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Is there more to folates than neural-tube defects?

Published online by Cambridge University Press:  05 March 2007

Paul M. Finglas ,
Anthony J. A. Wright ,
Caroline A. Wolfe ,
David J. Hart ,
Dawn M. Wright  and
Jack R. Dainty
Paul M. Finglas*
Affiliation:
Nutrition Department, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
Anthony J. A. Wright
Affiliation:
Nutrition Department, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
Caroline A. Wolfe
Affiliation:
Nutrition Department, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
David J. Hart
Affiliation:
Nutrition Department, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
Dawn M. Wright
Affiliation:
Nutrition Department, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
Jack R. Dainty
Affiliation:
Nutrition Department, Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK
*
*Corresponding author: Dr P. M. Finglas, fax +44 1603 507723, [email protected]
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Abstract

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The purpose of the present paper is to review our current understanding of the chemistry and biochemistry of folic acid and related folates, and to discuss their impact on public health beyond that already established in relation to neural-tube defects. Our understanding of the fascinating world of folates and C1 metabolism, and their role in health and disease, has come a long way since the discovery of the B-vitamin folic acid by Wills (1931), and its first isolation by Mitchell et al. (1941). However, there is still much to do in perfecting methods for the measurement of folate bioavailability, and status, with a high extent of precision and accuracy. Currently, examination of the relationships between common gene polymorphisms involved in C1 metabolism and folate bioavailability and folate status, morbidity, mortality and longevity is evaluated as a series of individual associations. However, in the future, examination of the concurrent effects of such common gene polymorphisms may be more beneficial.

Keywords

Folic acidBioavailabilityC1 metabolismGene polymorphismsHealth and disease
Type
Invited commentary
Information
Proceedings of the Nutrition Society , Volume 62 , Issue 3 , August 2003 , pp. 591 - 598
Copyright
Copyright © The Nutrition Society 2003

References

Alfthan, G, Aro, A & Gey, KF (1997) Plasma homocysteine and cardiovascular disease mortality. Lancet 349, 397.CrossRefGoogle ScholarPubMed
Babu, S & Srikantia, SG (1976) Availability of folates from some foods. American Journal of Clinical Nutrition 29, 376–379.CrossRefGoogle ScholarPubMed
Bagley, PJ & Selhub, J (1998) A common mutation in the methylenetetrahydrofolate reductase gene is associated with an accumulation of formylated tetrahydrofolates in red blood cells. Proceedings of the National Academy of Sciences USA 95, 13217–13220.CrossRefGoogle ScholarPubMed
Bailey, LB (1998) Dietary reference intakes for folate: The debut of dietary folate equivalents. Nutrition Reviews 56, 294–299.CrossRefGoogle ScholarPubMed
Bailey, LB, Cerda, JJ, Bloch, BS, Busby, MJ, Vargas, L, Chandler, CJ & Halsted, CH (1984) Effects of age on poly- and monoglutamyl folacin absorption in human subjects. Journal of Nutrition 114, 1770–1776.CrossRefGoogle ScholarPubMed
Blount, BC, Mack, MM, Wehr, CM, MacGregor, JT, Hiatt, RA, Wang, G, Wickramasinghe, SN, Everson, RB & Ames, BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proceedings of the National Academy of Sciences USA 94, 3290–3295.CrossRefGoogle ScholarPubMed
