Homocysteine synthesis is elevated but total remethylation is unchanged by the methylenetetrahydrofolate reductase 677C→T polymorphism and by dietary folate restriction in young women

The effects of folate status and the methylenetetrahydrofolate reductase (MTHFR) 677C -> T polymorphism on the kinetics of homocysteine metabolism are unclear. We measured the effects of dietary folate restriction on the kinetics of homocysteine remethylation and synthesis in healthy women (20-30 y old) with the MTHFR 677 C/C or T/T genotypes (n = 9/genotype) using i.v. primed, constant infusions of [C-13(5)] methionine, [3-C-13]serine, and [H-2(3)]leucine before and after 7 wk of dietary folate restriction (1115 mu g dietary folate equivalents/d). Dietary folate restriction significantly reduced folate status (similar to 65% reduction in serum folate) in both genotypes. Total remethylation flux was not affected by dietary folate restriction, the MTHFR 677C -> T polymorphism, or their combination. However, the percentage of remethylation from serine was reduced similar to 15% (P = 0.031) by folate restriction in C/C subjects. Further, homocysteine synthesis rates of T/T subjects and folate-restricted C/C subjects were twice that of C/C subjects at baseline. In conclusion, elevated homocysteine synthesis is a cause of mild hyperhomocysteinemia in women with marginal folate status, particularly those with the MTHFR 677 T/T genotype.