Folic acid handling by the human gut: implications for food fortification and supplementation

Imran Patanwala, Maria J King, David A Barrett, John Rose, Ralph Jackson, Mark Hudson, Mark Philo, Jack R Dainty, Anthony J A Wright, Paul M Finglas, David E Jones, Imran Patanwala, Maria J King, David A Barrett, John Rose, Ralph Jackson, Mark Hudson, Mark Philo, Jack R Dainty, Anthony J A Wright, Paul M Finglas, David E Jones

Abstract

Background: Current thinking, which is based mainly on rodent studies, is that physiologic doses of folic acid (pterylmonoglutamic acid), such as dietary vitamin folates, are biotransformed in the intestinal mucosa and transferred to the portal vein as the natural circulating plasma folate, 5-methyltetrahydrofolic acid (5-MTHF) before entering the liver and the wider systemic blood supply.

Objective: We tested the assumption that, in humans, folic acid is biotransformed (reduced and methylated) to 5-MTHF in the intestinal mucosa.

Design: We conducted a crossover study in which we sampled portal and peripheral veins for labeled folate concentrations after oral ingestion with physiologic doses of stable-isotope-labeled folic acid or the reduced folate 5-formyltetrahydrofolic acid (5-FormylTHF) in 6 subjects with a transjugular intrahepatic porto systemic shunt (TIPSS) in situ. The TIPSS allowed blood samples to be taken from the portal vein.

Results: Fifteen minutes after a dose of folic acid, 80 ± 12% of labeled folate in the hepatic portal vein was unmodified folic acid. In contrast, after a dose of labeled 5-FormylTHF, only 4 ± 18% of labeled folate in the portal vein was unmodified 5-FormylTHF, and the rest had been converted to 5-MTHF after 15 min (postdose).

Conclusions: The human gut appears to have a very efficient capacity to convert reduced dietary folates to 5-MTHF but limited ability to reduce folic acid. Therefore, large amounts of unmodified folic acid in the portal vein are probably attributable to an extremely limited mucosal cell dihydrofolate reductase (DHFR) capacity that is necessary to produce tetrahydrofolic acid before sequential methylation to 5-MTHF. This process would suggest that humans are reliant on the liver for folic acid reduction even though it has a low and highly variable DHFR activity. Therefore, chronic liver exposure to folic acid in humans may induce saturation, which would possibly explain reports of systemic circulation of unmetabolized folic acid.

Trial registration: ClinicalTrials.gov NCT02135393.

Figures

FIGURE 1.
FIGURE 1.
Location of the TIPSS in the liver. TIPSS, transjugular intrahepatic porto systemic shunt.
FIGURE 2.
FIGURE 2.
A: Mean (±SEM) concentrations of labeled folic acid (circles) and labeled 5-MTHF (squares) in the hepatic portal venous circulation after the ingestion of a labeled folic acid dose (n = 6). At time = 15 min, there was a significantly (P < 0.01) higher percentage of labeled folic acid than labeled 5-MTHF. B: Mean (±SEM) concentrations of labeled folic acid (circles) and labeled 5-MTHF (squares) in systemic plasma after the ingestion of a labeled folic acid dose (n = 6). C: Mean (±SEM) concentrations of labeled 5-FormylTHF (diamonds) and labeled 5-MTHF (squares) in the hepatic portal venous circulation after the ingestion of a labeled formyl dose (n = 4). At time = 15 min, there was a significantly (P < 0.001) higher percentage of labeled 5-MTHF than of labeled 5-FormylTHF. D: Mean (±SEM) concentrations of labeled 5-FormylTHF (diamonds) and labeled 5-MTHF (squares) in systemic plasma after the ingestion of a labeled formyl dose (n = 4). Note differences in study durations for portal (A and C) and systemic (B and D) elements of the study. Also note differences in y-axis scales between panels. 5-FormylTHF, 5-formyltetrahydrofolic acid; 5-MTHF, 5-methyltetrahydrofolic acid.
FIGURE 3.
FIGURE 3.
Proposed folate absorption from the gut lumen, metabolism in mucosal cells, and transport out into the hepatic portal vein. DHFR, dihydrofolate reductase; MRP3, multidrug resistance protein 3; PCFT, proton-coupled folate transporter; THF, tetrahydrofolate; 5-FormylTHF, 5-formyltetrahydrofolic acid; 5-MTHF, 5-methyltetrahydrofolic acid.

