The influence of dietary folate and methionine on the metabolic disposition of endotoxic homocysteine.

We have investigated the disposition of potentially endotoxic homocysteine (Hcy) and its transsulfuration metabolite cysteine (Cys) in 98 individuals (age range 20-66 years). Our study reports on the relationship between Hcy and two important dietary factors likely to influence plasma levels of this thiol: dietary folate and dietary methionine. chi2 analysis shows a low frequency of elevated plasma Hcy at high folate intake. This frequency for Hcy >10 micromol/liter with a folate intake >350 microg/day is significant (P < 0.02). The data reflect a tendency for elevated Hcy values to be associated with low dietary folate, although many subjects with a low dietary folate also had a low plasma Hcy. Intake of dietary methionine was found to be significantly higher in males than in females (P < .0001). This may account for the looser relationship between Hcy and its transsulfuration product, Cys, in females (R2 = 0.30) compared to males (R2 = 0.73), since conversion of methionine to SAM in males would activate cystathionine beta synthase and commit excess Hcy to transsulfuration. The generally lower methionine intake of females means that more Hcy is utilized in the remethylation cycle in which methionine is produced from the de novo methyl group of 5-methyltetrahydrofolate or from the preformed methyl group of betaine. Clearly a Hcy moiety locked up in remethylation would be further removed from Cys, the end product of transsulfuration. An increasing number of studies are clarifying the relationship between Hcy, folate, and other B vitamins. However, less attention seems to be given to the influence of dietary methionine on the disposition of Hcy. The present study supports biochemical theory and indicates that more focus should be given to the effect of dietary methionine on Hcy. These findings have particular significance since even moderate increases in plasma Hcy are associated with a toxic vascular effect. Consequently the relationship between dietary folate and Hcy levels should be a factor in evaluating recommended dietary allowances for this vitamin. The simplicity of our dietary folate questionnaire also raises the possibility of a screening test in which individuals can ascertain whether their folate intake is adequate to reduce Hcy levels to a benign value.