Skip to main content

Advertisement

SpringerLink
Log in

Ein Vitamin mit zwei Gesichtern

Folsäure – Prävention oder Promotion von Dickdarmkrebs?

A two-faced vitamin

Folic acid – prevention or promotion of colon cancer?

  • Leitthema
  • Published:
Bundesgesundheitsblatt - Gesundheitsforschung - Gesundheitsschutz Aims and scope

Zusammenfassung

In den 1930er-Jahren wurde beobachtet, dass bestimmte Formen der megaloblastischen Anämie in der Schwangerschaft mit Leber- und Hefeextrakten behandelt werden können. Der dafür verantwortliche Faktor wurde in den 1940er-Jahren aus Spinatblättern isoliert und in Anlehnung an das lateinische Wort für Blatt (folium) als Folat bezeichnet. Folat ist für den Menschen ein essenzieller Nährstoff. Die synthetische Form des Vitamins – Folsäure – wird in Nahrungsergänzungsmitteln, Arzneimitteln und angereicherten Lebensmitteln verwendet. Der gezielte Einsatz von Folsäure begann in den 1980er-Jahren, nachdem in einer Reihe von Studien beobachtet worden war, dass durch Folsäureeinnahmen vor und in der Schwangerschaft das Risiko für Neuralrohrdefekte (NRD) verringert werden kann. In der Folge wurden weltweit Empfehlungen zur perikonzeptionellen Folsäuresupplementierung gegeben und in vielen Ländern Anreicherungsprogramme gestartet. Die so erzielten Steigerungen der Folsäureaufnahme waren mit signifikanten Rückgängen der NRD-Raten verbunden. Jedoch wurde parallel dazu in den USA und Kanada ein – vorübergehender – Anstieg von Kolorektalkrebserkrankungen beobachtet. Aus tierexperimentellen und Humanstudiendaten lässt sich mittlerweile ein komplexer Zusammenhang zwischen Folat/Folsäure und Krebs ableiten: So sind Folataufnahmen in Höhe der Zufuhrempfehlungen bei gesunden Menschen im Allgemeinen mit einem geringeren Risiko für Krebserkrankungen verbunden, während unter bestimmten Bedingungen hohe Aufnahmen von Folsäure das Risiko für die Entstehung oder Progression von Krebs erhöhen können. Da Nahrungsfolat nicht mit unerwünschten Effekten assoziiert ist, steht Folsäure im Mittelpunkt des Forschungsinteresses zur Aufklärung der Ursachen für den beobachteten Zusammenhang.

Abstract

In the late 1930s, it was discovered that liver and yeast extracts can be used to correct certain cases of megaloblastic anemia in pregnancy. The factor responsible for this was isolated from spinach leaves in the 1940s, and referred to as folate, a term derived from the Latin word folium for leaf. Folate is considered an essential nutrient for human beings. Folic acid, the synthetic form of the vitamin, is used in dietary supplements, medicines and fortified foods. Since the 1980s, it has been recommended that women who plan to become pregnant and pregnant women during the first trimester of pregnancy take folic acid supplements. This recommendation was based on studies that revealed that periconceptional folic acid supplementation can reduce the risk for neural tube defects (NTDs). Many countries later implemented folic acid fortification programs. The resulting population-wide increase of folic acid intakes led to significant reductions in NTD rates. However, a temporarily increased colorectal cancer incidence has been reported to coincide with the fortification programs in the USA and Canada. On the basis of currently available data from experimental and human studies it can be concluded that the association between folate/folic acid and cancer is rather complex: Folate intake in the range of the dietary reference intake (DRI) is associated with a reduced risk for cancer in healthy populations, whereas high intakes of folic acid might result in an increased risk for cancer incidence or progression in persons with precancerous lesions and under certain conditions. Since no adverse effects have been observed in association with the intake of dietary folate, research activities that aim at investigating cause and effect relationships focus on folic acid.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2

Notes

  1. In Deutschland wird zum Beispiel empfohlen, dass Frauen mindestens vier Wochen vor einer Schwangerschaft bis zum Ende des ersten Schwangerschaftsdrittels zusätzlich zu einer folatreichen Ernährung 400 µg Folsäure pro Tag supplementieren.

