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Effect of fortified spread on homocysteine concentration in apparently healthy volunteers

Abstract

Objective:

To determine the effect of folic acid, vitamin B6 and B12 fortified spreads on the blood concentrations of these vitamins and homocysteine.

Design and setting:

A 6-week randomized, double-blinded, placebo-controlled, parallel trial carried out in a clinical research center.

Subjects:

One hundred and fifty healthy volunteers (50% males).

Interventions:

For 6 weeks, the subjects consumed the test spreads (20 g/day): containing per 20 g (1) 200 μg folic acid, 2 μg vitamin B12 and 1 mg vitamin B6, or (2) 400 μg folic acid, 2 μg vitamin B12 and 1 mg vitamin B6 or (3) no B-vitamins (control spread).

Results:

The B-vitamin status increased on using the test spreads, with the largest effect on the serum folate concentration: 48% in men and 58% in women on spread 1 and 92 and 146%, respectively, on spread 2 (P-values all <0.05). The plasma homocysteine decreased in the groups treated with the fortified spreads as compared to the control group. Average decreases were for males: 0.7±1.5 μmol/l (6.8%) on spread 1 and 1.7±1.7 μmol/l (17.6%) on spread 2 and for females: 1.4±1.2 μmol/l (14.2%) and 2.4±2.0 μmol/l (23.3%), respectively (P-values all <0.05).

Conclusions:

Consumption of a spread fortified with folic acid, vitamin B6 and vitamin B12 for 6 weeks significantly increases the blood concentrations of these vitamins and significantly decreases the plasma concentration of homocysteine. Fortified staple foods like spreads can contribute to the lowering of homocysteine concentrations.

Sponsorship:

Unilever Research and Development, Vlaardingen, The Netherlands.

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References

  • Accinni R, Campolo J, Bartesaghi S, De Leo G, Lucarelli C, Cursano CF et al. (1998). High-performance liquid chromatographic determination of total plasma homocysteine with or without internal standards. J Chromatogr A 828, 397–400.

    Article  CAS  PubMed  Google Scholar 

  • Andersson A, Brattstrom L, Israelsson B, Isaksson A, Hamfelt A, Hultberg B (1992). Plasma homocysteine before and after methionine loading with regard to age, gender, and menopausal status. Eur J Clin Invest 22, 79–87.

    Article  CAS  PubMed  Google Scholar 

  • Ashfield-Watt PA, Whiting JM, Clark ZE, Moat SJ, Newcombe RG, Burr ML et al. (2003). A comparison of the effect of advice to eat either ‘5-a-day’ fruit and vegetables or folic acid-fortified foods on plasma folate and homocysteine. Eur J Clin Nutr 57, 316–323.

    Article  CAS  PubMed  Google Scholar 

  • Bergmark C, Mansoor MA, Svardal A, de Faire U (1997). Redox status of plasma homocysteine and related aminothiols in smoking and nonsmoking young adults. Clin Chem 43, 1997–1999.

    CAS  PubMed  Google Scholar 

  • Blom HJ (1998). Determinants of plasma homocysteine. Am J Clin Nutr 67, 188–189.

    Article  CAS  PubMed  Google Scholar 

  • Brants HA, Hulshof KF (1995). The development of a food composition table with folate values [De ontwikkeling van een voedingsmiddelentabel met foliumzuurgehalten]. V95.089. 1995. Zeist, TNO.

  • Brants HAM, Brussaard JH, Bouman M, Lowik MRH (1997). Dietary intake among adults with special reference to vitamin B-6. Eur J Clin Nutr 51 (Suppl 3), S25–S31.

    PubMed  Google Scholar 

  • Brattstrom LE, Israelsson B, Jeppsson JO, Hultberg BL (1988). Folic acid – an innocuous means to reduce plasma homocysteine. Scand J Clin Lab Invest 48, 215–221.

    Article  CAS  PubMed  Google Scholar 

  • Brouwer IA, Van Dusseldorp M, Thomas CMG, Duran M, Hautvast JGAJ, Eskes TKAB et al. (1999a). Low-dose folic acid supplementation decreases plasma homocysteine concentrations: a randomized trial. Am J Clin Nutr 69, 99–104.

    Article  CAS  PubMed  Google Scholar 

  • Brouwer IA, Van Dusseldorp M, West CE, Meyboom S, Thomas CMG, Duran M et al. (1999b). Dietary folate from vegetables and citrus fruit decreases plasma homocysteine concentrations in humans in a dietary controlled trial. J Nutr 129, 1135–1139.

