Folic acid causes higher prevalence of detectable unmetabolized folic acid in serum than B-complex: a randomized trial
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Unmetabolized folic acid (UMFA) is common in serum of elderly individuals receiving folic acid (FA)-fortified foods or supplements. We studied the effect of supplementing FA or B-complex on serum concentrations of (6S)-5-methyltetrahydropteroylglutamate [(6S)-5-CH3-H4Pte] and UMFA in elderly people and explored factors associated with detectable UMFA post-supplementation.
This is a randomized single-blind non-controlled trial on 58 elderly people using daily 400 µg FA (n = 31) or 400 µg FA, 10 µg cyanocob(III)alamin and 8 mg pyridoxine (n = 27) for a median of 23 days. Main outcome includes changes in concentrations of serum (6S)-5-CH3-H4Pte and UMFA.
Total homocysteine declined by a median of 1.6 (p = 0.074) in the FA and 1.3 µmol/L (p = 0.009) in the B-complex arms (p = 0.66 between the arms). Serum (6S)-5-CH3-H4Pte significantly (p < 0.001 vs. baseline) increased by a median of 9.2 and 6.5 nmol/L in the FA and B-complex groups, respectively (p = 0.152 between the groups). Compared to FA, B-complex reduced cystathionine and caused lower post-intervention serum UMFA, percentage of UMFA to (6S)-5-CH3-H4Pte and prevalence of UMFA ≥ 0.21 nmol/L. Higher serum cystathionine and whole-blood folate predicted higher post-intervention serum UMFA.
FA caused higher UMFA as compared to B-complex. Pyridoxine appears to improve folate recycling. Data on serum UMFA should be interpreted in relation to other vitamins involved in folate metabolism. Serum UMFA is suggested to play a sensory role through which the cell recognizes FA available for metabolism via dihydrofolate reductase.
KeywordsUnmetabolized folic acid Elderly Supplementation Vitamin B6 Vitamin B12 Serum folate
Betaine hydroxymethyl transferase
Glomerular filtration rate
Mean corpuscular volume
Serine hydroxymethyl transferase
Unmetabolized folic acid
The study was registered: Clinical Trials NCT01105351.
Conflict of interest
The authors have no conflict of interest to declare.
- 5.Russell RM, Rosenberg IH, Wilson PD, Iber FL, Oaks EB, Giovetti AC, Otradovec CL, Karwoski PA, Press AW (1983) Increased urinary excretion and prolonged turnover time of folic acid during ethanol ingestion. Am J Clin Nutr 38:64–70Google Scholar
- 9.Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM (1997) Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 65:1790–1795Google Scholar
- 12.Zschabitz S, Cheng TY, Neuhouser ML, Zheng Y, Ray RM, Miller JW, Song X, Maneval DR, Beresford SA, Lane D, Shikany JM, Ulrich CM (2013) B vitamin intakes and incidence of colorectal cancer: results from the Women’s Health Initiative Observational Study cohort. Am J Clin Nutr 97:332–343CrossRefGoogle Scholar
- 14.Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E, Armitage J, Manson JE, Hankey GJ, Spence JD, Galan P, Bonaa KH, Jamison R, Gaziano JM, Guarino P, Baron JA, Logan RF, Giovannucci EL, den Heijer M, Ueland PM, Bennett D, Collins R, Peto R (2013) Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals. Lancet 381:1029–1036CrossRefGoogle Scholar
- 15.Neuhouser ML, Cheng TY, Beresford SA, Brown E, Song X, Miller JW, Zheng Y, Thomson CA, Shikany JM, Vitolins MZ, Rohan T, Green R, Ulrich CM (2015) Red blood cell folate and plasma folate are not associated with risk of incident colorectal cancer in the Women’s Health Initiative observational study. Int J Cancer. doi: 10.1002/ijc.29453 Google Scholar
- 16.Yetley EA, Pfeiffer CM, Phinney KW, Fazili Z, Lacher DA, Bailey RL, Blackmore S, Bock JL, Brody LC, Carmel R, Curtin LR, Durazo-Arvizu RA, Eckfeldt JH, Green R, Gregory JF III, Hoofnagle AN, Jacobsen DW, Jacques PF, Molloy AM, Massaro J, Mills JL, Nexo E, Rader JI, Selhub J, Sempos C, Shane B, Stabler S, Stover P, Tamura T, Tedstone A, Thorpe SJ, Coates PM, Johnson CL, Picciano MF (2011) Biomarkers of folate status in NHANES: a roundtable summary. Am J Clin Nutr 94:303S–312SCrossRefGoogle Scholar
- 21.Kauwell GP, Lippert BL, Wilsky CE, Herrlinger-Garcia K, Hutson AD, Theriaque DW, Rampersaud GC, Cerda JJ, Bailey LB (2000) Folate status of elderly women following moderate folate depletion responds only to a higher folate intake. J Nutr 130:1584–1590Google Scholar
- 27.Boilson A, Staines A, Kelleher CC, Daly L, Shirley I, Shrivastava A, Bailey SW, Alverson PB, Ayling JE, McDermott AP, MacCooey A, Scott JM, Sweeney MR (2012) Unmetabolized folic acid prevalence is widespread in the older Irish population despite the lack of a mandatory fortification program. Am J Clin Nutr 96:613–621CrossRefGoogle Scholar
- 31.Obeid R, Kirsch SH, Kasoha M, Eckert R, Herrmann W (2011) Concentrations of unmetabolized folic acid and primary folate forms in plasma after folic acid treatment in older adults. Metabolism 60:673–678Google Scholar
- 36.Kalmbach RD, Choumenkovitch SF, Troen AM, D’Agostino R, Jacques PF, Selhub J (2008) Circulating folic acid in plasma: relation to folic acid fortification. Am J Clin Nutr 88:763–768Google Scholar
- 37.Stabler SP, Lindenbaum J, Savage DG, Allen RH (1993) Elevation of serum cystathionine levels in patients with cobalamin and folate deficiency. Blood 81:3404–3413Google Scholar