  2. Die Aktivität der humanen DHFR beträgt etwa 2 % der Aktivität des entsprechenden Enzyms aus Rattenlebern [4]. Daher führen in Nagetieren erst sehr viel höhere Folsäureaufnahmen als beim Menschen zu unmetabolisierter Folsäure im Blutplasma.

  3. Mausmodell mit multipler intestinaler Neoplasie (min), das eine heterozygote Keimbahnmutation im APC-Tumorsuppressorgen enthält, die innerhalb von 160–180 Lebenstagen zur Entwicklung spontaner Tumoren im Dünn- und Dickdarm der Tiere führt. Mutationen im APC-Gen finden sich beim Menschen ebenfalls häufig in erblichen und spontanen Formen des Dickdarmkrebses.

  4. CDKN2A – „cyclin dependent kinase inhibitor 2 A“ (auch p16 genannt) ist ein Protein, das durch die Hemmung von Cyclinkinasen den Zellzyklus reguliert. In vielen Karzinomen, auch beim Darmkrebs, liegen Mutationen in diesem Gen vor.

Literatur

  1. Castillo-Lancellotti C, Tur JA, Uauy R (2013) Impact of folic acid fortification of flour on neural tube defects: a systematic review. Public Health Nutr 16:901–911

    Article  PubMed  Google Scholar 

  2. Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH (2007) A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 16:1325–1329

    Article  CAS  PubMed  Google Scholar 

  3. Hennessy Á, Walton J, Flynn A (2013) The impact of voluntary food fortification on micronutrient intakes and status in European countries: a review. Proc Nutr Soc 72:433–440

    Article  CAS  PubMed  Google Scholar 

  4. Bailey SW, Ayling JE (2009) 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 106:15424–15429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Sweeney MR, McPartlin J, Scott J (2007) Folic acid fortification and public health: report on threshold doses above which unmetabolised folic acid appear in serum. BMC Public Health 7:41

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bailey LB, Stover PJ, McNulty H, Fenech MF, Gregory JF 3rd, Mills JL et al (2015) Biomarkers of Nutrition for Development – Folate Review. J Nutrition 145:1636 S–1680 S

    Article  Google Scholar 

  7. Kennedy DA, Stern SJ, Moretti M, Matok I, Sarkar M, Nickel C et al (2011) Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol 35:2–10

    Article  CAS  PubMed  Google Scholar 

  8. Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ (2005) Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 113:825–828

    Article  CAS  PubMed  Google Scholar 

  9. van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E et al (2006) Low folate levels may protect against colorectal cancer. Gut 55:1461–1466

    Article  PubMed  PubMed Central  Google Scholar 

  10. Lee JE, Wei EK, Fuchs CS, Hunter DJ, Lee IM, Selhub J et al (2012) Plasma folate, methylenetetrahydrofolate reductase (MTHFR), and colorectal cancer in risk in three large nested case-control studies. Cancer Causes Control 23:537e45

    Google Scholar 

  11. Weinstein SJ, Albanes D, Selhub J, Graubard B, Lim U, Taylor PR et al (2008) One-carbon metabolism biomarkers and risk of colon and rectal cancers. Cancer Epidemiol Biomarkers Prev 17:3233–3240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Otani T, Iwasaki M, Sasazuki S, Inoue M, Tsugane S, Japan Public Health Center-based Prospective Study Group (2008) Japan Public Health Center-based prospective study. Cancer Causes Control 19:67–74

    Article  PubMed  Google Scholar 

  13. Kato I, Dnistrian AM, Schwartz M, Toniolo P, Koenig K, Shore RE et al (1999) Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study. Br J Cancer 79:1917–1922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Glynn SA, Albanes D, Pietinen P, Brown CC, Rautalahti M, Tangrea JA et al (1996) Colorectal cancer and folate status: a nested case-control study among male smokers. Cancer Epidemiol Biomarkers Prev 5:487–494

