Folate Supplementation: Too Much of a Good Thing?

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Abstract
Folate was isolated in 1941 from spinach and named after the Latin word folium (= leaf; ref. 1). Although the initial impetus for research on folate metabolism was to find a cure for anemia, it was soon recognized that the administration of folate enhanced the growth of existing tumors and that folate metabolism may be a promising target for anticancer drug design (2). Already developed by the late 1940s, folate antagonists, such as methotrexate, have rapidly become a mainstay of cancer chemotherapy (3). Because of the role of folate in nucleotide synthesis, deficiency affects primarily rapidly dividing tissues, such as the epithelium of the gastrointestinal tract, hematopoietic cells, and tumors. This increased need of proliferating tissues for folate explains why macrocytic anemia is one of the clinical manifestations of folate deficiency. Similarly, the crucial role of folate in preventing neural tube defects may be attributed to the high fetal requirement for folate to sustain rapid cell division; clinical trials have shown a clear reduction in neural tube defects with periconceptional folic acid administration (4-6). This success story led policy makers, including the USPHS in 1992 and the Institute of Medicine in 1998, to recommend that all women of reproductive age consume 400 μg folic acid daily from supplements or fortified foods (7, 8). Unfortunately, health promotion efforts targeting childbearing women have been largely unsuccessful in achieving this level of intake. Therefore, policy makers opted for generalized folic acid fortification of flour and uncooked cereal grain products at a targeted level of 140 μg/100 g. This level of fortification was mandatory in the United States by January 1998 and was also implemented in Canada (9, 10). Initial data suggest that this public health measure was successful, resulting in a substantial reduction in the prevalence of neural tube defects (11-14).

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