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Study: Folinic acid beneficial to 81% of CFS patients...plus biomarker?

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by dannybex, Feb 8, 2013.

  1. dbkita

    dbkita Senior Member

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    Heh it is not a belief :)

    And yes I meant dietary folates. Folinic acid has nothing to do with DHFR. It is processed by other enzymes. DHFR is used to process dietary folates. The oxidized version known as folic acid that only became available in modern times is not responsible for the existence of DHFR which has been in organisms well before man ever walked the planet. Folic acid can only be processed by DHFR in the liver not the intestinal lumen. Hope that helps.
  2. Lotus97

    Lotus97 Senior Member

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    I'm trying to find a list of how much methylfolate and folinic acid (and folic acid:lol:) each food has. So far I've only been able to find an very incomplete one, but it says that some veggies such as asparagus are almost all methylfolate (5-CH3-H4folate/5-methyl-tetrahydrofolate). Others are mostly 5-CH3-H4folate/5-methyl-tetrahydrofolate. It also mentions 10-HCO-PGA/10-formyl-folic acid. Is the third one what you're referring to, or is what they list as 5-CH3-H4folate/5-methyl-tetrahydrofolate (which I thought was folinic acid) what you're referring to as being processed like folic acid?
  3. dbkita

    dbkita Senior Member

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    Maybe this article will help (I have others somewhere in my "hopeless chaotic" bookmarks including a long review research article):
    http://www.fao.org/docrep/004/Y2809E/y2809e0a.htm

    Some of the stuff about the intestinal processing does not 100% jive with some other things I consider more authoritative but it should be still useful.

    Notice folic acid (synthetic folate) is a totally different animal in that 2nd ring (not reduced). It is also an oxidized form. You can search on wikipedia to see their diagrams for the various folates.

    Note also how much loss in activity there is with harvesting, storage, canning, etc. And notice the reduction loss in the conversion in the gut to unpack the polyglutamates. So yes if someone eats a ton out of their garden they may get more than they bargained for ... but most of us who buy food from a store are getting a lot less than what is listed on some food site. I would doubt the resultant amounts of folinic acid are high for normal diets. I only brought this all up since the de facto wisdom on these boards is that folinic acid is the folate in plants. Incorrect. In fact very incorrect. It is far more complicated.That is like saying the plant dominantly has folinic acid as its form of folate. Umm no.

    What I will try to dig up are the references that talk about the how there are natural analogs of folic acid are pteryl-L-glutmates that are NOT oxidized and in our foods. They are the reason we have dihdryfolate synthetase and dihydrofolate reductase. Otherwise if everything was only in foods in the reduced forms why would we even need those enzymes? The distinction is the DHFR acting on folic acid (the synthetic) is dominantly in the liver.

    I have seen nothing though in my research that really answers how much of each type is in our foods (especially given the attenuation variables I discussed above). It is easy to determine if food has folic acid in it, it is synthetic so it has to be added artificially. Eat thing that are not fortified. As to folinic acid, THY, methyleneTHF. the other formyl versions, 5mthf, etc. I have no clue. And honestly I am not sure of what utility it is unless you have some nasty MTHFS mutation or something. The only other exception is if someone bombs away with fresh produce right from their garden they may imbalance things. But cook it, store it, harvest it and put on a Whole Foods shelf, etc. is going to reduce bioactivity by quite a bit. Will you get some? Yes but it will be spread across the spectrum of folate (as was meant to be) and the resultant biocactivity is much less than people probably expect.

    That being said I agree with Freddd and others, the synthetic folic acid is *bleep*.
    Lotus97 likes this.
  4. Lotus97

    Lotus97 Senior Member

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    @ dbkita
    Thanks for that link. I actually already saw it when I was searching for lists, but didn't actually read it so I'll take a look at it. That paper I mentioned looked like it also had a lot of useful information, but I didn't read most of it either because I just wanted the list. I probably should have tried reading it through before I asked any questions, but maybe this dialogue will help others. That paper also talked about what you said about folate being lost in storage and cooking so maybe I'm not actually getting that much folate from my diet as I thought.

    Do you know what Rich meant by this:
    Many people's cells are able to convert folinic acid to 5-MTHF well, but many others have inherited genetic polymorphisms that slow this conversion down considerably. The polymorphisms in the MTHFR enzyme are a good example, and these are very prevalent in the population.