Botiglieri, T (1996) Folate, vitamin B12, and neuropsychiatric disorders. Nutrition Reviews 54 382–390CrossRefGoogle Scholar
Boushey, CJ Beresford, SAA Omenn, GS Motulsky, AG, (1995) A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Journal of the American Medical Association 274, 1049–1057.CrossRefGoogle ScholarPubMed
Bower, C, Stanley, FJ, Croft, M, De Clerk, NH, Davis, RE & Nicol, DJ (1993) Absorption of pteroylpolyglutamates in mothers of infants with neural tube defects. British Journal of Nutrition 69, 827–834.CrossRefGoogle ScholarPubMed
Brattstrom, L, Zhang, Y, Hurtig, M, Refsum, H, Ostensson, S, Fransson, L Jones, K, Landgren, F, Brudin, L & Ueland, PM (1999) A common methylenetetrahydrofolate reductase gene mutation and longevity. Atherosclerosis 146, 395–397.Google Scholar
Butterworth, CE, Newman, AJ & Krumdieck, CL (1974) Tropical sprue: a consideration of possible etiologic mechanism with emphasis on pteroyl polyglutamate metabolism. Transactions of the American Clinical and Climatological Association 86, 11–22.Google Scholar
Campbell, NR (1996) How safe are folic acid supplements?. Archives of Internal Medicine 156, 1638–1644.CrossRefGoogle ScholarPubMed
Chango, A, Potier de Courcy, G, Boisson, F, Guillard, JC, Barbe, F, Perrin, MO, Christides, JP, Rabhi, K, Pfister, M, Galan, P, Hercberg, S & Nicholas, JP (2000) 5,10-methylenetetrahydrofolate reductase common mutations, folate status and plasma homocyseteine in healthy French adults of the Supplementation en Vitamines et Mineraux Antioxydants (SU.VI.MAX) cohort. British Journal of Nutrition 84, 891–896.CrossRefGoogle ScholarPubMed
Chen, J, Stampfer, MJ, Ma, J, Selhub, J, Malinow, MR, Hennekens, CH & Hunter, DJ (2001) Influence of a methionine synthase (D919G) polymorphism on plasma homocysteine and folate levels and relation to risk of myocardial infarction. Atherosclerosis 154, 667–672.CrossRefGoogle ScholarPubMed
Choi, SW & Mason, JB (2000) Folate and carcinogenesis: an integrated scheme. Journal of Nutrition 130, 129–132.CrossRefGoogle ScholarPubMed
Christensen, B, Arbour, L, Tran, P, Leclerk, D, Sabbaghian, N, Platt, R, Gilfix, BM, Rosenblatt, DS, Gravel, RA, Forbes, P & Rozen, R (1999) Genetic polymorphisms in methylenetetrahydrofolate reductase and methionine synthase, folate levels in red blood cells, and risk of neural tube defects. American Journal of Medical Genetics 84, 151–157.3.0.CO;2-T>CrossRefGoogle ScholarPubMed
Czeizel, AE & Dudas, I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation New England Journal of Medicine 327, 1832–1835.Google Scholar
Daly, LE, Kirke, PN, Molloy, A, Weir, DG & Scott, JM (1995) Folate levels and neural tube defects. Implications for prevention. Journal of the American Medical Association 274, 1698–1702.CrossRefGoogle ScholarPubMed
Dekou, V, Whincup, P, Papcosta, O, Ebrahim, S, Lennon, L, Ueland, PM, Refsum, H, Humphries, SE & Gudnason, V (2001) The effect of the C6777T and A1298C polymorphisms in the methylenetetrahydrofolate reductase gene on homocysteine levels in elderly men and women from the British regional heart study. Atherosclerosis 154, 659–699.CrossRefGoogle Scholar
Department of Health and Social Security (1979) Recommended Daily Amounts of Food Energy and Nutrients for Groups of People in the United Kingdom. Report on Health and Social Subjects no. 15 London: H.M. Stationery Office.Google Scholar
Department of Health (1991) Dietary Reference Values for Food Energy and Nutrients for the United Kingdom. Report on Health and Social Subjects no. 41 London: H.M. Stationery Office.Google Scholar
