Is folic acid the ultimate functional food component for disease prevention?
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《英国医生杂志》
1 Human Nutrition, School of Applied Sciences, University of Newcastle, Brush Road, Ourimbah, NSW 2258, Australia Mark.Lucock@newcastle.edu.au
We are entering a new era in preventive medicine, which focuses on diet as a means to health. Folate has received much attention as a vitamin that can protect against many diseases, but do we know enough about the long term effects of supplementation?
Introduction
Clearly, the use of folate fortification has immense potential benefit. Interest in folate over the past decade has rocketed in comparison with other nutrients, largely because scientists have recognised the importance of this vitamin in treating a broad range of both developmental and degenerative disorders that are sensitive to even marginal deficiencies in B vitamins.6
Although Lucy Wills's 1931 description of yeast extract being effective against the tropical macrocytic anaemia of late pregnancy in India represents the first record of folate being used for prevention of disease, folate as the critical factor involved was not isolated, nor was its structure elucidated, until later. Furthermore, it was not until more than half a century later that the significance of folate in preventive medicine was once again shown in a series of papers culminating in that by the Medical Research Council Vitamin Study Group in 1991, documenting how periconceptional folate prevents spina bifida.7 This discovery was followed by a meta-analysis published in 1995, which presented data from 27 studies involving more than 4000 patients with occlusive vascular disease and a similar number of controls.8 Data showed that homocysteine was an independent, graded risk factor for atherosclerotic disease in the coronary, cerebral, and peripheral vessels. This was of particular interest, as dietary folate lowers homocysteine through de novo biosynthesis of methionine,9 and it opened new avenues for intervention with vitamins to prevent disease. Several single nucleotide polymorphisms that are related to folate and other B vitamins were also discovered in 1995. These affect the risk not only of birth defects and vascular disease but also of several cancers. The two most important cancers in this context are colorectal cancer and leukaemia.
In order to examine research trends in this area, I did a systematic key word search of the PubMed National Library of Medicine for the years 1992-2002. I noted the number of citations for folate in association with a range of developmental and degenerative conditions for each year. Figure 2 shows how interest in this vitamin has changed over the past 10 years. It is clear that all areas of research related to folate and disease have expanded, but interest in folate in relation to cancer has increased in particular (fig 2 (top)). However, when the data are expressed as a percentage of all papers on folate, only research in relation to vascular disease has expanded year on year in real terms (fig 2 (bottom)), presumably owing to worldwide interest in the beneficial effects on vasculotoxic homocysteine. Although not shown, numbers of publications on folate in general far exceed those relating to other similar micronutrients. To provide a limited illustration of how popular the field of folate-homocysteine interrelations has become, figure 3 shows how folate research and vitamin C research had similar outputs until the mid to late 1990s, when interest in folate began to surge. However, publications on homocysteine were fewer than those on either folate or vitamin C up to 1996, but at the time that research on folate surged (around 1997) homocysteine research substantially outstripped the number of publications dealing with either of the other vitamins. The antioxidant nature of vitamin C makes it a popular vitamin for biomedical studies, so it provides a fair baseline for comparison.
Fig 2 Number of publications on folate and specific diseases (top); publications on folate and specific diseases as a percentage of all publications on folate (bottom)
Fig 3 Interest in folate-homocysteine inter-relations relative to interest in vitamin C
Folate nutrigenomics
Lewis CJ, Crane NT, Wilson DB, Yatley EA. Estimated folate intake: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am J Clin Nutr 1999;70: 198-207.
Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid: final rule. Fed Regist 1996;61: 8781-97.
Lucock MD, Yates Z. A differential role for folate in developmental disorders, vascular disease and other clinical conditions: the importance of folate status and genotype. In: Massaro EJ, ed. Folate and human development. Totowa, NJ: Humana Press, 2001: 263-98.
Friso S, Choi SW. Gene-nutrient interactions and DNA methylation. J Nutr 2002;132: 2382-7S.
