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  • Original Article
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L-ascorbic acid improves the serum folate response to an oral dose of [6S]-5-methyltetrahydrofolic acid in healthy men

European Journal of Clinical Nutrition volume 62, pages 1224–1230 (2008)Cite this article

Abstract

Objective:

To investigate the effect of simultaneous administration of [6S]-5-methyltetrahydrofolic acid ([6S]-5-CH3H4PteGlu) with L-ascorbic acid (L-AA) on serum folate concentrations in healthy male subjects.

Subjects and methods:

A total of nine healthy male volunteers were recruited. Serum folate concentrations were measured before and up to 8 h after administration of each treatment (1) placebo, (2) 343 μg [6S]-5-CH3H4PteGlu), (3) 343 μg [6S]-5-CH3H4PteGlu) with 289.4 mg L-AA and (4) 343 μg [6S]-5-CH3H4PteGlu) with 973.8 mg L-AA (n=10 samples per treatment).

Results:

Serum folate concentrations significantly increased compared with baseline values, starting from 30 min after [6S]-5-CH3H4PteGlu administration and remained significantly higher than baseline values during the first 6 h for treatments 3 and 4, and during the first 4 h for treatment 2. Maximal serum folate responses were observed between 0.5 and 1.5 h after [6S]-5-CH3H4PteGlu consumption and significantly differed between treatments 2 and 4 (P<0.05). When [6S]-5-CH3H4PteGlu was concurrently administered with 289.4 or 973.8 mg L-AA, the total serum folate response, calculated as the area under the curve (AUC), was significantly improved (46.5±4.0 and 53.0±4.0 vs 34.3±3.8 h nmol/l, P<0.05). No significant difference in AUC was found between the 289.4 and the 973.8 mg L-AA treatments.

Conclusions:

Administration of a physiological dose of [6S]-5-CH3H4PteGlu with L-AA significantly improved the measured serum folate response in folate saturated healthy men.

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References

  • Altman DJ (1991). Serial measurements. In: Altman DJ (ed). Practical Statistics for Medical Research. Chapman and Hall: London, pp 426–433.

    Google Scholar 

  • Bates CJ, Fleming M, Paul AA, Black AE, Mandal AR (1980). Folate status and its relation to vitamin C in healthy elderly men and women. Age Ageing 9, 241–248.

    Article  CAS  Google Scholar 

  • Cafolla A, Dragoni F, Girelli G, Tosti ME, Costante A, De Luca AM et al. (2002). Effect of folic acid and vitamin C supplementation on folate status and homocysteine level: a randomised controlled trial in Italian smoker-blood donors. Atherosclerosis 163, 105–111.

    Article  CAS  Google Scholar 

  • Cahill E, McPartlin J, Gibney MJ (1998). The effects of fasting and refeeding healthy volunteers on serum folate levels. Int J Vitam Nutr Res 68, 142–145.

    CAS  PubMed  Google Scholar 

  • Cornel MC, de Smit DJ, de Jong-van den Berg LT (2005). Folic acid—the scientific debate as a base for public health policy. Reprod Toxicol 20, 411–415.

    Article  CAS  Google Scholar 

  • Czeizel AE, Dudas I (1992). Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327, 1832–1835.

    Article  CAS  Google Scholar 

  • de Meer K, Smulders YM, Dainty JR, Smith DEC, Kok RM, Stehouwer CDA et al. (2005). [6S]5-methyltetrahydrofolate or folic acid supplementation and absorption and initial elimination of folate in young and middle-aged adults. Eur J Clin Nutr 59, 1409–1416.

    Article  CAS  Google Scholar 

  • Donaldson KO, Keresztesy JC (1962). Naturally occurring forms of folic acid. III. Characterization and properties of 5-methyldihydrofolate, an oxidation product of 5-methyltetrahydrofolate. J Biol Chem 237, 3815–3819.

    CAS  PubMed  Google Scholar 

  • Eichholzer M, Tonz T, Zimmermann R (2006). Folic acid: a public-health challenge. Lancet 367, 1352–1361.

    Article  Google Scholar 

  • Gregory III JF (1995). The bioavailability of folate. In: Bailey LB (ed). Folate in Health and Disease. Marcel Dekker Inc.: New York, NY, pp 195–235.

    Google Scholar 

  • Gregory III JF (2002). In vivo kinetics of folate metabolism. Annu Rev Nutr 22, 199–220.

    Article  CAS  Google Scholar 

  • Gunter EW, Bowman BA, Caudill SP, Twite DB, Adams MJ, Sampson EJ (1996). Results of an international round robin for serum and whole-blood folate. Clin Chem 42, 1689–1694.

    CAS  PubMed  Google Scholar 

  • Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY (2001). Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 285, 2981–2986.