    Does that mean that people with the MTHFR polymorphism need to limit their folinic acid intake or is that just for the MHTFS? And for MTHFR is it just used for other purposes such as making new RNA and DNA and doesn't build up? I see you mentioned that thing about polyglutamates which Rich also mentioned about folinic acid being useful for glutamate-induced excitotoxicity. Sometimes I have to read things a couple of times before they sink in. A month or two ago you told me about the BHMT pathway twice in the same thread. It wasn't until I reread your first post that I realized you had already told me about it so I'm glad you repeated the information.
  5. dbkita

    dbkita Senior Member

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    I have to assume he meant MTHFS. Only MTHFS acts directly on folinic acid (though I think SHMT1 can produce it, but I have to verify). Think of folinic acid as a storage form of folates in the intracellular space. MTHFS is the means to tap that and bring it towards the 5,10 methylene intermediates (I get confused which one). Essentially it is the form that the cell uses as a folate buffer. Some of your folates go ultimately into the methylation cycle but others are diverted to RNA and DNA synthesis (separate discussion). Your body needs to do both.

    Taking folinic acid directly alters this buffering mechanism. I think Rich's concern was certain MTHFS mutations may lead to a build up of folinic acid that could through feedback inhibition alter the folate cycle. It easily penetrates the BBB and can go into the CNS hence its utility for medical studies but it may mean extra time to clear it out if there is a problem.

    Personally I don't take folinic acid right now, but when I used to it seemed to produce methylation. Just not the 100% that methylfolate does. Maybe for some people a little balance is ok. My only issue is that folinic acid is not a form we usually ingested at high levels as humans in the past. But then again people with our problems died out in the past. I may go back to folinic acid supplementation (200 mcg) simply to provide enough of the buffered form to aid in DNA synthesis only since I do not think I have any terrible MTHFS defects but have a SHMT1 homozygote SNP. But I need to study this carefully before I proceed on that.
  6. Lotus97

    Lotus97 Senior Member

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    I decided I'm going to start learning about SNPs. Partially because I'm going to get mine tested and also because I hope I can help others. There's a thread about MTHFS someone started last year.
    http://forums.phoenixrising.me/inde...d-intolerance-request-for-genetic-data.19168/
    I assume one of the main reasons Rich wanted to gather information about MTHFS was because he suspected Freddd had it and also Freddd insisted that he had heard reports of others with the same problem with folinic acid. Rich was probably concerned that other people might have problems with folinic acid and he wanted to find out how prevalent it was in this community.
    http://forums.phoenixrising.me/index.php?threads/attention-freddd-mthfs-deficiency.11524/
    As far as I know, Freddd seems to disagree with this theory. If that's the case then I really don't want to get into that here. Anyone can read his response in that thread so it really doesn't need to be repeated in this thread too since I'm already mentioning it. I'm bringing it up only because there other people here who have had their SNP tested and want to learn more about this issue for themselves. I'm not taking sides between Rich and Freddd. That's not what this is about.
  7. UM MAN

    UM MAN

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    Yep, there are 24 MTHFS haplotypes listed.
  8. Freddd

    Freddd Senior Member

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    Hi Lotus,

    Your statement "As far as I know, Freddd seems to disagree with this theory. " is wrong. I believe that Rich may have indeed put his finger right on a major part of my folate problems here. That you seem to think differently is just one more way you apparantly thoroughly misunderstand what I have been trying to say most explicitly. I agree that it is very important to get some idea of what percentage here have a problem with folinic acid and veggie folate.

    There are more possible causes of hangup at various stages. First, even if people can convert it, there is most going to be a biological maximum, as there is with folic acid. The folic acid maximum is generally stated as 800-1000mcg for 50% of population and less than that for 30% of population and zro for 20% of population. So sincve folinic acid is dependent upon an enzyme, sufficient methyl groups and sufficient ATP to do the energetic uphill (expensive) conversion. Then when more folic acid is taken than can be converted it is said to accumulate, actually BLOCKING methylfolate in some way. This is eveidenced by the way it takes sometimes weeks to build up to the point when it suddenly switches into blockage mode. Folinc acid, and veggie folate, exhibits a similar pattern. A small amount may not be any problems. At some point folinic acid reaches it's conversion maximum and then unconverted folinic accumulates and eventually blocks the l-methylfolate. Folic acid appears to block about 10x as much l-methylfolate. Unconverted folinic acid appears to block about 20x as much L-methylfolate. So the exact genetics may allow anywhere from zero conversion to some biological channel maximum and then suddenly it blocks varying amounts of L-methylfolate. Being able to convert up to the level means that there is a level past which the conversion doesn't happen and blockage starts and increases for some days. After discontinuing folinic acid (veggie folate) it can take several days for the folinic to recede enough to unblock the l-methylfolate. This is pragmatically observed and tested by titration in multiple people. It isn't nearly as simplistic. Further just not having enough of any one of the deadlock quartet is enough to temporarily stop conversion even if genetically able. So giving folinic acid and HyCbl to a person in parrtial methylation block has a sizable chance of not unblocking parrtial methylation block or to do so at an insufficient degree. So genetics influences all this considerably but it can only account for ONE reason that folinic may not work at all leaving several possible pathways of partial blockage. It isn't a binary this or that and nothing else. There are a whole spectrum of problems that a genetic hypothesis of all or nothing can't account for.