    Article  CAS  PubMed  Google Scholar 

  • Brussaard JH, Lowik MRH, vandenBerg H, Brants HAM, Goldbohm RA (1997). Folate intake and status among adults in the Netherlands. Eur J Clin Nutr 51 (Suppl 3), S46–S50.

    PubMed  Google Scholar 

  • Carrero JJ, Baro L, Fonolla J, Gonzalez-Santiago M, Martinez-Ferez A, Castillo R et al. (2004). Cardiovascular effects of milk enriched with omega-3 polyunsaturated fatty acids, oleic acid, folic acid, and vitamins E and B6in volunteers with mild hyperlipidemia. Nutrition 20, 521–527.

    Article  CAS  PubMed  Google Scholar 

  • Clarke R, Armitage J (2000). Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements. Semin Thromb Hemost 26, 341–348.

    Article  CAS  PubMed  Google Scholar 

  • Clarke R, Grimley EJ, Schneede J, Nexo E, Bates C, Fletcher A et al. (2004). Vitamin B12and folate deficiency in later life. Age Ageing 33, 34–41.

    Article  PubMed  Google Scholar 

  • Cuskelly GJ, McNulty H, Scott JM (1996). Effect of increasing dietary folate on red-cell folate: implications for prevention of neural tube defects [see comments]. Lancet 347, 657–659.

    Article  CAS  PubMed  Google Scholar 

  • de Bree A, Van Dusseldorp M, Brouwer IA, van het Hof KH, Steegers Theunissen RPM (1997). Folate intake in Europe: recommended, actual and desired intake. Eur J Clin Nutr 51, 643–660.

    Article  CAS  PubMed  Google Scholar 

  • de Bree A, Verschuren WM, Blom HJ, Kromhout D (2001a). Association between B vitamin intake and plasma homocysteine concentration in the general dutch population aged 20–65 y. Am J Clin Nutr 73, 1027–1033.

    Article  CAS  PubMed  Google Scholar 

  • de Bree A, Verschuren WM, Blom HJ, Kromhout D (2001b). Lifestyle factors and plasma homocysteine concentrations in a general population sample. Am J Epidemiol 154, 150–154.

    Article  CAS  PubMed  Google Scholar 

  • Dunn RT, Foster LB (1973). Radioassay of serum folate. Clin Chem 19, 1101–1105.

    CAS  PubMed  Google Scholar 

  • Friedewald WT, Levy RI, Fredrickson DS (1972). Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18, 499–502.

    CAS  PubMed  Google Scholar 

  • Fukagawa NK, Martin JM, Wurthmann A, Prue AH, Ebenstein D, O'Rourke B (2000). Sex-related differences in methionine metabolism and plasma homocysteine concentrations. Am J Clin Nutr 72, 22–29.

    Article  CAS  PubMed  Google Scholar 

  • Giles WH, Kittner SJ, Croft JB, Wozniak MA, Wityk RJ, Stern BJ et al. (1999). Distribution and correlates of elevated total homocyst(e)Ine: the stroke prevention in young women study. Ann Epidemiol 9, 307–313.

    Article  CAS  PubMed  Google Scholar 

  • Giltay EJ, Hoogeveen EK, Elbers JM, Gooren LJ, Asscheman H, Stehouwer CD (1998). Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females. J Clin Endocrinol Metab 83, 550–553.

    Article  CAS  PubMed  Google Scholar 

  • Givas JK, Gutcho S (1975). PH dependence of the binding of folates to milk binder in radioassay of folates. Clin Chem 21, 427–428.

    CAS  PubMed  Google Scholar 

  • Guidelines Subcommittee (1999). 1999 World Health Organization–International Society of Hypertension guidelines for the management of hypertension. J Hypertens 17, 151–183.

  • 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 

  • Heijden L, Van den Brouwer C, Roosemalen K, Van Dusseldorp M (1997). Vitamin B12values in food. An inventory based on the literature [Vitamine B12waarden in voedingsmiddelen. Een inventarisatie op basis van literatuur]. Uitgave in de seri publicaties van de afdeling Voeding en Epidemiology. Landbouw Universiteit Wageningen.

  • Holland B, Welch AA, Undin JD, Buss DH, Paul AA, Southgate DAT (1991). McCance and Widdowson's: the Composition of Foods. The Royal Society of Chemistry: Cambridge.

