Where is the initial site of folic acid biotransformation in humans?

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Recent results and a re-appraisal of historical literature suggests, contrary to accepted wisdom, that the site of biotransformation in humans of oral physiological doses of folic acid is not the mucosal absorptive cells of the upper small intestine. Instead, folic acid is hypothesised to be passed into the hepatic portal vein (HPV) and totally cleared by the liver on 'first-pass', thus preventing any significant amount from directly entering the systemic circulation; hepatic biotransformation and subsequent enterohepatic re-circulation ensuring entry of only 5-methyltetrahydrofolic acid into the systemic blood system. However, since human liver exhibits a comparatively poor ability to reduce folic acid, a regular daily intake of physiological doses of folic acid (from a policy of mandatory fortification) could eventually result in the chronic appearance of unmetabolised folic acid in the systemic circulatory blood system, potentially inducing polar 'positive' and 'negative' effects on health. An accurate estimate of plasma 'volume-of-distribution' would allow for better estimates of the fraction of any folate test dose appearing in the systemic plasma circulation; important for further evaluations of risk-benefit analysis of the proposed folic acid fortification in the UK. The project will; (a) carry out an in vivo kinetic investigation of absorption and initial biotransformation, using stable-isotope-labelled folic acid and 5-formyltetrahydrofolic acid (a 'natural' reduced folate), in 'stable' TIPSS patients (Newcastle University); (b) extend and validate a newly developed LC-MS-MS procedure (University of Nottingham) for folate profiling in human blood fractions for the additional analysis of 13C5 stable-isotope-labelled folate forms; (c) carry out an in vivo kinetic estimation of the sampled plasma 'volume-of-distribution', using i.v administered stable-isotope-labelled 5-methyltetrahydrofolic acid, in healthy volunteers (IFR).

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