Is Folate inhibiting Thiamine (B-1) ?

[jjxx]

DO you know what has changed it?

Simply moly....

 

[alethea]

Revisiting this thread after going downhill big time in the last year and a half -- realizing that I probably stopped or slowed down my folinic acid intake due to misinterpreting this study -- I was doing 'better' at least in some ways on the folinic, but stopped taking it on a regular basis about August of last year.


Thanks again to @Victronix for posting the full study. I wish I had analyzed it in more detail last year, as it seems that the author's conclusions just don't wash.


They say: "Folate binds to and is transported into cells by the rFC-1 trans- porter.8 High-dose folic acid supplementation might exacerbate thiamine deficiency at susceptible sites, such as the kidney and vascular cells in diabetic nephropathy, by competing with tmP and tPP and impairing their uptake into tissues, thereby inhibiting sharing of thiamine metabolites between tissues rich in thiamine and those deficient in it."


But the study they reference says "Although the reduced folate carrier RFC1 and the thiamine transporters THTR-1 and THTR-2 share approximately 40% of their identity in protein sequence, RFC1 does not transport thiamine and THTR-1 and THTR-2 do not transport folates." But then they go on to say that in murine leukemia cells the folate receptor "may be one of the alternative transport routes available for TMP in some tissues when THTR-1 is mutated in the autosomal recessive disorder thiamine-responsive megaloblastic anemia."


And finally, it turns out there are several folate receptors, not just one, which of course makes sense. Who knows, there are probably several more they don't even know about...


http://en.wikipedia.org/wiki/Folate_receptor


So…I'm sorry I started this thread in the first place. Sheesh...

I've been having a great result from combining high-dose Benfotiamine (3/day 200 mg from Pure Encapsulations) with TPP liquid from Metabolics (have to order from UK). On the Metabolics site it says that the active transport of thiamine in the small intestine is *inhibited* by folic acid deficiency. So you were right to suspect a relationship there .....

I believe the active transport of B1 is also sodium-dependent and that my (lifelong) thiamine issues may have resulted in -- or been a function of, hard to tell -- my borderline hyponatremia. Thiamine has certainly done wonders for orthostatic intolerance. And I suspect my mold sensitivity could be related to mycotoxins' anti-thiamine activities.

I also believe there is a major role for thiamine deficiency in my mother's dementia which is being called Alzheimer's but looks EXACTLY like B1 insufficiency to me ... I'm dosing her w multiple forms of B1 and would welcome advice on how to help B1 enter the brain if anyone has researched this.

http://www.metabolics.com/vitamin-b1-thiamine-pyrophosphate-100ml.html

 

[Eastman]

I also believe there is a major role for thiamine deficiency in my mother's dementia which is being called Alzheimer's but looks EXACTLY like B1 insufficiency to me ... I'm dosing her w multiple forms of B1 and would welcome advice on how to help B1 enter the brain if anyone has researched this.

Have you read the thread Pyruvate dehydrogenase function depends on thiamine (B1)? There are some posts related to your concerns there.

 

[alicec]

I'm dosing her w multiple forms of B1 and would welcome advice on how to help B1 enter the brain if anyone has researched this.

The allithiamine family (allithiamine, sulbutiamine, fursultiamine) enter cells via a different mechanism from thiamine and its derivatives.

They are lipophilic and cross cell membranes independantly of the thiamine transporters which so limit the uptake of thiamine. This includes the blood brain barrier. These are the substances you should be looking for.

Please note that while benfotiamine is often described as fat soluble, actually it is not. Higher levels of thiamine are achieved in liver and blood using benfotiamine compared with thiamine, but high levels in the brain were not achieved.

Here, here and here are a few articles which may be helpful.

It is true that TPP is the active form of thiamine within cells but supplementing it is no advantage.

Phosphorylation of substances is a good way of keeping them inside the cell since the presence of the phosphate group prevents them crossing membranes. This applies in the reverse direction also so that phosphorylated vitamins such as TPP have the phosphate groups clipped off by a phosphatase enzyme to enable them to be taken up from the intestine.