Lucock M. Folic acid: nutritional biochemistry, molecular biology and role in disease processes. Mol Genet Metab 2000;71: 121-38.
Fenech M. Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDA). Food Chem Toxicol 2002;40: 1113-7.
MRC Vitamin Study Group. Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet 1991;338: 131-7.
Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274: 1049-57.
Schorah CJ, Devitt H, Lucock MD, Dowell AC. The responsiveness of plasma homocysteine to small increases in dietary folic acid: a primary care study. Eur J Clin Nutr 1998;52: 407-11.
Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 1999;8: 513-8.
Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions and risk of colorectal cancer. Cancer Res 1997;57: 1098-102.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10: 111-3.
Kang S-S. Wong PWK, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary heart disease. Am J Hum Genet 1991;48: 536-45.
Van der Put NMJ, Steegers-Theunissen RPM, Frosst P, Trijbels FJM, Eskes TKAB, Van der Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995;346: 1070.
James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down's syndrome. Am J Clin Nutr 1999;70: 495-501.
Mills JL, Kirke PN, Molloy AM, Burke H, Conley MR, Lee J, et al. Methylenetetrahydrofolate reductase thermolabile variant and oral cleft. Am J Med Genet 1999;86: 71-4.
Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 1999;96: 12810-5.
Van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural tube defects? Am J Hum Genet 1998;62: 1044-51.
Yates Z, Lucock M. Methionine synthase polymorphism A2756G is associated with susceptibility for thromboembolic events and altered B vitamin/thiol metabolism. Haematologica 2002;87: 751-6.
Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab 1999;67: 317-23.
Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 2000;67: 623-30.
Skibola CF, Smith MT, Hubbard A, Shane B, Roberts AC, Law GR, et al. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocystic leukemia in adults. Blood 1999;99: 3788-91.
Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolised folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 1997;65: 1790-5.
Lucock MD, Wild J, Smithells R, Hartley R. Invivo characterisation of the absorption and biotransformation of pteroylglutamic acid in man: a model for future studies. Biochem Med Metab Biol 1989;42: 30-42.
Lucock MD, Green M, Priestnall M, Daskalakis I, Levene MI, Hartley R. Optimisation of chromatographic conditions for the determination of folates in foods and biological tissues for nutritional and clinical work. Food Chem 1995;53: 329-38.
Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF. Folic acid intake from fortification in United States exceeds predictions. J Nutr 2002;132: 2792-8.
Matthews RG, Baugh CM. Interactions of pig liver methylenetetrahydrofolate reductase with methylenetetrahydropteroylpolyglutamate substrates and with dihydropteroylpolyglutamate inhibitors. Biochemistry 1980;19: 2040-5.
Ross J, Green J, Baugh CM, MacKenzie RE, Matthews RG. Studies on the polyglutamate specificity of methylenetetrahydrofolate dehydrogenase from pig liver. Biochemistry 1984;23: 1796-801.
Rao KN. Pteroyl- and tetrahydropteroylpolyglutamate effects on the catalytic activity of thymidylate synthase from Lactobacillus leichmannii: a novel method for determining gamma-glutamyl chain lengths of the folylpolyglutamates. Indian J Biochem Biophys 1994;31: 184-90.
s(Mark Lucock, lecturer1)
We are entering a new era in preventive medicine, which focuses on diet as a means to health. Folate has received much attention as a vitamin that can protect against many diseases, but do we know enough about the long term effects of supplementation?