    CAS  PubMed  Google Scholar 

  15. Chuang SC, Rota M, Gunter MJ, Zeleniuch-Jacquotte A, Eussen SJ, Vollset SE et al (2013) 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 178:1028–1037

    Article  PubMed  Google Scholar 

  16. Ulrich CM, Kampman E, Bigler J, Schwartz SM, Chen C, Bostick R et al (1999) Colorectal adenomas and the C677T MTHFR polymorphism: evidence for gene-environment interaction? Cancer Epidemiol Biomarkers Prev 8:659–668

    CAS  PubMed  Google Scholar 

  17. Kim JW, Park HM, Choi YK, Chong SY, Oh D, Kim NK (2011) Polymorphisms in genes involved in folate metabolism and plasma DNA methylation in colorectal cancer patients. Oncol Rep 25:167–172

    CAS  PubMed  Google Scholar 

  18. Taioli E, Garza MA, Ahn YO, Bishop DT, Bost J, Budai B et al (2009) Meta- and pooled analyses of the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and colorectal cancer: a HuGE-GSEC review. Am J Epidemiol 170:1207–1221

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gibson TM, Weinstein SJ, Pfeiffer RM, Hollenbeck AR, Subar AF, Schatzkin A et al (2011) Pre- and postfortification intake of folate and risk of colorectal cancer in a large prospective cohort study in the United States. Am J Clin Nutr 94:1053–1062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Keum N, Giovannucci EL (2014) Folic acid fortification and colorectal cancer risk. Am J Prev Med 46:S65–S72

    Article  PubMed  Google Scholar 

  21. Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS et al (2007) Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 297:2351–2359

    Article  CAS  PubMed  Google Scholar 

  22. Paspatis GA, Karamanolis DG (1994) Folate supplementation and adenomatous colonic polyps. Dis Colon Rectum 37:1340–1341

    Article  CAS  PubMed  Google Scholar 

  23. Jaszewski R, Misra S, Tobi M, Ullah N, Naumoff JA, Kucuk O et al (2008) Folic acid supplementation inhibits recurrence of colorectal adenomas: a randomized chemoprevention trial. World J Gastroenterol 14:4492–4498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Logan RF, Grainge MJ, Shepherd VC, Armitage NC, Muir KR (2008) Aspirin and folic acid for the prevention of recurrent colorectal adenomas. Gastroenterology 134:29–38

    Article  CAS  PubMed  Google Scholar 

  25. Wu K, Platz EA, Willett WC, Fuchs CS, Selhub J, Rosner BA et al (2009) A randomized trial on folic acid supplementation and risk of recurrent colorectal adenoma. Am J Clin Nutr 90:1623–1631

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gao QY, Chen HM, Chen YX, Wang YC, Wang ZH, Tang JT et al (2013) Folic acid prevents the initial occurrence of sporadic colorectal adenoma in Chinese older than 50 years of age: a randomized clinical trial. Cancer Prev Res (Phila) 6:744–752

    Article  CAS  Google Scholar 

  27. Ding H, Gao QY, Chen HM, Fang JY (2016) People with low serum folate levels have higher risk of colorectal adenoma/advanced colorectal adenoma occurrence and recurrence in China. J Int Med Res 44:767–778

    Article  CAS  PubMed  Google Scholar 

  28. Clarke R, Halsey J, Lewington S, Lonn E, Armitage J, Manson JE et al (2010) Effects of lowering homocysteine levels with B vitamins on cardiovascular disease, cancer, and cause-specific mortality: Meta-analysis of 8 randomized trials involving 37 485 individuals. Arch Intern Med 170:1622–1631

    Article  CAS  PubMed  Google Scholar 

  29. Ebbing M, Bønaa KH, Nygård O, Arnesen E, Ueland PM, Nordrehaug JE et al (2009) Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 302:2119–2126