Department of Health (2000) Folic Acid and the Prevention of Disease. Report on Health and Social Subjects no. 50 London: The Stationery Office.Google Scholar
Devlin, AM, Ling, E-H, Peerson, JM, Fernando, S, Clarke, R, Smith, DA & Halsted, CH (2000) Glutamate carboxypeptidase II: a polymorphism associated with lower levels of serum folate and hyperhomocysteinemia. Human Molecular Genetics 9, 2837–2844.CrossRefGoogle ScholarPubMed
Finglas, PM, Dainty, JR, Hart, D, Wolfe, C, Wright, AJA, Southon, S & Gregory, JF (2002a) Modelling of labelled absorbed folates using plasma in humans. FASEB Journal 16 A748.Google Scholar
Finglas, PM, Witthöft, CM, Vahteristo, L, Wright, AJA, Southon, S, Mellon, F, Ridge, B & Maunder, P, (2002b) Use of an oral/intravenous dual-label stable-isotope protocol to determine folic acid bioavailability from fortified cereal grain foods in women. Journal of Nutrition 132, 936–939.CrossRefGoogle ScholarPubMed
Friso, S, Choi, SW, Girelli, D, Mason, JB, Dolnikowski, GG, Bagley, PJ, Oliveri, O, Jaques, PF, Rosenburg, IH, Corrocher, R & Selhub, J (2002) A common mutation in the 5,10-methylenetetrahydrofolate reductase gene affects genomic DNA methylation through an interaction with folate status. Proceedings of the National Academy of Sciences USA 99, 5606–5611.CrossRefGoogle Scholar
Frosst, P, Blom, HJ, Milos, R, Goyette, P, Sheppard, CA, Matthews, RG, Boers, GJH, den Heijer, M, Kluijtmans, LAJ, van den Heuvel, LP & Rozen, R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nature Genetics 10, 111–113.CrossRefGoogle ScholarPubMed
Gaughan, DJ, Kluijtmans, LAJ, Barbaux, S, McMaster, D, Young, IS, Yarnell, JWG, Evans, A & Whitehead, AS (2001) The methionine synthase reductase (MTRR) A66G polymorphism is a novel genetic determinant of plasma homocysteine concentrations. Atherosclerosis 157, 451–456.CrossRefGoogle ScholarPubMed
Ghitis, J (1967) The folate binding in milk. American Journal of Clinical Nutrition 20, 1–4.CrossRefGoogle ScholarPubMed
Gregory, JF & Toth, JP (1988) Chemical synthesis of deuterated folate monoglutamate and in vivo assessment of urinary excretion of deuterated folates in man. Analytical Biochemistry 170, 94–104.CrossRefGoogle ScholarPubMed
Gregory, JF III (1997) Bioavailability of folate. European Journal of Clinical Nutrition 51, S54–S59.Google ScholarPubMed
Gregory, JF III (2001) Case study: Folate bioavailability. Journal of Nutrition 131, 1376S–1382S.CrossRefGoogle ScholarPubMed
Halsted, CM (1980) Intestinal absorption and malabsorption of folates. Annual Review of Medicine 31, 79–87.CrossRefGoogle ScholarPubMed
Hart, DJ, Finglas, PM, Wolfe, CA, Mellon, F, Wright, AJA & Southon, S (2002) Determination of 5-methyltetrahydrofolate (13C-labelled and unlabelled) in human plasma and urine by combined liquid chromatography mass spectrometry (LC/MS). Analytical Biochemistry 305, 206–213.CrossRefGoogle Scholar
Heijmans, BT, Gussekloo, J, Kluft, C, Droog, S, Lagaay, AM, Knook, DL, Westendorp, RG & Slagboom, EP (1999) Mortality risk in men is associated with a common mutation in the methylenetetrahydrofolate reductase gene (MTHFR). European Journal of Human Genetics 7, 197–204.CrossRefGoogle Scholar
Herbert, V & Das, KC (1993) Folic acid and vitamin B12. In Modern Nutrition in Health and Disease 8th ed., pp.402–425 [Shils, ME Olson, JA and Shike, M, editors]. Philadelphia, PA: Lea & Febiger.Google Scholar
Hobbs, CA, Sherman, SL, Yi, P, Hopkins, SE, Torfs, CP, Hine, RJ, Pogribna, M, Rozen, R & James, SJ (2000) Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. American Journal of Human Genetics 67, 623–630.CrossRefGoogle ScholarPubMed
