Dietary folate: Bioavailability studies in humans

Keywords:Folate; Folic acid; Dietaryfolateintake;Folatebioavailability;Polyglutamylfolic acid;Homocysteine; GCPII 1561C>T polymorphism; Stable isotopes; Dose-findingLow intake of the B vitamin folicacid,orfolatecauseshyperhomocysteinaemiawhich may be a risk factor for cardiovascular disease. In the Netherlands, the recommended daily allowance (RDA) forfolateintake is300 µg/d. It is not known to what extent ingestedfolatein the diet isbioavailable, i.e. is absorbed and used or stored in the body. In food,folateis often conjugated to apolyglutamatechain, which has to be removedenzymaticallybyfolylpoly glutamylcarboxypeptidase(FGCP), encoded by the GCPII gene, before absorption can take place. Limitation or inhibition of this process may limit the bioavailability ofpolyglutamatefolate. The aim of the present research was to quantify the effect of thepolyglutamatechain onfolatebioavailability. This included the modulating effect of the 1561C>T polymorphism in the GCPII gene. Furthermore, we aimed to establish theminimal amountoffolatethat lowers plasmahomocysteineconcentrations adequately.The average intake of dietary folatein a representative Dutch population sample of 2,435 men and women aged 20-65 y was210 µg/d. About two thirds of dietaryfolateintake was in thepolyglutamateform. In a 12-w randomized trial, 180 subjects aged 50-75 y consumed daily either a low dose ofheptaglutamylfolic acid ormonoglutamylfolic acid, or a placebo capsule. Thebiovailabilityofheptaglutamylfolic acid relative to that ofmonoglutamylfolic acid was found to be 66%. This implies that the bioavailability offolatefrom the diet is maximally 77% due to the presence of two thirds offolateaspolyglutamate. No differences in bioavailability were found between GCPII 1561C>T genotypes. In order to reduce the sample size and duration of future studies onfolatebioavailability, a new dual isotopiclabellingmethod was developed. This method comprises that low quantities of two differentially isotopelabelledfolatecompounds are simultaneously administered to volunteers during several days. The ratio ofisotopicallylabelledfolatein plasma then reflects the bioavailability of one compound relative to the other. This method provides a sensitive, accurate and efficient method for measuringfolatebioavailability. In a 12-w randomized trial comprising 316 subjects aged 50-75 y, we established that the amount of folic acid required to reduce plasmahomocysteineconcentrations adequately isat least 400 µg/d.In conclusion,folatebioavailability from the diet is reduced by approximately 23% due to the presence offolatein thepolyglutamateform. The average intake offolatein the Netherlands is currently lower than the RDA. Moreover, a substantial increase offolateintake is required to reduce plasmahomocysteineconcentrations adequately, provided that such lowering of plasmahomocysteineconcentrations is desirable.