Benefit of Higher doses of folic acid is limited

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Higher doses of folic acid (vitamin B9) greater than 1 mg (U.S. daily value 0,4

mg) may not be usefull after a new study in the Proceedings of the National

Academy of Science because the human liver can´t procese it in greater amounts

in the form how it is used in the body and the surplus of the folic acid can be

found unprocesed in the blood and in the urine

http://www.pnas.org/content/early/2009/08/21/0902072106

(complete study can be downloded there)

Published online before print August 24, 2009, doi: 10.1073/pnas.0902072106

The extremely slow and variable activity of dihydrofolate reductase in human

liver and its implications for high folic acid intake

1. W. ,1 and

2. June E. Ayling,1,2

+ Author Affiliations

1.

Department of Pharmacology, University of South Alabama, 307 North

University Boulevard, Mobile, AL 36688

1.

& #8629;1S.W.B. and J.E.A. contributed equally to this work.

2.

Edited by Bruce N. Ames, University of California, Berkeley, CA, and

approved July 22, 2009 (received for review

February 25, 2009)

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.