There is no advantage to taking TPP, you would be much better off sticking to a mixture of benfotiamine and one of the allithiamines.

 

[Asklipia]

I'm dosing her w multiple forms of B1 and would welcome advice on how to help B1 enter the brain if anyone has researched this.

As per Dr Lonsdale magnesium/potassium aspartate
Do you use Sulbutiamine? This crosses the BBB.

 

[alethea]

As per Dr Lonsdale magnesium/potassium aspartate
Do you use Sulbutiamine? This crosses the BBB.

Thank you, Asklipia.
And thanks also for your earlier link to the odd yet fascinating book, Astrophysics and Yeast. I've forwarded it to many.
I'm wary of giving my mum potassium as she has tachycardia and other heart problems (see "wet beri beri") in addition to her short-term memory loss and confabulatory tendencies. ... If only the western medical complex weren't in the back pocket of the drug companie$ perhaps we'd be seeing more serious research into Alzheimer's & thiamine ..... B1 being necessary for pyruvate / Krebs / citric acid cycle and Az being akin to a kind of loss of glucose metabolism in the brain .... Makes even an English major go Hmmmmmmm.......
Sulbutiamine looks highly promising but seems to build tolerance and lose efficacy in just a matter of days. Is there a way around this? https://www.amazon.com/Sulbutiamine...8&qid=1501049799&sr=1-4&keywords=sulbutiamine

 

[alethea]

PS She takes atenolol twice daily but seems to need less since I've been giving her Benfotiamine.

 

[alethea]

She takes atenolol twice daily but seems to need less since I've been giving her Benfotiamine.

HA - I'm new to this forum and apparently don't have the hang of the REPLY function yet. Please forgive!

 

[Asklipia]

Sulbutiamine looks highly promising but seems to build tolerance and lose efficacy in just a matter of days. Is there a way around this?

Yes and no. You do not feel the effects in such a spectacular manner but I think it still works. Some people do 20 days on 20 days off to restore the initial feelings (source: the chemist around the corner who used it to pass his exams!!). In general people tend to forget there is a PULSE to everything, most probably linked to the stars and also to the light and colours. Thiamine seems to help to connect to it.
You are the first to dare comment on my offering of Astrophysiology and Yeast! Thank you, because sometimes I get a bit discouraged by the weight of general conformism. Which is a serious handicap to finding new solutions to problems .

 

[dannybex]

It is true that TPP is the active form of thiamine within cells but supplementing it is no advantage.

Phosphorylation of substances is a good way of keeping them inside the cell since the presence of the phosphate group prevents them crossing membranes. This applies in the reverse direction also so that phosphorylated vitamins such as TPP have the phosphate groups clipped off by a phosphatase enzyme to enable them to be taken up from the intestine.

There is no advantage to taking TPP, you would be much better off sticking to a mixture of benfotiamine and one of the allithiamines.

What about sublingual TPP? I noticed a distinct advantage over 'regular' thiamine, when I used the Source Naturals sublingual, which is the TPP form.

 

[alicec]

What about sublingual TPP? I noticed a distinct advantage over 'regular' thiamine, when I used the Source Naturals sublingual, which is the TPP form.

I think the whole area of sublingual active vitamins is very murky. There are almost no studies to know what is really going on.

Even if they are taken up directly into the blood they still have to get into cells and the presence of phosphate group interferes with this. One needs to postulate a different uptake mechanism for which there is little evidence, though maybe a few hints from a small study I once read on B6 (and now can't find).

Having said that I did for a short while find that I got a very positive response to sublingual active B2 and B6 that I didn't seem to get with swallowed plain or active forms of the vitamins.

But this was only for a short while. I now take plain B2 and B6 swallowed.

So if there is any advantage to sublingual active vitamins the mechanism is unknown, but if they seem to be more beneficial for any individual, then go for it.

 

[JasonUT]

This article says folate deficiency can cause thiamine deficiency. I'm really not sure what to believe.

This article by Dr Lonsdale says that thiamine deficiency causes cellular folate and b12 deficiency. Again, I'm not sure what to believe.

 

[alicec]

This article says folate deficiency can cause thiamine deficiency. I'm really not sure what to believe.

