British Journal of Nutrition

Review Article

Folic acid metabolism in human subjects revisited: potential implications for proposed mandatory folic acid fortification in the UK

Anthony J. A. Wrighta1 c1, Jack R. Daintya1 and Paul M. Finglasa1

a1 Institute of Food Research, Norwich Research Park, Colney, Norwich NR4 7UA, UK


Following an introduction of the importance of folates and the rationale for seeking to estimate fractional folate absorption from foods (especially for countries not having a mandatory folic acid fortification policy), scientific papers covering the mechanisms of folate absorption and initial biotransformation are discussed. There appears (post-1983) to be a consensus that physiological doses of folic acid undergo biotransformation in the absorptive cells of the upper small intestine to 5-methyltetrahydrofolic acid (as happens for all naturally-occurring reduced 1-carbon-substituted folates). This ‘validates’ short-term experimental protocols assessing ‘relative’ folate absorption in human subjects that use folic acid as the ‘reference’ dose. The underlying scientific premise on which this consensus is based is challenged on three grounds: (i) the apparent absence of a 5-methyltetrahydrofolic acid response in the human hepatic portal vein following absorption of folic acid, (ii) the low dihydrofolate reductase activity peculiar to man and (iii) the implications derived from recent stable-isotope studies of folate absorption. It is concluded that the historically accepted case for folic acid being a suitable ‘reference folate’ for studies of the ‘relative absorption’ of reduced folates in human subjects is invalid. It is hypothesised that the liver, and not the absorptive cells of the upper small intestine, is the initial site of folic acid metabolism in man and that this may have important implications for its use as a supplement or fortificant since human liver's low capacity for reduction may eventually give rise to saturation, resulting in significant (and potentially deleterious) unmetabolised folic acid entering the systemic circulation.

(Received December 06 2006)

(Revised May 21 2007)

(Accepted May 24 2007)


c1 Corresponding author: Mr A. J. A. Wright, fax +44 1603 507723, email


Abbreviations: AUC, area under the curve; DHF, dihydrofolic acid; DHFR, dihydrofolic acid reductase