Honein, MA, Paulozzi, LJ, Mathews, TJ, Ericksen, DJ & Wong, L-YC (2001) Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. Journal of the American Medical Association 285, 2981–2986.CrossRefGoogle ScholarPubMed
Hoppner, K & Lampi, B (1980) Folate levels in human liver autopsies in Canada. American Journal of Clinical Nutrition 33, 862–864.CrossRefGoogle ScholarPubMed
Institute of Medicine (2000) Dietary Reference Intakes for Thiamine, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. Washington, DC: National Academy Press.Google Scholar
Jacques, PF, Selhub, J, Bostom, AG, Wilson, PW & Rosenberg, IH (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentration. New England Journal of Medicine 340, 1449–1454.CrossRefGoogle Scholar
James, SJ, Pogribna, M, Porgribny, IP, Melnyk, S, Hine, RJ, Gibson, JB, Yi, P, Tafoya, DL, Swenson, DH, Wilson, VL & Gaylor, DW (1999) Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down syndrome. American Journal of Clinical Nutrition 70, 495–501.CrossRefGoogle ScholarPubMed
Kang, SS, Wong, PW, Susmano, A, Sora, J, Norusis, M & Ruggie, N (1991) Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary artery disease. American Journal of Human Genetics 48, 536–545.Google ScholarPubMed
Kang, SS, Wong, PWK, Malinow, MR (1992) Hyperhomocysteinemia as a risk factor for occlusive vascular disease. Annual Review of Nutrition 12, 279–298.CrossRefGoogle ScholarPubMed
Kelly, P, McPartlin, J, Goggins, M, Weir, DG & Scott, JM (1997) Unmetabolised folic acid in serum: acute studies in subjects consuming fortified food and supplements. American Journal of Clinical Nutrition 65, 1790–1795.CrossRefGoogle Scholar
Koga, T, Claycombe, K & Meydani, O (2002) Homocysteine increases monocyte and T-cell adhesion to human aortic endothelial cells. Atherosclerosis 161, 365–374.CrossRefGoogle ScholarPubMed
Konings, EJM, Troost, FJ, Castenmiller, JJM, Roomans, HHS, van den Brandt, PA & Saris, WHM (2002) Intestinal absorption of different types of folate in healthy subjects with an ileostomy. British Journal of Nutrition 88, 235–242.CrossRefGoogle ScholarPubMed
Lawrence, JM, Petitti, DB, Watkins, M & Umekubo, MA (1999) Trends in serum folate after food fortification. Lancet 354, 915–916.CrossRefGoogle ScholarPubMed
Lewis, CJ, Crane, NT, Wilson, DB & Yetley, EA (1999) Estimated folate intakes: data updated to reflect food fortification, increased bioavailability and dietary supplement use. American Journal of Clinical Nutrition 70, 198–207.CrossRefGoogle ScholarPubMed
Li, H, Lewis, A, Brodsky, S, Reiger, R, Iden, C & Gologorsky, MS (2002) Homocysteine induces 3-hydroxy-3-methylglutaryl coenzyme A reductase in vascular endothelial cells: a mechanism for development of atherosclerosis? Circulation 105, 1037–1043.CrossRefGoogle Scholar
Lucock, MD, Wild, J, Smithells, RW & Hartley, R (1989) In vivo characterization of the absorption and biotransformation of pteroylmonoglutamic acid in man: a model for future studies. Biochemical Medicine and Metabolic Biology 42, 30–42.CrossRefGoogle Scholar
Martin, JA, Smith, BL, Mathews, TJ & Ventura, MA (1999) Births and deaths: preliminary data for 1998. National Vital Statistics Reports 47, 1–45.Google ScholarPubMed
Mason, JB (1995) Folate status: effects on carcinogensis. In Folate in Health and Disease, pp.361–378 [Bailey, LB, editor]. NewYork: Marcel Dekker.Google Scholar
Mitchell, HK, Snell, EE & Williams, RJ (1941) The concentration of 'folic acid'. Journal of the American Chemistry Society 63, 2284.CrossRefGoogle Scholar
