Homocysteine Increases as Folate Decreases in Plasma of Healthy Men during Short-Term Dietary Folate and Methyl Group Restriction

Abstract

Ten healthy adult men were fed a diet low in folate and exogenous methyl groups to study the effects on folate requirement and status. The men were housed in a metabolic unit for the entire 108-d study. After a 9-d base-line period (P1), the men were fed an amino acid-defined soybean product diet for 45 d, which provided 25 micrograms/d of folate for 30 d (P2) and (with a folate supplement) 99 micrograms/d for 15 d (P3). During P2 and P3, the low methionine and choline diet was supplemented with methionine for half the subjects to vary the dietary methyl group intake. The periods were then repeated over the next 54 d (P4-P6), with a cross-over of methionine intakes in P5 and P6. Restricting dietary methyl group intake did not increase the dietary folate requirement. Plasma total homocysteine rose during folate depletion and correlated inversely with plasma folate; however, the response of homocysteine to changes in folate intake varied among individuals from very strong to absent. The results support previous suggestions that increased plasma homocysteine concentrations provide a marker of functional folate deficiency, and further indicate that individuals may differ greatly in their susceptibility to hyperhomocysteinemia due to low folate intakes. Judged by the lack of normalization of high homocysteine concentrations during folate repletion, the current folate RDA for adult men may not provide the expected margin of protection.

Folate intake in Europe: recommended, actual and desired intake

“…There is some evidence that 200 mg/d dietary folate is suf®cient to maintain`normal' homocysteine levels after normalisation with vitamin supplements (Ubbink et al, 1993b), which is in contrast with the results of the depletion study of Jacob et al (1994) and the balance study of O' Keefe et al (1995). From these studies it is dif®cult to estimate a desirable folate intake in light of`normal' plasma homocysteine levels, since no control groups were included and only a small number of subjects were investigated (Ubbink et al, 1993b;Jacob et al, 1994;O'Keefe et al, 1995).…”

“…Table 4b shows two studies in which plasma homocysteine levels were used as an index of`functional' folate de®ciency in healthy subjects. Jacob et al (1994) performed a controlled depletion/repletion/depletion/repletion study for 108 d. During the depletion periods the subjects were fed a diet providing $ 25 mg/d of dietary folate. Homocysteine levels increased signi®cantly during depletion and did not normalise in the repletion phases, when the participants were provided daily with 74 mg supplemental folic acid and 25 mg dietary folate.…”

“…Consequently, this has raised concern about the folate intake of the general population both by the scienti®c community Wald & Bower, 1994;Boushey et al, 1995) and health authorities (CDC, 1991;FNC, 1992b;EAG, 1992;DHHS/PHS, 1992;HC/FNC, 1993;FDA, 1994) Scientists have proposed to increase the current recommended intake levels for folate (Selhub et al, 1993;Jacob et al, 1994;O'Keefe et al, 1995;Verhoef et al, 1996), which has resulted in a discussion on possible strategies to raise the folate intake of the general population (Wald & Bower, 1994;Picciano et al, 1994;McNulty, 1995;Boushey et al, 1995).…”

Folate intake, plasma folate and homocysteine status in a random Finnish population

“…The concept of homocysteine being a functional marker of suboptimal folate status has gained popularity (Jacob et al, 1994. This means that by measuring plasma tHcy one can distinguish between functional folate deficiency vs a low folate intake (Jacob et al, 1994). In our population we estimated that the cut-off value for plasma folate concentration was 8.0 nmol=l, which would be necessary to maintain a 'normal' plasma homocysteine level.…”

“…Homocysteine may be a marker of endothelial dysfunction (Woo et al, 1997) and thrombotic events (Ridker et al, 1997). The concept of homocysteine being a functional marker of suboptimal folate status has gained popularity (Jacob et al, 1994. This means that by measuring plasma tHcy one can distinguish between functional folate deficiency vs a low folate intake (Jacob et al, 1994).…”