References

    1. Czeizel AE, Dudás I. Prevention of first occurrence of neural-tube defects by periconceptual vitamin supplementation. N Engl J Med 1992;327:1832–5.
    1. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 2002;325:1202–8.
    1. Casas JP, Bautista LE, Smeeth L, Sharma P, Hingorani A. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 2005;365:224–32.
    1. Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PWF, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 2002;346:476–83.
    1. Duthie SJ. Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis 2011;34:101–9.
    1. Chuang SC, Rota M, Gunter MJ, Zeleniuch-Jacquotte A, Eussen SJ, Vollset SE, Ueland PM, Norat T, Ziegler RG, Vineis P. Quantifying the dose-response relationship between circulating folate concentrations and colorectal cancer in cohort studies: a meta-analysis based on a flexible meta-regression model. Am J Epidemiol 2013;178:1028–37.
    1. Osterhues A, Holzgreve W, Michels KB. Shall we put the world on folate. Lancet 2009;374:959–61.
    1. Bailey RL, Mills JL, Yetley EA, Gahche JJ, Pfeiffer CM, Dwyer JT, Dodd KW, Sempos CT, Betz JM, Picciano MF. Unmetabolised serum folic acid and its relation to folic acid intake from diet and supplements in a nationally representative sample of adults aged > or = 60 y in the United States. Am J Clin Nutr 2010;92:383–9.
    1. Schneider JA, Tangney CC, Morris MC. Folic acid and cognition in older persons. Expert Opin Drug Saf 2006;5:511–22.
    1. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007;85:193–200.
    1. Selhub J, Morris MS, Jacques PF, Rosenberg IH. Folate-vitamin-B12 interaction in relation to cognitive impairment, anemia, and biochemical indicators of vitamin B12 deficiency. Am J Clin Nutr 2009;89(suppl):702S–6S.
    1. Roswall N, Olsen A, Christensen J, Hansen L, Dragsted LO, Overvad K, Tjonneland A. Micronutrient intake in relation to all-cause mortality in a prospective Danish cohort. Food Nutr Res 2012;56.
    1. Stolzenberg-Solomon RZ, Chang S-C, Leitzmann MF, Johnson KA, Johnson C, Buys SS, Hoover RN, Ziegler RG. Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 2006;83:895–904.
    1. Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS, Burke CA, McKeown-Eyssen GE, Baron JA. Folic acid and risk of prostate cancer: results from a randomised clinical trial. J Natl Cancer Inst 2009;101:432–5.
    1. Hirsch S, Sanchez H, Albala C, de la Maza MP, Barrera G, Leiva L, Bunout D. Colon cancer in Chile before and after the start of the flour fortification program with folic acid. Eur J Gastroenterol Hepatol 2009;21:436–9.
    1. Zhao R, Matherly LH, Goldman ID. Membrane transporters and folate homeostasis: intestinal absorption and transport into systemic compartments and tissues.Expert Rev Mol Med.2009;11:e4.
    1. Whitehead VM, Pratt R, Viallet A, Cooper BA. Intestinal conversion of folinic acid to 5-methyltetrahydrofolic acid in man. Br J Haematol 1972;22:63–72.
    1. Strum WB. Enzymatic reduction and methylation of folate following pH-dependent, carrier-mediated transport in rat jejunum. Biochim Biophys Acta 1979;554:249–57.
    1. Tani M, Iwai Z. High-performance liquid chromatographic separation of physiological folate monoglutamate compounds. Investigation of absorption and conversion of pteroylglutamic acid in the small intestine of the rat in situ. J Chromatogr 1983;267:175–81.
    1. Wright AJA, Dainty JR, Finglas PM. Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK. Br J Nutr 2007;98:667–75.
    1. Perry J, Chanarin I. Intestinal absorption of reduced folate compounds in man. Br J Haematol 1970;18:329–39.
    1. Wright AJA, Finglas PM, Dainty JR, Wolfe CA, Hart DJ, Wright DM, Gregory JF. Differential kinetic behaviour and distribution of pteroylglutamic acid and reduced folates: a revised hypothesis of the primary site of PteGlu metabolism in humans. J Nutr 2005;135:619–23.
    1. King MJ, Brima EI, Dainty JR, Barrett DA, Wright AJA, Willis G, Finglas PM. Estimation of the 5-methyltetrahydrofolate apparent volume of distribution in humans. J Nutr 2012;142:389–95.
    1. Bailey SW, Ayling JE. The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake. Proc Natl Acad Sci USA 2009;106:15424–9.
    1. Kamen BA, Nylen PA, Whitehead VM, Abelson HT, Dolnick BJ, Peterson DW. Lack of dihydrofolate reductase in human tumor and leukemia cells in vivo. Cancer Drug Deliv 1985;2:133–8.
    1. Whitehead VM, Cooper BA. Absorption of unaltered folic acid from the gastro-intestinal tract in man. Br J Haematol 1967;13:679–86.
    1. Melikian V, Paton A, Leeming RJ, Portman-Graham H. Site of reduction and methylation of folic acid in man. Lancet 1971;2:955–7.
    1. Ohrvik VE, Buttner BE, Rychlik M, Lundin E, Witthoft CM. Folate bioavailability from breads and a meal assessed with a human stable-isotope area under the curve and ileostomy model. Am J Clin Nutr 2010;92:532–8.
    1. Pietrzik K, Lamers Y, Bramswig S, Prinz-Langenohl R. Calculation of red blood cell folate steady state conditions and elimination kinetics after daily supplementation with various folate forms and doses in women of childbearing age. Am J Clin Nutr 2007;86:1414–9.
    1. Zeng H, Chen Z-S, Belinsky MG, Rea PA, Kruth GD. Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP)3 and MRP1: effect of polyglutamylation on MTX transport. Cancer Res 2001;61:7225–32.
    1. Sweeney MR, McPartlin J, Weir DG, Daly L, Scott JM. Postprandial serum folic acid response to multiple doses of folic acid in fortified bread. Br J Nutr 2006;95:145–51.
    1. Wright AJ, King MJ, Finglas PM. Folate supplemented oral contraceptives: does 6S-5-methyltetrahydrofolic acid (Metafolin) offer advantages over folic acid? Gynaecol Forum 2010;15:29–32.
    1. Tomiuk S, Liu Y, Green TJ, King MJ, Finglas PM, Kitts DD. Studies on the retention of microencapsulated L-5-methyltetrahydrofolic acid in baked bread using skim milk powder. Food Chem 2012;133:249–55.

Source: PubMed

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