Molloy, AM (2002) Folate bioavailability and health. International Journal of Vitamin and Nutrition Research 72, 46–52.CrossRefGoogle ScholarPubMed
Molloy, AM, Daly, S, Mills, JL, Kirke, PN, Whitehead, AS, Ramsbottom, D, Conley, MR, Weir, DG & Scott, JM (1997) Thermolabile varient of 5,10-methylenetetrahydrofolate reductase associated with low red cell folates: implications for folate intake recommendations. Lancet 349, 1591–1593.CrossRefGoogle Scholar
Molloy, AM, Mills, JL, Kirke, PN, Whitehead, AS, Weir, DG & Scott, JM (1998) Whole-blood folate values in subjects with different methylenetetrahydrofolate reductase genotypes: Differences between the radioassay and microbiological assays. Clinical Chemistry 44, 186–188.CrossRefGoogle ScholarPubMed
MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: Results of the Medical Research Council Vitamin Study. Lancet 338, 131–137.CrossRefGoogle Scholar
Ou, CY, Stevenson, RE, Brown, VK, Schwartz, CE, Allen, WP, Khoury, MJ, Rozen, R, Oakley, GP & Adams, MJ Jr (1996) 5,10 Methylenetetrahydrofolate reductase genetic polymorphism as a risk factor for neural tube defects. American Journal of Medical Genetics 63, 610–614.3.0.CO;2-L>CrossRefGoogle ScholarPubMed
Perry, J & Chanarin, I (1972) Observations on folate absorption with particular reference to folate polyglutamate and possible inhibitors to its absorption. Gut 13, 544–550.CrossRefGoogle ScholarPubMed
Pietrzik, K, Hages, M & Remer, T, (1990) Methodological aspects in vitamin bioavailability testing. Journal of Micronutrient Analysis 7, 207–222.Google Scholar
Prinz-Langenohl, R, Bronstrup, A, Thorand, B, Hages, M & Pietrzik, K (1999) Availability of food folate in humans. Journal of Nutrition 129, 913–916.CrossRefGoogle ScholarPubMed
Quere, I, Perneger, TV, Zittoun, J, Bellet, H, Gris, J-C, Daures, J-P, Schved, J-F, Mercier, E, Laroche, J-P, Dauzat, M, Bounameaux, H, Janbon, C & de Moerloose, P (2002) Red blood cell methyfolate and plasma homocysteine as risk factors for venous thromboembolism: a matched case-control study. Lancet 359, 747–752.CrossRefGoogle ScholarPubMed
Quinlivan, EP, McPartlin, J, McNulty, H, Ward, M, Strain, JJ, Weir, DG & Scott, JM (2002) Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet 359, 227–228.CrossRefGoogle ScholarPubMed
Rady, PL, Szucs, S, Grady, J, Hudnall, SD, Kellner, LH, Nitowsky, H, Tyring, SK & Matalon, RK (2002) Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. American Journal of Medical Genetics 107, 162–168.CrossRefGoogle ScholarPubMed
Reisenauer, AM, Krumdieck, CL & Halsted, CH (1977) Folate conjugase: two separate activities in human jejunum. Science 198, 196–197.CrossRefGoogle ScholarPubMed
Rogers, LM, Pfeiffer, CM, Bailey, LB & Gregory, JF (1997) A dual label stable isotopic protocol is suitable for determination of folate bioavailabiltiy in humans: evaluation of urinary excretion and plasma folate kinetics of intravenous and oral doses of [13 C 5 ] and [2 H 2 ] folic acid. Journal of Nutrition 127, 2321–2327.CrossRefGoogle Scholar
Russell, RM, Dahr, GJ, Dutta, SK & Rosenburg, IH (1979) Influence of intraluminal pH on folate absorption. Studies in control subjects and in patients with pancreatic insufficiency. Journal of laboratory and Clinical Medicine 93, 428–436.Google ScholarPubMed
Ryan, BM & Weir, DG (2001) Relevance of folate metabolism in the pathogenesis of colorectal cancer. Journal of Laboratory and Clinical Medicine 138, 164–176.CrossRefGoogle ScholarPubMed
Schneider, JA, Rees, DC, Liu, Y-T & Clegg, JB (1998) Worldwide distribution of a common methylenetetrahydrofolate reductase mutation. American Journal of Human Genetics 62, 1258–1260.CrossRefGoogle ScholarPubMed