    Article  CAS  Google Scholar 

  • Jagerstad M, Piironen V, Walker C, Ros G, Carnovale E, Holasova M et al. (2005). Increasing natural food folates through bioprocessing and biotechnology. Trends Food Sci Tech 16, 298–306.

    Article  Google Scholar 

  • Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM (1997). Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 65, 1790–1795.

    Article  CAS  Google Scholar 

  • Kim YI (1999). Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10, 66–88.

    Article  CAS  Google Scholar 

  • Kim YI (2004). Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr 80, 1123–1128.

    Article  CAS  Google Scholar 

  • Kyllastinen MJ, Elfving SM, Gref CG, Aro A (1990). Dietary vitamin c supplementation and common laboratory values in the elderly. Arch Gerontol Geriatr 10, 297–301.

    Article  CAS  Google Scholar 

  • Lamers Y, Prinz-Langenohl R, Bramswig S, Pietrzik K (2006). Red blood cell folate concentrations increase more after supplementation with [6S]-5-methyltetrahydrofolate than with folic acid in women of childbearing age. Am J Clin Nutr 84, 156–161.

    Article  CAS  Google Scholar 

  • Lamers Y, Prinz-Langenohl R, Moser R, Pietrzik K (2004). Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women. Am J Clin Nutr 79, 473–478.

    Article  CAS  Google Scholar 

  • Liau LS, Lee BL, New AL, Ong CN (1993). Determination of plasma ascorbic acid by high-performance liquid chromatography with ultraviolet and electrochemical detection. J Chromatogr 612, 63–70.

    Article  CAS  Google Scholar 

  • Lucock MD, Priestnall M, Daskalakis I, Schorah CJ, Wild J, Levene MI (1995). Nonenzymatic degradation and salvage of dietary folate: physicochemical factors likely to influence bioavailability. Biochem Mol Med 55, 43–53.

    Article  CAS  Google Scholar 

  • McNulty H, Pentieva K (2004). Folate bioavailability. Proc Nutr Soc 63, 529–536.

    Article  CAS  Google Scholar 

  • Melse-Boonstra A, Verhoef P, West C (2004). Quantifying folate bioavailability: a critical appraisal of methods. Curr Opin Clin Nutr Metab Care 7, 539–545.

    Article  Google Scholar 

  • Mix JA (1999). Do megadoses of vitamin C compromise folic acid's role in the metabolism of plasma homocysteine? Nutr Res 19, 161–165.

    Article  CAS  Google Scholar 

  • Moat SJ, Lang D, McDowell IF, Clarke ZL, Madhavan AK, Lewis MJ et al. (2004). Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem 15, 64–79.

    Article  CAS  Google Scholar 

  • Oey I, Verlinde P, Hendrickx M, Van Loey A (2006). Temperature and pressure stability of L-ascorbic acid and/or [6S] 5-methyltetrahydrofolic acid: a kinetic study. Eur Food Res Tech 223, 71–77.

    Article  CAS  Google Scholar 

  • Owen WE, Roberts WL (2003). Comparison of five automated serum and whole blood folate assays. Am J Clin Pathol 120, 121–126.

    Article  CAS  Google Scholar 

  • Pentieva K, McNulty H, Reichert R, Ward M, Strain JJ, McKillop DJ et al. (2004). The short-term bioavailabilities of [6S]-5-methyltetrahydrofolate and folic acid are equivalent in men. J Nutr 134, 580–585.

    Article  CAS  Google Scholar 

  • Pfeiffer CM, Rogers LM, Bailey LB, Gregory III JF (1997). Absorption of folate from fortified cereal-grain products and of supplemental folate consumed with or without food determined by using a dual-label stable-isotope protocol. Am J Clin Nutr 66, 1388–1397.

    Article  CAS  Google Scholar 

  • Pietrzik K, Hages M, Remer T (1990). Methodological aspects in vitamin bioavailability testing. J Micronutr Anal 7, 207–222.

    CAS  Google Scholar 

  • Prinz-Langenohl R, Lamers Y, Moser R, Pietrzik K (2003). Effect of folic acid preload on the bioequivalence of [6S]-5-methyltetrahydrofolate and folic acid in healthy volunteers. J Inherit Metab Dis 26, 126 (abstract).

    Google Scholar 

  • Qiu A, Jansen M, Sakaris A, Min SH, Chattopadhyay S, Tsai E et al. (2006). Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption. Cell 127, 917–928.

    Article  CAS  Google Scholar 

  • Said HM (2004). Recent advances in carrier-mediated intestinal absorption of water-soluble vitamins. Annu Rev Physiol 66, 419–446.

    Article  CAS  Google Scholar 

  • Said HM, Ghishan FK, Redha R (1987). Folate transport by human intestinal brush-border membrane vesicles. Am J Physiol Gastrointest Liver Physiol 252, G229–G236.