    However, whether the percentage is 19% that can't use it at all, leaving 81% that can use folinic at least in small doses below their maximum and still leaving 100% who might develop paradoxical folate insufficiency at some level to some degree, for any of several reasons. Not having everyrthing a binary yes or no does complicate matters. There are a lot more than 50 shades of grey in all this.
  9. dbkita

    dbkita Senior Member

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    Hi Um Man,
    In your signature you say Mn 10 mg helped based on your SNPs. Was this based on your CBS SNPs? How did it help you? Just curious.
  10. dbkita

    dbkita Senior Member

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    My guess is Rich was onto to something since the only two enzymes I am aware of that directly interact with folinic acid (the intracellular buffer form) are to my knowledge MTHFS and SHMT1.

    Here is a tantalizing abstract:
    http://www.ncbi.nlm.nih.gov/pubmed/12764149

    Note the 5formyl variant is folinic acid. So low storage levels vis a vis an upregulated MTHFS may deplete cellular folate levels interrupting the flow of the folate cycle and the demands needed for DNA synthesis et al. On other hand one could imagine a downregulated MTHFS may lead to increase excessive storage of folinic acid which may compete for folate transport with 5mthf and lead to its own stalls. I need to research more to see how SHMT fits into all of this. Especially for those people with SHMT SNPs that would impact the generation of folinic acid in situ.

    Hmmm I smell something here ... just not quite sure what yet.

    One question:

    Some people in the thread Lotus linked state folinic acid inhibits the SHMT2 isozyme in the mitochondria. That would be worrisome. Does anyone have any literature that supports that assertion? I know that folinic acid regulates de novo purine biosynthesis but I had not heard of the SHMT2 connection. There is a massive difference between the roles of SHMT1 (the one tested in the Yasko panel for instance) and SHMT2 (which is the moneymaker to move 5,10 methyleneTHF to the active 5mthf form). Mice which express SHMT1 but not SHMT2 are glycine auxotrophs (very bad).
    Victronix likes this.
  11. UM MAN

    UM MAN

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    I should have given you profs for the Mn supplement. You are my hero. Mo caused such an improvement in my MCAD that I was hoping that Mn was just as dramatic. I feel that Mn helped a little, but it is hard, for me, to be sure. Next, I am testing my ammonia and homocystiene levels. Interesting to me, is the fact that increased levels of TMG, Choline, or Mo do NOT (my bad) yield any increased benefits.
  12. Lotus97

    Lotus97 Senior Member

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    Maybe you've changed your mind because a month or two you stated very emphatically and loudly that Rich's theories about you were wrong:
    http://forums.phoenixrising.me/inde...o-con-arguments-confuse-me.21963/#post-336198
  13. Lotus97

    Lotus97 Senior Member

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    I think Rich might have meant folic acid rather than folinic acid because he's said he believes that MTHFS polymorphisms are rare so he probably was referring to MTHFR.
  14. dbkita

    dbkita Senior Member

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    All three of those (TMG, Choline, and Mo) are going to help with CBS issues. The first two indirectly by stimulating the BHMT path. The latter by balancing zinc / copper ratios and increasing sulfite -> sulfate conversion. Ammonia is turning out to be a bigger issue for me than I first suspected.
  15. dbkita

    dbkita Senior Member

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    I think he meant exactly what he said. Folinic acid. Then he gives an example where SNPs are prevalent and have big impact (i.e. MTHFR). He also says many can convert folinic acid and many others have SNPs that slow this conversion (here he is talking MTHFS).

    So why from that statement do you believe he thinks MTHFS Snps are rare?

    In fact if you look at the information for MTHFS Snps in the public databases they are not rare. The question I took away from the thread you linked was which SNPs are relevant. And that appears to still be unknown. Heck the one implicated in that thread by Nandixon and Rich Vank is dominantly heterozygote, so by definition that particular SNP is NOT rare.

    Can I ask why you are trying to re-interpret all of Rich's posts? Are you trying to better understand them for yourself? Do you feel they are getting forgotten on these forums? If the former then that makes sense but then wouldn't it be better served to ask direct questions of the community? If the latter then might I suggest you be careful of the interpretations? In this case I think your supposition is not only incorrect but could really confuse people. Sorry.
  16. dannybex

    dannybex Senior Member

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    Okay, I'll bite -- what's a glycine auxotroph? :)
  17. Xara

    Xara Senior Member

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    A glycine auxotroph is very bad. :)

    Sorry, danny, could not resist it.
    dannybex likes this.
  18. Xara

    Xara Senior Member

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    My guess: a thing that makes it impossible to synthesize glycine?
  19. Xara

    Xara Senior Member

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    Source:
    http://en.m.wikipedia.org/wiki/Auxotrophy
    dannybex likes this.
  20. dbkita

    dbkita Senior Member

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    Correct :)
    dannybex likes this.

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