Scott, JM (1999) Folate and vitamin B 12. Proceedings of the Nutrition Society 58, 441–448.CrossRefGoogle Scholar
Selhub, J, Dhar, GJ & Rosenburg, IH (1983) Gastrointestinal absorption of folates and antifolates. Pharmacology and Therapeutics 20, 397–418.CrossRefGoogle ScholarPubMed
Selhub, J, Powell, GM & Rosenburg, IH (1984). Intestinal transport of 5-methyltetrahydrofolate. American Journal of Physiology 246, G515–G520.Google ScholarPubMed
Silaste, M-L, Rantala, M, Sampi, M, Alfthan, G, Aro, A & Kesaniemi, A (2001) Polymorphisms of key enzymes in homocysteine metabolism affect diet responsiveness of plasma homocysteine in healthy women. Journal of Nutrition 131, 2643–2647.CrossRefGoogle ScholarPubMed
Steinberg, SE, Campbell, CL & Hillman, RS (1979) Kinetics of the normal folate enterohepatic cycle. Journal of Clinical Investigation 64, 83–88.CrossRefGoogle ScholarPubMed
Tamura, T & Stokstad, ELR (1973) The availability of food folate in man. British Journal of Haematology 25, 513–532.CrossRefGoogle ScholarPubMed
Tsai, MY, Bignell, M, Yang, F, Welge, BG, Graham, KJ & Hanson, NQ (2001) Polygenic influence on plasma homocysteine: association of two prevalent mutations, the 844ins68 of cystathione beta-synthase and A(2756)G of methionine synthase, with lowered plasma homocysteine levels. Atherosclerosis 149, 131–137.CrossRefGoogle Scholar
Vollset, SE, Refsum, H, Tverdal, A, Nygard, O, Nordrehaug, JE, Tell, GS & Ueland, PM (2001) Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland homocysteine study. American Journal of Clinical Nutrition 74, 130–136.CrossRefGoogle ScholarPubMed
Voutilainen, S, Lakka, TA, Porkkala-Sarataho, E, Rissanen, T, Kaplan, GA & Salonen, JT, (2000) Low serum folate concentrations are associated with an excess incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. European Journal of Clinical Nutrition 54, 424–428.CrossRefGoogle ScholarPubMed
Wagner, C (1985) Folate-binding proteins. Nutrition Reviews 43, 293–299.Google ScholarPubMed
Wagner, C (1996) Symposium on the subcellular compartmentation of folate metabolism. Journal of Nutrition 126, 1228S–1234S.CrossRefGoogle ScholarPubMed
Weir, DG, McGing, PG & Scott, JM (1985) Commentary: Folate metabolism, the enterohepatic circulation and alcohol. Biochemical Pharmacology 34, 1–7.CrossRefGoogle Scholar
Whetstine, JR, Gifford, AJ, Witt, T, Liu, XY, Flatley, RM, Norris, M, Haber, M, Taub, JW, Ravindranath, Y & Matherly, LH (2001) Single nucleotide polymorphisms in the human reduced folate carrier: characterization of a high-frequency G/A variant at position 80 and transport properties of the His 27 and Arg 27 carriers. Clinical Cancer Research 7, 3416–3422.Google ScholarPubMed
Whitehead, VM (1973) Polygammaglutamyl metabolites of folic acid in humans liver. Lancet i, 743–745.CrossRefGoogle Scholar
Wills, L (1931) Treatment of 'pernicious anaemia of pregnancy' and 'tropical anaemia' with special reference to yeast extract as a curative agent. British Medical Journal 1, 1059–1064.CrossRefGoogle Scholar
Wilson, A, Platt, R, Wu, Q, Leclerc, D, Christensen, B, Yang, H, Gravel, RA & Rozen, R (1999) A common variant in methionine synthase reductase combined with low cobalamin (vitamin B-12) increases risk for spina bifida. Molecular Genetics and Metabolism 67, 317–323.CrossRefGoogle ScholarPubMed
Wright, AJA, Finglas, PM & Southon, S (2001) Proposed mandatory fortification of the UK diet with folic acid: have potential risks been underestimated. Trends in Food Science and Technology 12, 313–321.CrossRefGoogle Scholar