UNMETABOLIZED FOLIC ACID IN PLASMA IS ASSOCIATED WITH REDUCED NATURAL KILLER CELL CYTOTOXICITY AMONG POSTMENOPAUSAL WOMEN

Authors: TROEN, ARON - TUFTS/HNRCA; MITCHELL, BREEANA - FRED HUTCH. CANC RES CTR; SORENSEN, BESS - FRED HUTCH. CANC RES CTR; WENER, MARK - UNIV WASHINGTON; JOHNSTON, ABBEY - TUFTS/HNRCA; WOOD, BRENT - UNIV WASHINGTON; Selhub, Jacob; MCTIERNAN, ANNE - FRED HUTCH. CANC RES CTR; YASUI, YUTAKA - UNIV ALBERTA, CANADA; ORAL, EVRIM - MIDDLEEAST TECH UNIV,TURK; POTTER, JOHN - FRED HUTCH. CANC RES CTR; ULRICH, CORNELIA - FRED HUTCH. CANC RES CTR

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/19/2005
Publication Date: 1/1/2006
Citation: Troen, A.M., Mitchell, B., Sorensen, B., Wener, M.H., Johnston, A., Wood, B., Selhub, J., Mctiernan, A., Yasui, Y., Oral, E., Potter, J.D., Ulrich, C.M. 2006. Unmetabolized folic acid in plasma is associated with reduced natural killer cell cytotoxicity among postmenopausal women. Journal of Nutrition. 136(1):189-94.

Interpretive Summary: Folic acid (FA) supplements and food fortification are used to prevent neural tube defects and to lower the concentration of homocystiene in blood. Through exposure to food fortification and vitamin supplement use, large populations in the USA and elsewhere have an unprecedented high FA intake. We evaluated dietary and supplemental intakes of folate and folic acid in relation to a parameter of immune function, natural killer cell (NK) activity, among 105 healthy, postmenopausal women. Among women with a diet low in folate those who used FA-containing supplements had significantly greater NK cell activity. However, those who consumed a folate-rich diet and in addition used FA supplements showed reduced NK activity compared to those with a low-folate diet and no supplements. Prompted by this observation we assessed the presence of unmetabolized FA in plasma as a marker of excess FA. Unmetabolized folic acid was detected in 78% of fasting plasma samples from the participants. NK cytotoxicity was about 23% lower among women with detectable folic acid. This inverse relationship was stronger among women aged 60 years and older and more pronounced with increasing unmetabolized FA concentrations. 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.

Technical 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 USA and elsewhere have an unprecedented high FA intake. We evaluated dietary and supplemental intakes of folate and folic acid in relation to an immune function parameter, natural killer cell cytotoxicity, among 105 healthy, postmenopausal women. Among women with a diet low in folate (<233mcg/day), those who used FA-containing supplements had significantly greater natural killer cell (NK) cytotoxicity (p=0.01). However, those who consumed a folate-rich diet and in addition used FA supplements >400mcg/day showed reduced NK cytotoxicity compared to those with 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. We found an inverse relationship between the presence of unmetabolized FA in plasma and natural killer cell cytotoxicity. Unmetabolized folic acid was detected in 78% of fasting plasma samples from the participants. NK cytotoxicity was about 23% lower among women with detectable folic acid (p=0.04). This inverse relationship was stronger among women aged 60y and above 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