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Article

Conversion of 5-Formyltetrahydrofolic Acid to 5-Methyltetrahydrofolic Acid Is Unimpaired in Folate-Adequate Persons Homozygous for the C677T Mutation in the Methylenetetrahydrofolate Reductase Gene¹

Vitamin Metabolism Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston MA 02111

²To whom correspondence and reprint requests should be addressed.

Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolic acid (5-CH₃-H₄ folic acid), the methyl donor for the formation of methionine from homocysteine. A common C677T transition in the MTHFR gene results in a variant with a lower specific activity and a greater sensitivity to heat than the normal enzyme, as measured in vitro. This study was undertaken to determine the capacity of homozygotes for the MTHFR C677T transition to convert 5-formyltetrahydrofolic acid (5-HCO-H₄ folic acid) to 5-CH₃-H₄ folic acid, a process that requires the action of MTHFR. Six subjects homozygous for the C677T transition (T/T) and 6 subjects with wild-type MTHFR (C/C) were given a 5-mg oral dose of (6R,S)-5-HCO-H₄ folic acid. Plasma and urine were analyzed for 5-CH₃-H₄ folic acid concentrations using affinity/HPLC coupled with fluorescence or UV detection. The mean areas under the curves created by the rise and fall of plasma 5-CH₃-H₄ folic acid after the oral dose did not differ between the two genotypes, 424.5 ± 140.3 (T/T) vs. 424.1± 202.4 h·nmol/L (C/C). There also was no significant difference in the mean cumulative 7-h urinary excretion of 5-CH₃-H₄ folic acid between the T/T (2.5 ± 1.4 µmol) and C/C (1.9 ± 1.0 µmol) genotypes. Under the conditions employed, the conversion of oral 5-HCO-H₄ folic acid to 5-CH₃-H₄ folic acid is not impaired in persons with the T/T MTHFR genotype. Possible reasons for these findings are discussed.

KEY WORDS: • folate • methylenetetrahydrofolic acid • formyltetrahydrofolic acid • homocysteine • polymorphism • humans

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