy subjects with a plasma folate level >6.8 nmol/L and red blood cell folate concentrations >317 nmol/L participated in this study. Subjects with a low folate status were not included (Sauberlich 1995 ), and none of the participating women was pregnant or lactating. To avoid the problem of increasing plasma folate during fasting as described by Cahill et al. (1998) and Pietrzik et al. (1990) , an energy-adequate but folate-free diet was given to the volunteers during the test days as a basal diet to control for hepatic influences on folate metabolism. Rather than increasing, the plasma response curve decreased slightly but significantly after consumption of the folate-free control meal and the basal diet during the day, indicating that influences of fasting were eliminated. The maximal mean difference was 5.1 nmol/L (0 vs. 10 h postprandially). Therefore, using the predose level for correction of the plasma folate concentrations postprandially results in a small underestimation of AUC+.

Results from this study were determined under standardized conditions that may not reflect usual dietary habits. Meals consisting of a single folate-containing food item are rare. In a more complex meal, interactions with other food components might occur. Thus, the results observed may not be typical for the absorption values occurring under usual dietary conditions. The large amount of food consumed after an overnight fast may alter normal digestive functions (e.g., intestinal transit time).

Previous studies of folate bioavailability in humans determined either the increases in folate in plasma (Bailey et al. 1988 , Colman et al. 1975 , Keagy et al. 1988 , Kelly et al. 1997 ), red blood cells (Margo et al. 1975 ) or urine (Babu and Srikantia 1976 , Keagy et al. 1988 , Tamura and Stokstad 1973 , Tamura et al. 1976 ) or followed the fate of labeled folates using different techniques (Gregory et al. 1990 , 1991 and 1992 , Pfeiffer et al. 1997 , Wei et al. 1996 ). In these studies, short- or long-term protocols were used. Long-term administration studies as conducted by Cuskelly et al. (1996) are useful to evaluate the relative bioavailability of folate from different sources, but they are time-consuming and very demanding of the volunteers' compliance. Labeling techniques using radioisotopes and stable isotopes are obviously the best method for bioavailability testing because of their high sensitivity. However, the use of radiolabeled folate is difficult to justify. Labeling methods with stable isotopes are better suited for studies in humans because of the greater safety (Gregory 1995 ), but sophisticated and expensive equipment for synthesis and measurement of the labeled substances are required.

Protocols based on a limited number of plasma or serum folate measurements (e.g., 1- to 2-h blood samples) may underestimate the bioavailability of folates. In a study by Keagy et al. (1988) , the effect of wheat bran or California small white beans in the diet on absorption of mono- and heptaglutamyl folic acid was studied in six men. Relative folate absorption was determined by measuring folate excretion in 24-h urine samples and serum folate concentrations at 0, 1 and 2 h after consumption of a formula meal containing the two folate derivatives. Serum folate concentrations indicated a more rapid absorption of the mono- compared with the heptaglutamyl form. Calculating the AUC values with serum folate values at the three time points resulted in 22.6 h x nmol/L after uptake of monoglutamyl and 12.8 h x nmol/L after heptaglutamyl folic acid. As discussed by the authors, the limited number of serum samples may have led to an underestimation of net utilization if the absorption of the heptaglutamyl form occurred to the same extent but at a different rate.

In our study, frequent and numerous blood sampling for up to 10 h was chosen because the time needed for return to baseline after consumption of the test meals was unknown. Because the plasma folate level dropped below baseline during the measurement period, absorption was complete within 10 h and the period chosen was sufficient Our data suggest that a measurement period as short as 8 h would have been sufficient in this case (Table 1) .

Bailey et al. (1988) reported that the plasma response after small oral folate doses (250 µg folic acid) is low. In contrast, other authors showed a distinct response curve at an intake as low as 150 µg folic acid in aqueous solution with a linearity of the AUC for doses between 150 and 5000 µg (Pietrzik et al. 1990 ). In our study, the AUC obtained after consumption of 600 g spinach was less than double that after 300 g spinach. This may have been due to an altered digestion process resulting from either the high quantity of foodstuff (e.g., exceeding the capacity of intestinal deconjugation) or the high fiber content of spinach.

In summary, the results of this study indicate that the AUC method with multiple blood sampling over a period of 8 h and a standardized folate-free basal diet is a valid approach for assessing the availability of food folate in humans. Increases in plasma folate can be used as an indicator of available folate. In contrast to other protocols, e.g., techniques using stable isotopes, this method is applicable with standard technical equipment. Thus, the AUC method may considerably facilitate research in bioavailability assessment.

	FOOTNOTES

 
¹ Abbreviations used: AUC, area-under-the-plasma-response-curve; C_max, peak plasma concentration; NTD, neural tube defect.

² Composition of the folate-free formula diet was as follows: 100 g of diet powder contained 1668 kJ, 29 g protein, 53 g carbohydrates, 7.2 g fat, 700 mg calcium, 12 mg iron, 600 µg vitamin A, 1.2 mg thiamin, 1.2 mg riboflavin, 1.2 mg vitamin B-6, 57 mg vitamin C, 1.7 µg vitamin D and 8 mg vitamin E (Multaben Diätdrink, Aktivkost, Hamburg, Germany).

Manuscript received September 7, 1998. Revision accepted January 7, 1999.

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