    Google Scholar 

  • Homocysteine Lowering Trialists' Collaboration (2005). Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr 82, 806–812.

  • Jacques PF, Bostom AG, Wilson PW, Rich S, Rosenberg IH, Selhub J (2001). Determinants of plasma total homocysteine concentration in the framingham offspring cohort. Am J Clin Nutr 73, 613–621.

    Article  CAS  PubMed  Google Scholar 

  • Johansson M, Witthoft CM, Bruce A, Jagerstad M (2002). Study of wheat breakfast rolls fortified with folic acid. The effect on folate status in women during a 3-month intervention. Eur J Nutr 41, 279–286.

    Article  CAS  PubMed  Google Scholar 

  • Koehler KM, Baumgartner RN, Garry PJ, Allen RH, Stabler SP, Rimm EB (2001). Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use. Am J Clin Nutr 73, 628–637.

    Article  CAS  PubMed  Google Scholar 

  • Lowik MR, Hulshof KF, van der Heijden LJ, Brussaard JH, Burema J, Kistemaker C et al. (1998). Changes in the diet in The Netherlands: 1987–1988 to 1992. Int J Food Sci Nutr 49 (Suppl 1), S1–S64.

    Google Scholar 

  • Lucock M (2004). Is folic acid the ultimate functional food component for disease prevention? BMJ 328, 211–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mansoor MA, Bergmark C, Svardal AM, Lonning PE, Ueland PM (1995). Redox status and protein binding of plasma homocysteine and other aminothiols in patients with early-onset peripheral vascular disease. Homocysteine and peripheral vascular disease. Arterioscler Thromb Vasc Biol 15, 232–240.

    Article  CAS  PubMed  Google Scholar 

  • NEVO (1996). Dutch Nutrient Data Base, The Hague, Voorlichtingsbureau voor de Voeding. Den Haag, Voorlichtingsbureau voor de voeding.

  • Norlund L, Grubb A, Fex G, Leksell H, Nilsson JE, Schenck H et al. (1998). The increase of plasma homocysteine concentrations with age is partly due to the deterioration of renal function as determined by plasma cystatin C. Clin Chem Lab Med 36, 175–178.

    Article  CAS  PubMed  Google Scholar 

  • Nygard O, Refsum H, Ueland PM, Vollset SE (1998). Major lifestyle determinants of plasma total homocysteine distribution: the hordaland homocysteine study. Am J Clin Nutr 67, 263–270.

    Article  CAS  PubMed  Google Scholar 

  • Nygard O, Vollset SE, Refsum H, Stensvold I, Tverdal A, Nordrehaug JE et al. (1995). Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine study. JAMA 274, 1526–1533.

    Article  CAS  PubMed  Google Scholar 

  • Olszewski AJ, Szostak WB, Bialkowska M, Rudnicki S, McCully KS (1989). Reduction of plasma lipid and homocysteine levels by pyridoxine, folate, cobalamin, choline, riboflavin, and troxerutin in atherosclerosis [Published Erratum Appears in Atherosclerosis 1991 May;88(1):978]. Atherosclerosis 75, 1–6.

    Article  CAS  PubMed  Google Scholar 

  • Pentieva K, McKillop D, Duffy N, de Deckere EA, Jacobs RG, van der Put NM et al. (2003). Acute absorption of folic acid from a fortified low-fat spread. Eur J Clin Nutr 57, 1235–1241.

    Article  CAS  PubMed  Google Scholar 

  • Piyathilake CJ, Hine RJ, Dasanayake AP, Richards EW, Freeberg LE, Vaughn WH et al. (1992). Effect of smoking on folate levels in buccal mucosal cells. Int J Cancer 52, 566–569.

    Article  CAS  PubMed  Google Scholar 

  • Pryor WA, Stone K (1993). Oxidants in cigarette smoke. Radicals, hydrogen peroxide, peroxynitrate, and peroxynitrite. Ann NY Acad Sci 686, 12–27.

    Article  CAS  PubMed  Google Scholar 

  • Rasmussen LB, Ovesen L, Bulow I, Knudsen N, Laurberg P, Perrild H (2000). Folate intake, lifestyle factors, and homocysteine concentrations in younger and older women. Am J Clin Nutr 72, 1156–1163.

    Article  CAS  PubMed  Google Scholar 

  • Riddell LJ, Chisholm A, Williams S, Mann JI (2000). Dietary strategies for lowering homocysteine concentrations. Am J Clin Nutr 71, 1448–1454.

