MODERATE FOLATE-DEPLETION INCREASES PLASMA HOMOCYSTEINE AND DECREASESLYMPHOCYTE DNA METHYLATION IN POSTMENOPAUSAL WOMEN

To determine the human folate requirement on the basis of changes in b iochemical pathways, we studied the effect of controlled folate intake s on plasma homocysteine and lymphocyte DNA methylation and deoxynucle otide content in healthy postmenopausal women. Eight women (49-63 y of age) were housed in a metabolic unit and fed a low folate diet contai ning 56 mu g/d of folate for 91 d. Folate intake was varied by supplem enting 55-460 mu g/d of folic acid (pteroylglutamic acid) to the diet to provide total folate intake periods of 5 wk at 56 mu g/d, 4 wk at 1 11 mu g/d and 3 wk at 286-516 mu g/d. A subclinical folate deficiency with decreased plasma folate was created during the first two periods. This resulted in significantly elevated plasma homocysteine and urina ry malondialdehyde, and lymphocyte DNA hypomethylation. The folate dep letion also resulted in an increased ratio of dUTP/dTTP in mitogen-sti mulated lymphocyte DNA and decreased lymphocyte NAD, changes suggestin g misincorporation of uracil into DNA and increased DNA repair activit y. The DNA hypomethylation was reversed with 286-516 mu g/d of folate repletion, whereas the elevated homocysteine decreased with 516 but no t 286 mu g/d of folate. The results indicate that marginal folate defi ciency may alter DNA composition and that the current RDA of 180 mu g/ d may not be sufficient to maintain low plasma homocysteine concentrat ions of some postmenopausal women.