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High homocysteine / CBS / P5P / 2-Hydroxybutyric

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by renski, Jan 10, 2018.

  1. renski

    renski Senior Member

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    My homocysteine is 9.6, I've been taking P5P for about 6 months but only recently increased it to about 15mg. I get weird side effects from P5P and B6 and even after 6 months those side effects haven't improved. I was taking it in the hope it would lower my homocysteine but I'm wondering if all it's doing is speeding up the CBS pathway? Don't know if anyone can make sense of this but I've been told my CBS pathway is upregulated, so I assume that means it's sped up very fast, and that's why my homocysteine is accumulating? Or do I have it the wrong way round, is CBS slowed down because B6 is low and that's why homocysteine is accumulating? My methionine is high as well, so I don't think taking folate/B12 would help. I'm taking Allithamine/Benfotamine, R5P, Niacitol, Niacinamide (some days), Biotin, Zinc, Manganese, Selenium (all of these were low). I've read P5P can increase quinnolic acid (which mine was high) so I wonder if that's why I'm having issues with P5P. Or is it just that my other B's are possibly still too low to introduce P5P/B6 yet?

    In one of my OAT tests 2-Hydroxybutyric reports as being high, this seems to indicate the CBS pathway is sped up.

    According to Great plains laboratory, 2-Hydroxybutyric is a marker of cysteine accumulation, they describe it here:
    https://www.greatplainslaboratory.com/gpl-blog-source/2016/4/14/dna-methylation-pathway
    Great plains also says this about 2-Hydroxybutyric acid in the OAT report:
     
    Last edited: Jan 11, 2018
  2. renski

    renski Senior Member

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    This is what I think is happening with me and possibly why b6/p5p just makes me worse even though i'm low in it.

    http://www.themethylationdoctor.com/part-4-homocysteine-and-the-transsulfuration-pathway/
     
  3. juniemarie

    juniemarie Senior Member

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    Albuquerque
    @renski I’m CBS +/+ and have high homocysteine also. Please keep posting any info you come across or anything you find that helps lower it.
     
  4. alicec

    alicec Senior Member

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    Lots of people are sensitive to B6 - there could be several reasons for this but it is not because you have some SNP which is upregulating CBS.

    All the SNPs known to have significant effects on activity of the CBS enzyme are downregulations. A couple of the more well known ones are mentioned in the GPL quote.

    There is no research supporting the two said to be upregulations, nor would you expect them to have any real effect since they result in no change to the protein product. The enzyme produced by the variant is identical to that produced by the wildtype gene.

    There is another SNP not mentioned in that quote, rs234706 AKA C699T, which is usually the one claimed to result in dramatic upregulation. This claim is wildly exaggerated and is based on a complete misreading and misinterpretation of research unrelated to the SNP. There are a couple of studies which suggest there might be a slight upregulation associated with this SNP but this appears to be protective, since it slightly lowers homocysteine.

    Other studies though have not reproduced this so it may be a study error. Again this SNP causes no change to the enzyme, so the explanation for the observed effects, if real, may lie elsewhere.

    Here is a thread discussing CBS.

    The quote in your second post is just fudging it. There are indeed multiple influences on CBS activity but, as already explained, not upregulating SNPs, nor has B6 been described as a significant regulator of the enzyme.

    Of course if B6 were deficient, enzyme activity might be slowed and so addressing the deficiency might stimulate the enzyme. In cases of known genetic defects producing an enzyme with very reduced activity, very high doses of its cofactor B6 can sometimes stimulate the defective enzyme.

    These genetic defects are very rare and not I suspect what the author is referring to.

    In any case you were taking quite a small dose of B6 - this in itself would have little influence on CBS.

    You seem to be confused about what CBS does and how this affects homocysteine. CBS is the first enzyme in a pathway which converts homocysteine to cysteine and then to a variety of other products depending on cellular needs. One of the most important of these is the master antioxidant glutathione (GSH). Need for GSH is one of the important upregulators of CBS activity.

    High CBS activity means that more homocysteine is converted to cysteine and so homocysteine levels will be lower.

    Low CBS activity means that less homocysteine is converted to cysteine and so homocysteine levels will be higher.

    In your own case your homocysteine is in the normal range. This gives no clues to what is happening with CBS.

    The elevated 2 hydroxy butyric acid does indicate increased flux through the pathway. Perhaps you are under oxidative stress and your needs for GSH have increased.

    You say you have high methionine. This could be another reason for increased flux through CBS.

    Homocysteine can follow two pathways. It can remain in the methylation cycle and be remethylated to methionine by the action of the enzyme methionine synthase (B12 dependant), which in turn is dependant on the enzyme MTHFR to supply methylfolate which is the ultimate methyl donor in the reaction. The enzyme BHMT also carries out the same conversion but using betaine as the methyl donor rather than methyl folate.

    Alternatively homocysteine can exit the methylation cycle via the action of CBS and be used to make GSH and other things.

    The other important regulator of the balance of these two pathways is the universal methyl donor S adenosyl methionine (SAM) which is derived from methionine. When methionine is high (eg after a protein rich meal), SAM is high. This stimulates CBS to remove homocysteine so levels of SAM don't become too high. In addition, SAM inhibits MTHFR and BHMT to slow down formation of methionine and again prevent SAM getting too high.

    As SAM falls, CBS slows down so less homocysteine exits the methylation cycle and MTHFR and BHMT speed up so more homocysteine is converted to methionine.

    The normal overall balance in the cell is about 50:50 between the two pathways, but there is considerable variation in this balance depending on cellular need.

    Your results could just reflect things like a high protein diet and an increased need for antioxidants.
     
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  5. renski

    renski Senior Member

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    @alicec:

    Thanks for explaining it, really helps. I've got CBS A360A +/+ but not the main CBS snp.. I wasn't worried about the snps just whether CBS was upregulated. Fairly sure I'm in oxidative stress.. so that explains it. I'm just trying to figure out why I can't tolerate B6 or P5P :/ I also have trouble with magnesium, if I take this in the evening, the following morning I wake up feeling hyped/over energized. I wonder if it's pushing a pathway but something else is deficient.. I know I'm low in a lot of things so it's possible.

    My SAMe is low and methionine little high on the methylation panel, but methionine isn't high on a plasma amino acids I had done in Australia, although I think some of their testing is suspect (Nutripath). I'm going to check plasma amino acids in my next Nutraeval though.
     

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  6. renski

    renski Senior Member

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    I think what is happening with me is - high homocysteine due to B6 depletion, due to oxidative stress/inflammation. Anything that takes homocysteine away from flowing down CBS makes me feel 10x worse, ie Betaine/B12/folate

    It seems to stem from gut issues and toxicity. :/

    MTHFR and Homocysteine - Part II
     

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