    Article  CAS  PubMed  Google Scholar 

  30. Cravo ML, Mason JB, Dayal Y, Hutchinson M, Smith D, Selhub J et al (1992) Folate deficiency enhances the development of colonic neoplasia in dimethylhydrazine-treated rats. Cancer Res 52:5002–5006

    CAS  PubMed  Google Scholar 

  31. Bird CL, Swendseid ME, Witte JS, Shikany JM, Hunt IF, Frankl HD et al (1995) Red cell and plasma folate, folate consumption, and the risk of colorectal adenomatous polyps. Cancer Epidemiol Biomarkers Prev 4:709–714

    CAS  PubMed  Google Scholar 

  32. Song J, Medline A, Mason JB, Gallinger S, Kim YI (2000) Effects of dietary folate on intestinal tumorigenesis in the apcMin mouse. Cancer Res 60:5434–5440

    CAS  PubMed  Google Scholar 

  33. Song J, Sohn KJ, Medline A, Ash C, Gallinger S, Kim YI (2000) Chemopreventive effects of dietary folate on intestinal polyps in Apc+/−Msh2−/− mice. Cancer Res 60:3191–3199

    CAS  PubMed  Google Scholar 

  34. Al-Numair KS, Waly MI, Ali A, Essa MM, Farhat MF, Alsaif MA (2011) Dietary folate protects against azoxymethane-induced aberrant crypt foci development and oxidative stress in rat colon. Exp Biol Med (Maywood) 236:1005–1011

    Article  CAS  Google Scholar 

  35. Lin YW, Wang JL, Chen HM, Zhang YJ, Lu R, Ren LL et al (2011) Folic acid supple-mentary reduce the incidence of adenocarcinoma in a mouse model of colorectal cancer: microarray gene expression profile. J Exp Clin Cancer Res 30:116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Nicken P, Brauer N, Lampen A, Steinberg P (2012) Influence of a fat-rich diet, folic acid supplementation and a human-relevant concentration of 2‑amino-1-methyl-6-phenylimidazo[4,5-b]pyridine on the induction of preneoplastic lesions in the rat colon. Arch Toxicol 86:815–821

    Article  CAS  PubMed  Google Scholar 

  37. Duthie SJ, Narayanan S, Blum S, Pirie L, Brand GM (2000) Folate deficiency in vitro induces uracil misincorporation and DNA hypomethylation and inhibits DNA excision repair in immortalized normal human colon epithelial cells. Nutr Cancer 37:245–251

    Article  CAS  PubMed  Google Scholar 

  38. Linhart HG, Troen A, Bell GW, Cantu E, Chao WH, Moran E et al (2009) Folate deficiency induces genomic uracil misincorporation and hypomethylation but does not increase DNA point mutations. Gastroenterology 136:227–235

    Article  PubMed  Google Scholar 

  39. Kang GH (2011) Four molecular subtypes of colorectal cancer and their precursor lesions. Arch Pathol Lab Med 135:698–703

    PubMed  Google Scholar 

  40. Protiva P, Mason JB, Liu Z, Hopkins ME, Nelson C, Marshall JR et al (2011) Altered folate availability modifies the molecular environment of the human colorectum: implications for colorectal carcinogenesis. Cancer Prev Res 4:530–543

    Article  CAS  Google Scholar 

  41. Pufulete M, Al-Ghnaniem R, Khushal A, Appelby P, Harris N, Gout S et al (2005) Effect of folic acid supplementation on genomic DNA methylation in patients with colorectal adenoma. Gut 54:648–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Sauer J, Jang H, Zimmerly EM, Kim KC, Liu Z, Chanson A et al (2010) Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colon. Br J Nutr 104:24–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Piyathilake CJ, Macaluso M, Celedonio JE, Badiga S, Bell WC, Grizzle WE (2010) Mandatory fortification with folic acid in the United States appears to have adverse effects on histone methylation in women with pre-cancer but not in women free of pre-cancer. Int J Womens Health 1:131–137

