Unmetabolized Folic Acid in Plasma Is Associated with Reduced Natural Killer Cell Cytotoxicity among Postmenopausal Women

Abstract

Folic acid (FA) supplements and food fortification are used to prevent neural tube defects and to lower plasma homocysteine. Through exposure to food fortification and vitamin supplement use, large populations in the United States and elsewhere have an unprecedented high FA intake. We evaluated dietary and supplemental intakes of folate and FA in relation to an index of immune function, natural killer cell (NK) cytotoxicity, among 105 healthy, postmenopausal women. Among women with a diet low in folate (<233 microg/d), those who used FA-containing supplements had significantly greater NK cytotoxicity (P = 0.01). However, those who consumed a folate-rich diet and in addition used FA supplements > 400 microg/d had reduced NK cytotoxicity compared with those consuming a low-folate diet and no supplements (P = 0.02). Prompted by this observation, we assessed the presence of unmetabolized FA in plasma as a biochemical marker of excess FA. Unmetabolized folic acid was detected in 78% of plasma samples from fasting participants. We found an inverse relation between the presence of unmetabolized FA in plasma and NK cytotoxicity. NK cytotoxicity was approximately 23% lower among women with detectable folic acid (P = 0.04). This inverse relation was stronger among women >or= 60 y old and more pronounced with increasing unmetabolized FA concentrations (P-trend = 0.002). Because of the increased intake of FA in many countries, our findings highlight the need for further studies on the effect of long-term high FA intake on immune function and health.

Homocysteine, B-vitamins and CVD

“…4 mg/d. Clearly, the issue as to the lowest dose of folic acid associated with a maximum reduction in tHcy remains controversial and requires further investigation, especially in light of recent reports that highlight potential adverse effects of overexposure to higher intakes of folic acid (19,20) .…”

Moderately high intake of folic acid has a negative impact on mouse embryonic development

“…These concerns include increased tumor growth (Cole et al, 2007;Mason et al, 2007;Lawrance et al, 2009), although this has been refuted by other investigations (Gibson et al, 2011;Stevens et al, 2011) and perturbations in immune function (Troen et al, 2006;Halsted, 2008). There is also evidence that high maternal folate concentrations can be associated with greater adiposity and higher insulin resistance in the offspring, which could increase the risk for type 2 diabetes (Yajnik et al, 2008).…”

The extremely slow and variable activity of dihydrofolate reductase in human liver and its implications for high folic acid intake

“…Although folate deficiency has been linked to cancer susceptibility via increased uracil misincorporation (10), recent evidence suggests that high intake (Ն1 mg/d) of FA may exacerbate some preexisting cancers or progression of precancerous lesions, such as in the colon (11) or prostate (12). The activity of natural killer cells has been reported to be decreased in older women having higher plasma levels of unmetabolized FA (13). Unmetabolized FA has also been hypothesized to cause masking of B12 deficiency and/or aggravate the neurological damage associated with prolonged B12 deficiency (14)(15)(16).…”