Lotus97
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Created in 2008, Phoenix Rising is the largest and oldest forum dedicated to furthering the understanding of, and finding treatments for, complex chronic illnesses such as chronic fatigue syndrome (ME/CFS), fibromyalgia, long COVID, postural orthostatic tachycardia syndrome (POTS), mast cell activation syndrome (MCAS), and allied diseases.
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One of the drugs involving CYP1B1 metabolism is Rituximab ... it's one of (many) genes which are implicated in determining non-responders. But if it's down-regulated then maybe that means it's being "expressed" less, which might mean there's less chance of being a non-responder.CYP1B1 is involved in synthesizing cholesterol, steroids, and other fats, as well as vitamin D metabolism and some drug and toxin metabolism. Not a lot of data about CYP1B1 is known yet, but maybe those are some things to keep an eye on.
You have the same CBS as me A360A and I am wondering although this is not the really bad one if I may still have sulphur issues and if I should get strips and test or just move on to treating MTRR & MTHFR???
I will keep an eye on what you decide about that Lotus........you are much sharper about this stuff than I am. Also I have high homocysteine
During a period where I was making a recovery I was taking a lot of MSM, ALA, and NAC and seemed to do ok, but I wasn't doing methylation at the time and I've read that methylation can make CBS issues worse. I want to start taking MSM and glucosamine sulfate because I'm hoping they'll help my joint pain. I'm getting to the point where I'm skeptical of most supplements so I don't have high hopes for either of them working. Someone also recommended D-phenylalanine for pain so I'm going to try that as well.Lotus As far as I KNOW I have never had bad reactions to sulphur foods or meds. But maybe since I have the least problematic of the 2 SNP's it could be that even though its not bad enough to produce pronounced symptoms it may still be messing with me below the radar. Thats why I am considering the test strips. The cheapest ones I could find are $30 for 100 plus shipping. If you decide to go that route and want to split the cost let me know.
I'm at least glad I don't have to worry about avoiding sulfur supplements. I assume I don't since I don't have CBS.
Have you noticed whether methylation and/or B6/P5P make your CBS issues worse?I guess technically I should be sensitive to sulfur supplements because of my CBS upregulation, but I've done well with the sulfur supplements in the past.
I sure know when when I can't tolerate the sulfur stuff now. Brain fog, foot pain, stomach pain, etc....
Today I'm wondering if it may have been the biofilm enzymes that caused some gut permeability issues that are causing the sensitivity to sulfur supplements. Before I thought it may have been the calcium removed form my gut with the biofilm chelator I took.
I retain the right to change my mind, and only use the snp's for general guidance.
Have you noticed whether methylation and/or B6/P5P make your CBS issues worse?
I assume then that it would be for other reasons besides CBS since it seems like P5P would be more likely than B6 to make that worse since it's in its coenzymated/active form (unless you were taking a much higher dose of B6 compared to P5P). I seem to remember someone else saying B6 caused them problems, but P5P didn't (unless you were the one who posted it in another thread).B6 is something that makes me worse, not sure what it is related to though. P5P is more tolerable.
I was just about to ask about that. dbkita said that stimulating the BHMT pathway will potentially cause more dopamine to be converted into norepinephrine. If I'm COMT+/+ and VDR Taq -/- that means I'm already going to be high in norepinephrine. Also, what about taking choline to stimulate the BHMT pathway?TMG/phosphatidyl choline for the BHMT.
Your COMT+/+ and VDR Taq -/- is the most sensitive combination for mood swings, so Yasko suggests using mostly hydroxycobalamin for B12. This would definitely explain norepinephrine type symptoms you were experiencing.
So that means I probably don't have a problem processing folinic acid? I don't fully understand what's going on because it sounds like I need both MTHFS (different than MTHFR) and SHMT mutations. I'm just rereading what I posted below from Rich and Nandixon and I'm confused. Nandixon said it might be both MTHFS and SHMT, but then it also sounds like it could only be MTHFS.There's no SHMT.
And this is from Rich:In January, Rich asked people to share their 23andMe results for the MTHFS gene to see if we can sort out which SNP or SNPs may be detrimental in ME/CFS. I didn't see where anyone responded. (You can find your MTHFS results by going to https://www.23andme.com/you/explorer/ and logging in and entering "MTHFS" for the gene name.)
It's important people contribute so we can try to figure out when folinic acid should be supplemented or avoided for certain people as part of a methylation protocol.
I may be intolerant to folinic acid (seems to cause exacerbation of fatigue, irritation of taste buds) and so am providing my DNA results. We need MTHFS results from as many other people as possible, though, whether intolerant or not.
If you could also include the one SHMT result that Yasko tests for, that may be helpful also. I'm heterozygous (AG) for that SNP (SHMT1 C1420T rs1979277), and the first day I took folinic acid it helped, as might be expected, but then I seemed to gradually get worse over several days (800-1600 mcg/day).