    PubMed  PubMed Central  Google Scholar 

  44. Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH (2001) Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis 60:729–735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Mangoni AA (2006) Folic acid, inflammation, and atherosclerosis: false hopes or the need for better trials? Clin Chim Acta 367:11–19

    Article  CAS  PubMed  Google Scholar 

  46. Kadaveru K, Protiva P, Greenspan EJ, Kim YI, Rosenberg DW (2012) Dietary methyl donor depletion protects against intestinal tumorigenesis in Apc(Min/+) mice. Cancer Prev Res (Phila) 5:911–920

    Article  CAS  Google Scholar 

  47. Ho GY, Xue X, Cushman M, McKeown-Eyssen G, Sandler RS, Ahnen DJ et al (2009) Antagonistic effects of aspirin and folic acid on inflammation markers and subsequent risk of recurrent colorectal adenomas. J Natl Cancer Inst 101:1650–1654

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B et al (2006) Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. J Nutr 136:189–194

    CAS  PubMed  Google Scholar 

  49. Sawaengsri H, Wang J, Reginaldo C, Steluti J, Wu D, Meydani SN et al (2016) High folic acid intake reduces natural killer cell cytotoxicity in aged mice. J Nutr Biochem 30:102–107

    Article  CAS  PubMed  Google Scholar 

  50. Sebastian S, Hernández V, Myrelid P, Kariv R, Tsianos E, Toruner M et al (2014) Colorectal cancer in inflammatory bowel disease: results of the 3rd ECCO pathogenesis scientific workshop (I). J Crohns Colitis 1:5–18

    Article  Google Scholar 

  51. Carrier J, Medline A, Sohn KJ, Choi M, Martin R, Hwang SW et al (2003) Effects of dietary folate on ulcerative colitis-associated colorectal carcinogenesis in the interleukin 2‑ and beta(2)-microglobulin-deficient mice. Cancer Epidemiol Biomarkers Prev 12:1262–1267

    CAS  PubMed  Google Scholar 

  52. MacFarlane AJ, Behan NA, Matias FM, Green J, Caldwell D, Brooks SP (2013) Dietary folate does not significantly affect the intestinal microbiome, inflammation or tumorigenesis in azoxymethane-dextran sodium sulphate-treated mice. Br J Nutr 109:630–638

    Article  CAS  PubMed  Google Scholar 

  53. RKI (2015) Krebs in Deutschland 2011/2012. 10. Ausgabe. Robert Koch-Institut (Hrsg) und die Gesellschaft der epidemiologischen Krebsregister in Deutschland e. V. (Hrsg). Berlin, 2015. http://www.gekid.de/Doc/krebs_in_deutschland_2015.pdf. Zugegriffen: 1. Sep. 2016

    Google Scholar 

  54. Tannapfel A, Neid M, Aust D, Baretton G (2010) Entstehung kolorektaler Karzinome. Dtsch Arztebl Int 107:760–766

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Abt. Lebensmittelsicherheit, Bundesinstitut für Risikobewertung, Max-Dohrn-Str. 8–10, 10589, Berlin, Deutschland

    Anke Weißenborn, Anke Ehlers, Karen-I. Hirsch-Ernst, Alfonso Lampen & Birgit Niemann

Authors
  1. Anke Weißenborn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anke Ehlers
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karen-I. Hirsch-Ernst
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Alfonso Lampen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Birgit Niemann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anke Weißenborn.

Ethics declarations

Interessenkonflikt

A. Weißenborn, A. Ehlers, K.-I. Hirsch-Ernst, A. Lampen und B. Niemann geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Weißenborn, A., Ehlers, A., Hirsch-Ernst, KI. et al. Ein Vitamin mit zwei Gesichtern. Bundesgesundheitsbl 60, 332–340 (2017). https://doi.org/10.1007/s00103-016-2505-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00103-016-2505-6

Schlüsselwörter

Keywords

Search

Navigation