This article [Levitt et al., 1971: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?rendertype=abstract&artid=292061) (http://www.ncbi.nlm.nih.gov/pubmed/5314166)] is interesting and shows that only labeled 5-methyltetrahydrofolate (MTHF) is taken up into the cerebrospinal fluid (CSF) after the intravenous injection, in dogs, of either MTHF or folic acid. It's generally accepted that the epithelial cells of the choroid plexuses transport only MTHF across the blood-CSF barrier, from the blood to the CSF.
These articles show how resistant the brains of rats are, in comparison to other tissues, to the accumulation of intracellular folates, in response to graded increases in the dietary contents of folic acid [Vareila-Moreiras and Selhub, 1992: (http://jn.nutrition.org/cgi/reprint/122/4/986) (http://www.ncbi.nlm.nih.gov/pubmed/1552373?dopt=Abstract); Ladjimi et al., 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1380335)]. I've made some better choices for conversion factors (http://hardcorephysiologyfun.blogspot.com/2008/12/cell-biology-conversion-factors-for-ngg.html), and I'll try to eventually go through some of the old conversions and hopefully improve upon them by using the new conversion factors.
It's valid to assume that most of the tissue folate content is in the intracellular water, given that, in the case of folates, the extracellular concentrations are much lower than the intracellular concentrations. If one assumes, for example, that the cerebrospinal fluid MTHF concentration is at the upper limit of the normal range for humans [119.6 nM (Hansen and Blau, 2004: (http://www.biopku.org/pdf/blau_hansen.pdf) (http://www.ncbi.nlm.nih.gov/pubmed/15781200)] and that the concentration of MTHF in the interstitial fluid (ISF) is the same as the CSF MTHF concentration(http://hardcorephysiologyfun.blogspot.com/2009/01/estimating-interstitial-fluid.html), then one can estimate the percentage of a tissue folate concentration, such as the value of 0.65 nmol/g ww found in the brains of folate-supplemented rats (Vareila-Moreiras and Selhub, 1992), as this [assuming that one gram of wet weight of tissue in the brain, as in the heart (http://hardcorephysiologyfun.blogspot.com/2008/12/cell-biology-conversion-factors-for-ngg.html), consists of 0.175 mL extracellular water/g ww and 0.615 mL intracellular H2O/g ww]:
(0.175 mL extracellular H2O/1 g ww) x (1 L extracellular H2O/1000 mL extracellular H2O) x (119.6 nmol/1 L extracellular H2O) = 0.02093 nmol MTHF in the extracellular fluid content of one gram of wet weight of brain tissue
That amount is only 3.2 percent [(0.02093/0.65) x 100] of the 0.65 nanomoles that are in one gram of wet weight, and that tells you that almost 97 percent of the folate content is going to be intracellular (in the 0.615 mL intracellular H2O/g ww).
These are the values from Vareila-Moreiras and Selhub (1992) [using these assumptions and scaling factors, which I've updated a little but are still not perfectly complete: (http://hardcorephysiologyfun.blogspot.com/2008/12/equations-for-animal-food-intake-and.html)]:
Folic acid (FA)-supplemented (8 mg FA/kg diet) = 8 x 0.100 = 800 ug/kg bw for 60-g rats.
I'm going to do a weight-specific scaling factor for the small rats: (70 kg/0.06 kg)^(0.3) = 8.32
That's 800/8.32 = 96.2 ug/kg bw for a 70-kg human, and that's 6.731 mg folic acid/d. The concentration of intracellular folates in the supplemented group, in the brain cells, is:
(0.65 nmol/g ww) x (1 g ww/0.615 mL intracellular H2O) x (1000 mL/1 L) = 1057 nM
The levels in the unsupplemented group aren't much lower, but Ladjimi et al. (1992) found similarly-low levels in rats (even in response to 200 mg folic acid/kg diet). In response to that high dose, the tissue content in the brain was 0.99 nmol folates/g ww (compared to 0.83 nmol folates/g ww in the 1 mg/kg diet group). So the brain cells are really resistant to attempts at increasing the intracellular folate levels by supplementing with folic acid.
