To understand the absorption, metabolism and biological consequences of folate and folic acid in the diet

Lead Research Organisation: Quadram Institute Bioscience
Department Name: Contracts


The project seeks to provide underpinning knowledge in formulating nutrition policy recommendations - particularly for subgroups with common genetic polymorphism(s) in folate enzyme genes, and the national debate on mandatory fortification. The project currently tests the following hypotheses: A. That a mixed diet rich in natural food folates has the same bioefficacy as taking (a) folic acid and (b) 5-methyltetrahydrofolic acid (Metafolin) supplements in raising folate status. Using human volunteers, a placebo-controlled 16-week folate-supplementation study will be undertaken. B. That folic acid is actually transferred unmetabolised into the hepatic portal vein (HPV) and, contrary to previous estimates of ca. 30 litres, the sampled plasma pool `volume-of-distribution¿ will be ca. 4 litres. Two studies will be undertaken; (a) one in Transjugular Intrahepatic Portal Systemic Shunt patients, with concurrent monitoring of HPV and systemic plasma responses; (b) one in normal volunteers, with the decay kinetics of an i.v. bolus of [13C5]-5-methyltetrahydrofolic acid (the natural circulating plasma folate form) over the following 2 hours being used to model the plasma concentration at time t=zero. The 'apparent plasma volume-of-distribution' then being estimated (a theoretical volume into which an absorbed oral dose is dispersed) for use in future studies to calculate 'apparent' folate absorption. C. That aberrant red cell folate speciation rather than the C677T MTHFR T allele per se is the true marker for disease risk and/or cancer drug response and toxicity. Human volunteers will be screened for 'common' gene SNPs in folate-enzymes, red cell folate speciation (by newly-developed LC-MS/MS), and folate/iron/riboflavin/B12 status. Gene and/or nutrient interaction with the MTHFR T allele will be investigated in predicting what 'triggers' some (but not all) human carriers of the MTHFT T allele into aberrant red cell folate metabolism and hence aberrant folate speciation.


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