The explanation given in the article for this statement is garbled nonsense.

It claims thiamine is regenerated by proton donation from NADH.

If we look at the two Kreb's cycle-related steps where TPP is a cofactor, namely in the pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase complexes (which use analogous 3 enzyme complexes and the same mechanisms, just starting with a different substrate), TPP, which is used by the first enzyme in the complex, is released from the first substrate and made ready for reacting again by the action of the lipoic acid moiety of the second enzyme in the complex.

The branched-chain amino acid dehydrogenase complex uses a similar mechanism.

The transketolase mechanism is different but it doesn't depend on NADH to regenerate TPP.

The article then claims folate is necessary to have enough dihydrofolate reductase (DHFR) to regenerate NADH. This is even more non-sensical.

Dihydrofolate (DHF) is generated from 5,10 methylene THF during the production of thymidylate (by the enzyme TYMS). DHF is then funneled back into the folate cycle by conversion to THF by the enzyme DHFR. This reaction uses NADPH (not NADH) and consumes the cofactor, rather than generates it.

So I wouldn't take too much notice of that article.

Lonsdale is hypothesising to explain his observation of high folate and B12 in blood of a severely B1 deficient patient. It is a plausible hypothesis and the fact that the values dropped when B1 was repleted supports it, but more work needs to be done to know if this is what is really going on.

It certainly has more credibility than the other claim.

 

[sb4]

My POTS got substantially worse after experimenting with higher doses of methylfolate, could this possibly have been the folate causing my thiamine to drop further?

 

[aquariusgirl]

Anyone tried Mitosynergy copper w/B1? See the sheep study for a rationale

 

[dannybex]

I think the whole area of sublingual active vitamins is very murky. There are almost no studies to know what is really going on.

Even if they are taken up directly into the blood they still have to get into cells and the presence of phosphate group interferes with this. One needs to postulate a different uptake mechanism for which there is little evidence, though maybe a few hints from a small study I once read on B6 (and now can't find).

Having said that I did for a short while find that I got a very positive response to sublingual active B2 and B6 that I didn't seem to get with swallowed plain or active forms of the vitamins.

But this was only for a short while. I now take plain B2 and B6 swallowed.

So if there is any advantage to sublingual active vitamins the mechanism is unknown, but if they seem to be more beneficial for any individual, then go for it.

Thanks for your reply. I've been tempted to try the sublingual B2, but the citric acid in the B1 was what made me stop. My teeth are pretty weakened, and couldn't take the acid. And yes, there are certainly studies that have shown sublingual B12 at least to be as effective as shots.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922551/

I still don't understand the phosphate issue though. Why would nature make it more difficult for the active forms to be utilized?

 

[aquariusgirl]

After reading thie link ......on this thread about the sheep ..I took my B1 & my MITOSYNERGY copper together. Seems to work,...early days though .....& suddenly I want folate....well isn't that cool?


I suspect that the copper transporter in the gut is deregulated or down regulated.

 

[Silence]

Can anyone comment on Andy cutlers views on TTFD here: (taken from onibasu wiki)

link: http://onibasu.com/wiki/TTFD

• Cutler speculates the hepatoxic effect of TTFD comes from the tetrahydrofurfuryl when it separates and becomes a mercaptan (single thiol). Due to its toxicity there is no reason to use it - http://onibasu.com/archives/am/106469.html

• TTFD does not have two sulfhydrl groups, it has a disulfide bond, not effective as mercury chelators - http://onibasu.com/archives/am/56724.html

• Disulfide bonds do not capture inorganic or organic mercury. If TTFD becomes a dimercaptan (dithiol, two sulfhydryls), it doesn't stay intact - http://onibasu.com/archives/am/106524.html

• Why Cutler thinks the real adverse reaction rate is around 20% or higher, based on multiple populations. Explains how sample bias results in TTFD advocates (specifically Derek Lonsdale) understating adverse reaction rates. Adverse reactions generally relate to liver issues (liver damage) - http://onibasu.com/archives/am/101501.html