Introduction
Clearly, the use of folate fortification has immense potential benefit. Interest in folate over the past decade has rocketed in comparison with other nutrients, largely because scientists have recognised the importance of this vitamin in treating a broad range of both developmental and degenerative disorders that are sensitive to even marginal deficiencies in B vitamins.6
Although Lucy Wills's 1931 description of yeast extract being effective against the tropical macrocytic anaemia of late pregnancy in India represents the first record of folate being used for prevention of disease, folate as the critical factor involved was not isolated, nor was its structure elucidated, until later. Furthermore, it was not until more than half a century later that the significance of folate in preventive medicine was once again shown in a series of papers culminating in that by the Medical Research Council Vitamin Study Group in 1991, documenting how periconceptional folate prevents spina bifida.7 This discovery was followed by a meta-analysis published in 1995, which presented data from 27 studies involving more than 4000 patients with occlusive vascular disease and a similar number of controls.8 Data showed that homocysteine was an independent, graded risk factor for atherosclerotic disease in the coronary, cerebral, and peripheral vessels. This was of particular interest, as dietary folate lowers homocysteine through de novo biosynthesis of methionine,9 and it opened new avenues for intervention with vitamins to prevent disease. Several single nucleotide polymorphisms that are related to folate and other B vitamins were also discovered in 1995. These affect the risk not only of birth defects and vascular disease but also of several cancers. The two most important cancers in this context are colorectal cancer and leukaemia.
In order to examine research trends in this area, I did a systematic key word search of the PubMed National Library of Medicine for the years 1992-2002. I noted the number of citations for folate in association with a range of developmental and degenerative conditions for each year. Figure 2 shows how interest in this vitamin has changed over the past 10 years. It is clear that all areas of research related to folate and disease have expanded, but interest in folate in relation to cancer has increased in particular (fig 2 (top)). However, when the data are expressed as a percentage of all papers on folate, only research in relation to vascular disease has expanded year on year in real terms (fig 2 (bottom)), presumably owing to worldwide interest in the beneficial effects on vasculotoxic homocysteine. Although not shown, numbers of publications on folate in general far exceed those relating to other similar micronutrients. To provide a limited illustration of how popular the field of folate-homocysteine interrelations has become, figure 3 shows how folate research and vitamin C research had similar outputs until the mid to late 1990s, when interest in folate began to surge. However, publications on homocysteine were fewer than those on either folate or vitamin C up to 1996, but at the time that research on folate surged (around 1997) homocysteine research substantially outstripped the number of publications dealing with either of the other vitamins. The antioxidant nature of vitamin C makes it a popular vitamin for biomedical studies, so it provides a fair baseline for comparison.
Fig 2 Number of publications on folate and specific diseases (top); publications on folate and specific diseases as a percentage of all publications on folate (bottom)
Fig 3 Interest in folate-homocysteine inter-relations relative to interest in vitamin C
Folate nutrigenomics
Lewis CJ, Crane NT, Wilson DB, Yatley EA. Estimated folate intake: data updated to reflect food fortification, increased bioavailability, and dietary supplement use. Am J Clin Nutr 1999;70: 198-207.
Food standards: amendment of standards of identity for enriched grain products to require addition of folic acid: final rule. Fed Regist 1996;61: 8781-97.
Lucock MD, Yates Z. A differential role for folate in developmental disorders, vascular disease and other clinical conditions: the importance of folate status and genotype. In: Massaro EJ, ed. Folate and human development. Totowa, NJ: Humana Press, 2001: 263-98.
Friso S, Choi SW. Gene-nutrient interactions and DNA methylation. J Nutr 2002;132: 2382-7S.
Lucock M. Folic acid: nutritional biochemistry, molecular biology and role in disease processes. Mol Genet Metab 2000;71: 121-38.
Fenech M. Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDA). Food Chem Toxicol 2002;40: 1113-7.
MRC Vitamin Study Group. Prevention of neural tube defects: results of the Medical Research Council vitamin study. Lancet 1991;338: 131-7.
Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274: 1049-57.
Schorah CJ, Devitt H, Lucock MD, Dowell AC. The responsiveness of plasma homocysteine to small increases in dietary folic acid: a primary care study. Eur J Clin Nutr 1998;52: 407-11.
Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 1999;8: 513-8.
Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, et al. Methylenetetrahydrofolate reductase polymorphism, dietary interactions and risk of colorectal cancer. Cancer Res 1997;57: 1098-102.
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, et al. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 1995;10: 111-3.
Kang S-S. Wong PWK, Susmano A, Sora J, Norusis M, Ruggie N. Thermolabile methylenetetrahydrofolate reductase: an inherited risk factor for coronary heart disease. Am J Hum Genet 1991;48: 536-45.
Van der Put NMJ, Steegers-Theunissen RPM, Frosst P, Trijbels FJM, Eskes TKAB, Van der Heuvel LP, et al. Mutated methylenetetrahydrofolate reductase as a risk factor for spina bifida. Lancet 1995;346: 1070.
James SJ, Pogribna M, Pogribny IP, Melnyk S, Hine RJ, Gibson JB, et al. Abnormal folate metabolism and mutation in the methylenetetrahydrofolate reductase gene may be maternal risk factors for Down's syndrome. Am J Clin Nutr 1999;70: 495-501.
Mills JL, Kirke PN, Molloy AM, Burke H, Conley MR, Lee J, et al. Methylenetetrahydrofolate reductase thermolabile variant and oral cleft. Am J Med Genet 1999;86: 71-4.
Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, et al. Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci USA 1999;96: 12810-5.
Van der Put NM, Gabreels F, Stevens EM, Smeitink JA, Trijbels FJ, Eskes TK, et al. A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural tube defects? Am J Hum Genet 1998;62: 1044-51.
Yates Z, Lucock M. Methionine synthase polymorphism A2756G is associated with susceptibility for thromboembolic events and altered B vitamin/thiol metabolism. Haematologica 2002;87: 751-6.
Wilson A, Platt R, Wu Q, Leclerc D, Christensen B, Yang H, et al. A common variant in methionine synthase reductase combined with low cobalamin (vitamin B12) increases risk for spina bifida. Mol Genet Metab 1999;67: 317-23.
Hobbs CA, Sherman SL, Yi P, Hopkins SE, Torfs CP, Hine RJ, et al. Polymorphisms in genes involved in folate metabolism as maternal risk factors for Down syndrome. Am J Hum Genet 2000;67: 623-30.
Skibola CF, Smith MT, Hubbard A, Shane B, Roberts AC, Law GR, et al. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocystic leukemia in adults. Blood 1999;99: 3788-91.
Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolised folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 1997;65: 1790-5.
Lucock MD, Wild J, Smithells R, Hartley R. Invivo characterisation of the absorption and biotransformation of pteroylglutamic acid in man: a model for future studies. Biochem Med Metab Biol 1989;42: 30-42.
Lucock MD, Green M, Priestnall M, Daskalakis I, Levene MI, Hartley R. Optimisation of chromatographic conditions for the determination of folates in foods and biological tissues for nutritional and clinical work. Food Chem 1995;53: 329-38.
Choumenkovitch SF, Selhub J, Wilson PW, Rader JI, Rosenberg IH, Jacques PF. Folic acid intake from fortification in United States exceeds predictions. J Nutr 2002;132: 2792-8.
Matthews RG, Baugh CM. Interactions of pig liver methylenetetrahydrofolate reductase with methylenetetrahydropteroylpolyglutamate substrates and with dihydropteroylpolyglutamate inhibitors. Biochemistry 1980;19: 2040-5.
Ross J, Green J, Baugh CM, MacKenzie RE, Matthews RG. Studies on the polyglutamate specificity of methylenetetrahydrofolate dehydrogenase from pig liver. Biochemistry 1984;23: 1796-801.
Rao KN. Pteroyl- and tetrahydropteroylpolyglutamate effects on the catalytic activity of thymidylate synthase from Lactobacillus leichmannii: a novel method for determining gamma-glutamyl chain lengths of the folylpolyglutamates. Indian J Biochem Biophys 1994;31: 184-90.
s(Mark Lucock, lecturer1)