Below are Rich's personal MTHFS results with mine next to his in parentheses (he volunteered to be the DNA "standard"). At the time Rich was tested, 23andMe only gave results for 22 SNPs. They gave 24 for me. (36 are known?) There was only one instance of a flip in homozygosity between Rich's results and mine, rs7177659, and I discuss it after:
We're not likely to be so lucky right away that rs7177659 is the "bad" SNP, but it's interesting because having the hetero version (AC) for that SNP actually seems to be "normal" (58% frequency according to openSNP) and apparently results in a 29% decrease in cardiovascular disease risk compared to the homo versions (AA/CC). (This is from a May 2012 publication: http://jn.nutrition.org/content/early/2012/05/28/jn.111.157180.abstract - I don't have access to the full text; it's not mentioned in the abstract.)
So with respect to that SNP it might be that I have a detrimental down-regulation of MTHFS and Rich has a detrimental up-regulation (or vice versa). A down-reg would cause a build up of folinic acid and thus inhibition of SHMT (and several other enzymes outside the methylation cycle as well) and create an intolerance to supplementation. An up-reg can cause an increased turnover rate and depletion of cellular folate. Note: The C allele - what Rich has two copies of - is the ancestral (wild type) allele according to the NCBI data page.
if your MTHFS is not working well, i.e., not doing a good job converting folinic acid to methenyl THF (different than methylene THF) then you might be pretty sensitive to supplementing with folinic acid - because an excess will inhibit SHMT (folinic acid is both a product of SHMT and an inhibitor of that same enzyme).
Perhaps people are mostly only going to be sensitive to folinic acid when they have defects in both SHMT1 and MTHFS, but folinic acid also inhibits other enzymes, including the mitochondrial version of SHMT, which is encoded by the SHMT2 gene. (SHMT1, which Yasko tests for, is the cytoplasmic version.)
So if, for example, you're not sensitive to folinic acid, then perhaps your MTHFS SNPs will be more closely aligned with Rich's, or with mine if you are.
BTW, in theory, P-5-P and zinc should increase the activity and quantity of SHMT. Too much vitamin A (not beta-carotene) may decrease it.
The book "Nutrient-Gene Interactions in Cancer" gives more detail about all of the above (SHMT & folinic acid). Available as a Google book, pages 218-222 are free.
Folinic acid is a buffer or storage form of folate that can be converted to other forms readily in most people.
The reason for including it in the simplified methylation protocol is that it can supply forms of folate needed to make new RNA and DNA while the methionine synthase enzyme is still running its reaction slowly. This reaction is fed directly by methylfolate, but until it goes through the reaction to produce tetrahydrofolate, it can't be used for forming other folates.
In order to use folinic acid a person must have a normally functioning MTHFS enzyme (not the same as MTHFR). If this enzyme is slow for genetic reasons, folinic acid can build up. and that will inhibit the SHMT reaction, which in turn will inhibit the normal production of MTHF, which in turn will hinder formation of DNA and formation of methylfolate.
According to Freddd, he cannot tolerate folinic acid, and there seem to be some others who can't, also. It would be helpful to pin down what SNP or SNPs are responsible for this.
Best regards,
Rich
Hi Lotus. Yep your results on one hand are bad, but I'd actually view it as a positive - potentially some good answers for your state of health and some direction to head to make things a lot better.
Personally I'd be disappointed if the gene testing showed nothing and was just another dead end
DMG and the supplement TMG also stimulate the BHMT pathway to convert homocysteine to methionine, but one should take caution if they are sensitive to methyl donors.
A little TMG is often helpful when methylfolate and B12 supplementation are started, because it can help to raise SAMe, needed for recycling methyl B12. After these supplements are well underway and methionine synthase is coming up in activity, the TMG can be stopped, or DMG can be added to counter the BHMT pathway, so as to route more of the homocysteine to the methionine synthase pathway and the transsulfuration pathway.
Betaine and TMG are the same substance. Betaine HCl has a hydrochloric acid molecule bound to it. Yes, if you take betaine HCl, you will also have the benefit of TMG. However, note that TMG stimulates the alternative BHMT pathway from homocysteine to methionine in the liver and kidneys. TMG will promote production of SAMe, but it can shunt flow away from the methionine synthase enzyme, which is partially blocked in ME/CFS. It's important to get this enzyme going, because it is linked to the folate metabolism, which is needed to make new DNA and RNA, and also because it regulates the entire sulfur metabolism. In Amy Yasko's protocol, she recommends starting with some TMG, and then after the B12 and folate have been built up some, to add DMG, which will inhibit the BHMT reaction by product inhibition, and that will push more of the homocysteine through the methionine synthase reaction.
Best regards,
Rich