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

Abstract

Numerous clinical trials using folic acid for prevention of cardiovascular disease, stroke, cognitive decline, and neural tube defects have been completed or are underway. Yet, all functions of folate are performed by tetrahydrofolate and its one-carbon derivatives. Folic acid is a synthetic oxidized form not significantly found in fresh natural foods; to be used it must be converted to tetrahydrofolate by dihydrofolate reductase (DHFR). Increasing evidence suggests that this process may be slow in humans. Here we show, using a sensitive assay we developed, that the reduction of folic acid by DHFR per gram of human liver (n ‫؍‬ 6) obtained from organ donors or directly from surgery is, on average, less than 2% of that in rat liver at physiological pH. Moreover, in contrast to rats, there was almost a 5-fold variation of DHFR activity among the human samples. This limited ability to activate the synthetic vitamer raises issues about clinical trials using high levels of folic acid. The extremely low rate of conversion of folic acid suggests that the benefit of its use in high doses will be limited by saturation of DHFR, especially in individuals possessing lower than average activity. These results are also consistent with the reports of unmetabolized folic acid in plasma and urine.folate ͉ provitamin utilization ͉ unmetabolized folic acid ͉ vitamin supplements ͉ nutrition

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

“…The daily recommended intake of FA for mice (0.4 mg/kg body weight) is $70-fold higher than the recommended intake for humans (0.006 mg/kg body weight). Rodents may be able to handle the higher doses of FA better than humans because dihydrofolate reductase activity is considerably higher in rats compared to humans (Bailey and Ayling, 2009). Plasma total homocysteine levels were not affected by diet in this study or in our previous study with even higher folate (Pickell et al, 2011).…”

Luteolinidin Protects the Postischemic Heart through CD38 Inhibition with Preservation of NAD(P)(H)

“…We have previously shown BH 4 to be a highly redox-sensitive eNOS cofactor that is severely depleted by the oxidative stress that occurs following the onset of ischemia. The recovery of BH 4 after ischemia may be regulated by levels of NADPH, as there are NADPH-dependent enzymes in both the de novo synthesis and recycling pathways (Bailey and Ayling, 2009;Gao et al, 2009). De novo synthesis begins with GTP cyclohydrolase I-catalyzed conversion of GTP to 7,8-dihydroneopterin triphosphate, continues with conversion of 7,8-dihydroneopterin triphosphate to 6-pyruvoyl-BH 4 and ends with NADPH-dependent conversion of 6-pyruvoyl-BH 4 to BH 4 by sepiapterin In the same hearts, the levels of NAD + were also preserved with luteolinidin treatment compared with vehicle-treated I/R controls.…”

Evaluation of Surfactants-Assisted Folic Acid-Loaded Pectin Submicrospheres: Characterization and Hemocompatibility Assay

“…As such, folic acid is not biologically active but the biological properties of the molecule relay upon its reduction to tetrahydrofolate and other related forms. It is evident from earlier reports that tetrahydrofolate is converted into dihydrofolic acid in the liver [2]. Both adults and children need folic acid to make normal red blood cells and prevent anemia.…”