The data from those articles is relevant to strategies that are intended to increase the intracellular folate concentrations in the cells of the brain. Doses of folic acid larger than 200-266 ug [Kelly et al., 1997: (http://www.ajcn.org/cgi/content/abstract/65/6/1790) (http://www.ncbi.nlm.nih.gov/pubmed/9174474?dopt=Abstract)] or 500 ug [Melikian et al., 1971: (http://www.ncbi.nlm.nih.gov/pubmed/4107904?dopt=Abstract)] are absorbed as unmetabolized folic acid, and the concentration of folic acid is known to increase in the portal vein after relatively small doses of 1,000 ug or less [Melikian et al., 1971; Whitehead and Cooper, 1967: (http://www.ncbi.nlm.nih.gov/pubmed/6050860?dopt=Abstract)]. A certain percentage of serum folate, especially in a person who takes high doses of folic acid, may be unmetabolized folic acid and not MTHF. Even though some unmetabolized folic acid that reaches the portal blood can be taken up by the liver, reduced and methylated, and then exported to the systemic circulation as MTHF [Anthony Wright et al., 2005: (http://jn.nutrition.org/cgi/content/full/135/3/619) (http://www.ncbi.nlm.nih.gov/pubmed/15735104?dopt=Abstract)], the use of supplemental folic acid, as opposed to L-5-methyltetrahydrofolate, may limit the long-term increases in serum folate that occur in response to supplementation. Presumably the liver has a limited capacity to export MTHF to the systemic circulation. But even if the steady-state serum folate levels in response to either folic acid or MTHF are comparable and are mostly MTHF, a short-term increase in the concentration of unmetabolized folic acid in the systemic circulation, in response to a large dose of oral folic acid, could produce excessive intracellular concentrations of folic acid that would then, as discussed below, be expected to be more quickly degraded than newly-transported, intracellular reduced folates would be. And given that MTHF is the only or predominant circulating folate to be transported into the brain (Levitt et al., 1971), this unmetabolized folic acid would probably not contribute much to the CSF MTHF concentrations.
The magnitude and percentage of the steady-state serum folate that is MTHF may not even be the most important variables to consider in comparisons of methylfolate and folic acid. For example, Bostom et al. (2000) [Bostom et al., 2000: (http://circ.ahajournals.org/cgi/content/full/101/24/2829) (http://www.ncbi.nlm.nih.gov/pubmed/10859289?dopt=Abstract)] found that equimolar doses of folic acid or MTHF (15 mg folic acid or 17 mg MTHF) produced similar increases in the steady-state concentration of serum folate, and most of this was MTHF in both groups. But when the acute elevations of serum folate were analyzed, only the group taking folic acid showed "a sizeable increase" (Bostom et al., 2000, p. 2830) in the concentration of unmetabolized folic acid. I don't like to quote articles, but it's important to note these differences. Willems et al. (2004) found that, in response to an oral dose of either 5 mg of folic acid or 5 mg of (R,S)-5-MTHF (racemic methylfolate, which is more or less equivalent, from the standpoint of bioavailability assessments, to a dose of 2.5 mg of L-methylfolate), the Cmax values of (6S)-5-MTHF, which are the peak concentrations in the blood of the biologically-active diastereomer of MTHF, in response to MTHF and folic acid were 129 ng/mL (~292 nM) and 14 ng/mL (~32 nM). The peak serum MTHF concentration was more than 9 times higher in response to methylfolate. The AUC of the concentration vs. time curves were 73 (ng hrs/mL?) for oral folic acid and 383 (ng hrs/mL) for oral MTHF.
Given that one must consider the amount of MTHF that is available for uptake into the brain both in the hours following a dosage (of MTHF or folic acid) and in the hours during which the steady-state serum folate has become reestablished, it follows that more MTHF is likely to enter the brain in response to oral MTHF than in response to folic acid. The steady-state serum folate represents the equilibrium that has been re-established and is likely to be dictated primarily by the balance of export and uptake from the liver and kidneys. The brain should really be considered as being almost independent of the tissues outside the brain, and one cannot infer that the intracellular total folate concentration (or the percentages that exist in different forms) will be equivalent in different cell types, in response to MTHF vs. folic acid, merely because the steady-state serum MTHF concentrations are similar in response to either folic acid or MTHF. Folic acid that cannot be reduced is likely to be degraded intracellularly and exported, and MTHF that enters cells is more likely to be retained. Reduced folates are much more potent than folic acid (between about 8 and 100 times) in inducing cell proliferation in cultured cells, and a much lower concentration of extracellular, racemic folinic acid was required, in comparison to a given extracellular concentration of folic acid, to elevate the intracellular total folate concentration to a given level [Watkins and Cooper, 1983: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1152268); Balk et al., 1978: (http://cancerres.aacrjournals.org/cgi/reprint/38/11_Part_1/3966.pdf) (http://www.ncbi.nlm.nih.gov/pubmed/212184)]; (http://hardcorephysiologyfun.blogspot.com/2009/01/effects-of-reduced-folates-vs-folic.html)].
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