• No clear benefit to using TTFD, Lonsdale's own data shows no increased heavy metal excretion, and plenty of risks - http://onibasu.com/archives/am/101623.html

• No reason to use TTFD as a Vitamin B1 alternative. Benfotiamine is a much better choice - http://onibasu.com/archives/am/116173.html

• Analysis of Lonsdale's paper showing that the data cannot support the conclusions - http://onibasu.com/archives/am/116222.html and http://onibasu.com/archives/am/120510.html

• Benfotiamine is already phosphorylated once, thiamine needs to be phosphorylated twice in the body to be useful. Phosphorylating is not easy for the body so benfotiamine has an advantage over thiamine. TTFD needs to be phosphorylated twice. Regression from using TTFD is consistent with liver damage but not all kids show elevated liver enzymes - http://onibasu.com/archives/am/116239.html

He seems to argue against Derek lonsdale, a big proponent of ttfd, and cautions supplementing with ttfd due to its heptotoxic effects. He suggests benfotiamine as a better alternative.

On another note, I am using source naturals b1 sublingual to help with my current beri-beri. I have noticed that it has raised my serum levels of b1, but does not alleviate the neuropathy associated with beriberi as much as the benfotiamine does.

 

[alicec]

Why would nature make it more difficult for the active forms to be utilized?

Phosphorylation makes it possible to keep important cofactors like some B vitamins where they are most needed - inside the cell - ie the addition of the phosphate group means that the substance can't readily cross the cell membrane and so leak out of the cell.

Some food sources of these B vitamins - though by no means all - are phosphorylated but there are abundant phosphatase enzymes around in the gut to clip off the phosphate and ensure there is maximum uptake of all available forms of the vitamin.

Once inside the cell the phosphate is attached to keep it there.

 

[alicec]

Can anyone comment on Andy cutlers views on TTFD here: (taken from onibasu wiki)

I'm not prepared to wade through all the detail of the disjointed exchange on that forum, nor am I prepared to track down the original studies from Japan on the safety of the allithiamines, including TTFD to give references.

With those provisos, it appears that Culter is making claims designed to fit his pet theories, rather than commenting on the efficacy of TTFD as a thiamine.

Much of his criticism centres on whether or not TTFD acts as a chelating agent. I don't think any one has suggested that it is, nor would one expect it to. Its action as thiamine is the issue and the heavy metal issue is a red herring.

An even bigger red herring is the claim that since benfotiamine is monophosphorylated and thus needs only one further phospharylation to form active thiamine, while TTFD needs two phosphorylations, the former form is metabolically less demanding.

As per my previous posts, the phosphate group on benfotiamine is no advantage - it is clipped before the molecule is taken up into the cell.

Studies on benfotiamine indicate that it is taken up into the cell in the same way as thiamine. The difference appears to be that it is absorbed from the gut better than thiamine and so higher concentrations of thiamine within the cell are achieved.

The mechanism of uptake of the allithiamines is different. Their lipophilic nature means they can cross cell membranes readily (including the BBB) and don't rely on thiamine transporters. High levels of thiamine can be achieved within the cell.

With both types of thiamine, once in the cell, both need to be phosphorylated in the same way.

I was very interested in Culter's claim of an adverse reaction rate of 20%. For someone who prides himself on his command of statistics, all I can say is that this calculation is decidedly flaky and based on very thin data from a tiny pilot study from Lonsdale on 10 autistic children (notorious for sensitivities) and people self-reporting to him of problems with the supplement.

Well I think everyone on PR can relate to adverse reactions to supplements, how individual it is and how mostly the reason is unknown or dependent on changeability of other things. Various health conditions seem to be associated with increased sensitivities.

Cutler has advanced the theory that the reason for the adverse reaction is the toxicity of the tetrahydrofurfuryl group. He weaves this in to his own narrative and pet theories by claiming the presence of a free thiol is the issue.

He presents no evidence whatsoever on the toxicity of the prosthetic group and ignores the extensive studies of the Japanese on the allithiamines as well as Lonsdale's other studies.

I can readily accept the some people have trouble with TTFD and so it is not a thiamine supplement to be universally recommended. Nor is it to be universally condemned on spurious grounds.