    Article  CAS  PubMed  Google Scholar 

  • Ruggeri S, Zappacosta B, Ricci R, Persichilli S, Mistura L, Turrini A et al. (2003). Natural folate versus supplements: effect on plasma homocysteine and RBC folate in healthy adults. Ann Nutr Metab 47, 623.

    Google Scholar 

  • Schrijver J, Speek AJ, Schreurs WH (1981). Semi-automated fluorometric determination of pyridoxal-5′-phosphate (vitamin B6) in whole blood by high-performance liquid chromatography (HPLC). Int J Vitam Nutr Res 51, 216–222.

    CAS  PubMed  Google Scholar 

  • Selhub J, Jacques PF, Wilson PW, Rush D, Rosenberg IH (1993). Vitamin status and intake as primary determinants of homocysteinemia in an elderly population. JAMA 270, 2693–2698.

    Article  CAS  PubMed  Google Scholar 

  • Selhub J, Miller JW (1992). The pathogenesis of homocysteinemia: interruption of the coordinate regulation by s-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr 55, 131–138.

    Article  CAS  PubMed  Google Scholar 

  • Tapola NS, Karvonen HM, Niskanen LK, Sarkkinen ES (2004). Mineral water fortified with folic acid, Vitamins B6, B12, D and calcium improves folate status and decreases plasma homocysteine concentration in men and women. Eur J Clin Nutr 58, 376–385.

    Article  CAS  PubMed  Google Scholar 

  • The Homocysteine Studies Collaboration (2002). Homocysteine and risk of ischemic heart disease and stroke: a meta- analysis. JAMA 288, 2015–2022.

    Article  Google Scholar 

  • Tucker KL, Olson B, Bakun P, Dallal GE, Selhub J, Rosenberg IH (2004). Breakfast cereal fortified with folic acid, vitamin B-6, and vitamin B-12 increases vitamin concentrations and reduces homocysteine concentrations: a randomized trial. Am J Clin Nutr 79, 805–811.

    Article  CAS  PubMed  Google Scholar 

  • Ubbink JB, van der Merwe A, Vermaak WJ, Delport R (1993). Hyperhomocysteinemia and the response to vitamin supplementation. Clin Investig 71, 993–998.

    Article  CAS  PubMed  Google Scholar 

  • Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC (1994). Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr 124, 1927–1933.

    Article  CAS  PubMed  Google Scholar 

  • Vahteristo L, Kariluoto S, Barlund S, Karkkainen M, Lamberg-Allardt C, Salovaara H et al. (2002). Functionality of endogenous folates from Rye and orange juice using human in vivo model. Eur J Nutr 41, 271–278.

    Article  CAS  PubMed  Google Scholar 

  • van Oort FV, Melse-Boonstra A, Brouwer IA, Clarke R, West CE, Katan MB et al. (2003). Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose–response study. Am J Clin Nutr 77, 1318–1323.

    Article  CAS  PubMed  Google Scholar 

  • Wald DS, Bishop L, Wald NJ, Law M, Hennessy E, Weir D et al. (2001). Randomized trial of folic acid supplementation and serum homocysteine levels. Arch Intern Med 161, 695–700.

    Article  CAS  PubMed  Google Scholar 

  • Wald DS, Law M, Morris JK (2002). Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ 325, 1202.

    Article  PubMed  PubMed Central  Google Scholar 

  • Ward M, McNulty H, McPartlin J, Strain JJ, Weir DG, Scott JM (1997). Plasma homocysteine, a risk factor for cardiovascular disease, is lowered by physiological doses of folic acid. Q J Med 90, 519–524.

    Article  CAS  Google Scholar 

  • WHO/FAO (2003). Joint WHO/FAO expert consultation ‘Diet, Nutrition, and the prevention of chronic diseases’. WHO Technical report series 916 Geneve.

  • Wright AJ, Finglas PM, Southon S (2000). Erythrocyte folate analysis: saponin added during lysis of whole blood can increase apparent folate concentrations, depending on hemolysate PH. Clin Chem 46, 1978–1986.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the volunteers for their participation and Gery Steenge, who was in charge of the conduct of the experiment at TNO Nutrition and Food Research, for her dedication.

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Correspondence to A de Bree.

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van Vliet, T., Jacobs, R., de Deckere, E. et al. Effect of fortified spread on homocysteine concentration in apparently healthy volunteers. Eur J Clin Nutr 61, 769–778 (2007). https://doi.org/10.1038/sj.ejcn.1602570

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