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,2,#,**,**,3
* Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA; Fred Hutchinson Cancer Research Center, Cancer Prevention Program, Seattle, WA; Departments of ** Epidemiology, Molecular and Cellular Biology and Laboratory Medicine, University of Washington, Seattle, WA; Department of Public Health Sciences, University of Alberta, Edmonton, AB, Canada; and # Middle East Technical University, Department of Statistics, Ankara, Turkey
3 To whom correspondence should be addressed. E-mail: nulrich{at}fhcrc.org.
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 µg/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 µg/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 
23% lower among women with detectable folic acid (P = 0.04). This inverse relation was stronger among women 
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.
KEY WORDS: • carcinogenesis • folic acid • immune function • natural killer cells
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