    Article  CAS  Google Scholar 

  • Seeuws C, Vansant G, Van Havere R, Gielen J, Beernaert H, Keymolen R et al. (1995). Nutriments Belgium—Belgian Food Composition Tables. NUBEL vzw: Brussels.

    Google Scholar 

  • Selhub J, Bagley LC, Miller J, Rosenberg IH (2000). B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr 71, 614s–620s.

    Article  CAS  Google Scholar 

  • Selhub J, Powell GM, Rosenberg IH (1984). Intestinal transport of 5-methyltetrahydrofolate. Am J Physiol Gastrointest Liver Physiol 246, G515–G520.

    Article  CAS  Google Scholar 

  • Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB et al. (2002). Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346, 476–483.

    Article  CAS  Google Scholar 

  • Seyoum E, Selhub J (1998). Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action. J Nutr 128, 1956–1960.

    Article  CAS  Google Scholar 

  • Stover P (2004). Physiology of folate and viamin B12 in health and disease. Nutr Rev 62, S3–S12.

    Article  Google Scholar 

  • Sundrehagen E (1990). Enzymatic essay for homocysteine and a kit therefore (Patent EP 623174/US 56 31127).

  • Tamura T (1998). Determination of food folate. J Nutr Biochem 9, 285–293.

    Article  CAS  Google Scholar 

  • Thien KR, Blair JA, Leeming RJ, Cooke WT, Melikian V (1977). Serum folates in man. J Clin Pathol 30, 438–448.

    Article  CAS  Google Scholar 

  • Venn BJ, Green TJ, Moser R, Mann JI (2003). Comparison of the effect of low-dose supplementation with L-5-methyltetrahydrofolate or folic acid on plasma homocysteine: a randomized placebo-controlled study. Am J Clin Nutr 77, 658–662.

    Article  CAS  Google Scholar 

  • Venn BJ, Green TJ, Moser R, McKenzie JE, Skeaff CM, Mann J (2002). Increases in blood folate indices are similar in women of childbearing age supplemented with [6S]-5-methyltetrahydrofolate and folic acid. J Nutr 132, 3353–3355.

    Article  CAS  Google Scholar 

  • Witthöft CM, Stralsjö L, Berglund G, Lundin E (2003). A human model to determine folate bioavailability from food: a pilot study for evaluation. Scand J Nutr 47, 6–18.

    Article  Google Scholar 

  • Wright AJ, Finglas PM, Southon S (2001). Proposed mandatory fortification of the UK diet with folic acid: have potential risks been underestimated? Trends Food Sci Tech 12, 313–321.

    Article  CAS  Google Scholar 

  • Wright AJ, Finglas PM, Dainty JR, Hart DJ, Wolfe CA, Southon S et al. (2003). Single oral doses of 13C forms of pteroylmonoglutamic acid and 5-formyltetrahydrofolic acid elicit differences in short-term kinetics of labelled and unlabelled folates in plasma: potential problems in interpretation of folate bioavailability studies. Br J Nutr 90, 363–371.

    Article  CAS  Google Scholar 

  • Wright AJ, Finglas PM, Dainty JR, Wolfe CA, Hart DJ, Wright DM et al. (2005). Differential kinetic behavior and distribution for pteroylglutamic acid and reduced folates: a revised hypothesis of the primary site of PteGlu metabolism in humans. J Nutr 135, 619–623.

    Article  CAS  Google Scholar 

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Acknowledgements

This research was funded by the Institute for the Promotion of Innovation through Science and Technology Flanders, FWO-Flanders and the Unilever Chair in Nutrition and Health at KULeuven. Merck Eprova kindly provided [6S]-5-methyltetrahydrofolate (Metafolin) for the whole study. We acknowledge Baudenelle and Verhoeven for excellent technical/medical assistance.

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Authors and Affiliations

  1. Department of Microbial and Molecular Systems, Centre for Food and Microbial Technology, Laboratory of Food Technology, Katholieke Universiteit Leuven, Heverlee, Belgium

    P H C J Verlinde, I Oey, M E Hendrickx & A M Van Loey

  2. Division of Nutritional Epidemiology, Department of Public Health, Katholieke Universiteit Leuven, Leuven, Belgium

    E H M Temme

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  1. P H C J Verlinde
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  2. I Oey
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Correspondence to A M Van Loey.

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Contributors: PHCJV designed the study, developed the experiments, prepared the original draft and wrote the final paper; IO and PHCJV performed the laboratory measurements; EHMT and PHCJV analyzed the data; MEH, AMVL, IO and EHMT contributed to the study design and protocol and writing of the paper; all contributors edited the paper.

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Verlinde, P., Oey, I., Hendrickx, M. et al. L-ascorbic acid improves the serum folate response to an oral dose of [6S]-5-methyltetrahydrofolic acid in healthy men. Eur J Clin Nutr 62, 1224–1230 (2008). https://doi.org/10.1038/sj.ejcn.1602840

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