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Accutane, Methylation Block and Glycine N-Methyltransferase

Discussion in 'Detox: Methylation; B12; Glutathione; Chelation' started by droit, Oct 23, 2013.

  1. droit

    droit

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    Dr. Van Konynenburg had previous post a few times on a well established pattern of Accutane causing a hyperactive Glycine N-Methyltransferase (1-6).

    http://forums.phoenixrising.me/inde...ed-depression-isotretinoin.12117/#post-206039
    http://forums.phoenixrising.me/inde...h-can-you-pitch-in-on-this.16078/#post-257280

    As Rich explains Glycine N-Methyltransferase which regulates the ratio of SAMe to SAH. If hyperactive in the way that the cited research says, SAMe is quickly converted to SAH, losing its methyl group to glycine.

    I would agree that it would be tough to overcome that force to rebuild the methylation cycle without the right intervention.

    Rich said that for some it was persistently in a locked increased activity/expression even after stopping Accutane. And noted that this enzyme is allosterically inhibited by Methyl-folate, as is documented in the literature (5-6).

    I wonder if anyone on the board tried higher doses of methyl-folate this and what doses they tried? What was the outcome?

    1. "All-trans-Retinoic Acid Rapidly Induces Glycine N-methyltransferase in a Dose-Dependent Manner and Reduces Circulating Methionine and Homocysteine Levels in Rats," http://nutrition.highwire.org/content/133/12/4090.full

    2. "Retinoic Acid and Glucocorticoid Treatment Induce Hepatic Glycine N-Methyltransferase and Lower Plasma Homocysteine Concentrations in Rats and Rat Hepatoma Cells," http://jn.nutrition.org/content/133/11/3392.full

    3. "Activation and induction of glycine N-methyltransferase by retinoids are tissue- and gender-specific," http://www.ncbi.nlm.nih.gov/pubmed/12054489

    4. "Decreased plasma folate concentration in young and elderly healthy subjects after a short-term supplementation with isotretinoin," http://onlinelibrary.wiley.com/doi/...sCustomisedMessage=&userIsAuthenticated=false

    5. "Inhibition of glycine N-methyltransferase by folate derivatives: implications for regulation of methyl group metabolism," http://www.sciencedirect.com/science/article/pii/S0006291X85800061

    6. "Phosphorylation modulates the activity of glycine N-methyltransferase, a folate binding protein. In vitro phosphorylation is inhibited by the natural ligand," http://www.jbc.org/content/264/16/9638.full.pdf
     
    Laurel6123 likes this.
  2. GenDylan

    GenDylan

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    funny that this thread pops up now.. i am about to go on All Trans Retenioc Acid (like Accutane) so i can increase the GNMT enzyme.. why? because i took Methionine, and it raised my SAM - SAM is an allosteric inhibitor to MTHFR - im having severe histamine reactions now due to the SAM induced lack of Folate.
     
  3. Ivmi

    Ivmi

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    I took accutane in 2009. for 9 days only...and all those years later I'm experiencing longl list of symptoms: hair loss, impared wound healing, skin thinning, dry eyes... Month ago I did the liver cleanse by Hulda Clark, and new symptoms appeared that freaked me out: my armpit got swollen, and some wierd feeling on my neck on the same side appeared...few weeks later ultrasound found that i have lymph node swelling. I panicked! I wan't to forget about accutane and its side effects...could supplements like homocysteX Plus from Seeking health, help? What about Rick Simpson oil? Some guys were writting that it has help them... Please give me some answers :(
     
  4. ggingues

    ggingues $10 gift code at iHerb GAS343 of $40

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    Concord, NH
    I have taken accutane also in the past, I see that some lawyers try to sue them for something, wonder what, if anything, accutance had to do with my illness?

    GG
     
  5. Ivmi

    Ivmi

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    GG what is your illness? What are you dealing with? I'm not interested in suing anyone I just want to get better. If anyone succeded with methylation or something...please tell me...
     
  6. ggingues

    ggingues $10 gift code at iHerb GAS343 of $40

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    Concord, NH
    Been diagnosed with CFS and Fibromyalgia, and also Myofascial Pain Syndrome. So dealing with pain all the time, not as bad as it used to be, but on a daily basis. Fatigue from the most trivial things, brain fog, TMJ, sore muscles and joints and perhaps IBS?

    GG
     
  7. zzz0r

    zzz0r Senior Member

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    Very interesting thread. I was receiving accutane for 2 years. The symptoms of accutane treatment are very similar to folate deffeciency symptoms
     
  8. name

    name

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    Hello,i know this is an old thread but i have some qustions. i hope it will be seen, i am new to this site.
    Have to note that i am not an english speaker.

    My b12 level measured 2 1/2 years ago at 123 pmol/L
    received crappy suplingual tablets that each contain 1 mg ciano and 400 mcg folic acid, was on it for three months and then i was measured at 369 pmol/L
    from that point two years ago i took maybe 13 more tablet from those bad ones tablets till this day.
    As you can see my situation is not looking good, considering it was cyano and folic acid and that in even at the most positive scenario where it was converted in my body to all the right forms it still only reached to a low level.

    I started a b12 prtocol two weeks ago :
    b12 methylcoblamin - source naturals 1mg- half to one tablet a day
    folate - nutricology quatreactiv 500 mcg- half to one capsule a day
    b12adenosylcobalamin - Anabol dibencoplex-half to one tablet a week(1/4 every some days)
    L-carnitine fumarate- not yet

    Others:
    potassium- nedd alot
    Magnesium
    B complex
    Vitamin E
    ZINC

    vitamin A from beef liver
    Omega 3 from sardines .
    Vitamin D from the sun
    calcium- from the sardines bones and goat yogurt.



    I took roccatane or accutane 10 years ago. i think i got alot of sensation problems from it.

    So from this thread and the other two droit linked to i get that the retonic acid (accutane) causes Glycine n-methyltransferase to be hyperacvtive .

    Rich said that maybe alot of folate can downreglate it, but he said that on the base that this is what happen normaly(in a non toxicated with accutane person this mean i guess) and talked about a case where folate did not help. and otherwise it is for now just a theroy that no one else seems to tried, or at least to report about the outcome.(if post accutame symptoms to get cured)
    http://forums.phoenixrising.me/inde...ed-depression-isotretinoin.12117/#post-206039
    quoting Rich
    ''
    I'm aware of one case in which testing indicates that glycine N-methyltransferase has remained upregulated even years after Roaccutane treatment was ended. I don't know why.
    Glycine N-methyltransferase is normally inhibited by 5L-methyl tetrahydrofolate, which is a form of folate used in the methylation treatments. If glycine N-methyltransferase is responsive to it, as it normally is, the methylation treatment should downregulate it. In the case I refer to, this doesn't seem to work, and I don't know why. Perhaps there is a genetic polymorphism in glycine N-methyltransferase in some people that causes it to be unresponsive to methylfolate
    ''

    but i wonder what is the role of this enzyme glycine N-methyltransferase , and if maybe it need to do something to fix damage from the drug and that is whay it is hyperactive

    http://en.wikipedia.org/wiki/GNMT
    ''
    GNMT acts as an enzyme to regulate the ratio of S-adenosylmethionine to S-adenosylhomocysteine (AdoHcy) and participates in the detoxification pathway in liver cells
    ''

    so the problem is in the liver maybe.

    so in a case of assuming the GNMT enzyme need to do something in the body or the liver wich is benefical:
    clearly folate being depleted in the proces of this enzyme action, but maybe other factors being depleted, and by giving the body all of them the body (the
    glycine N-methyl transferase) will be able to finish it work wich is maybe detoxification, and then the depletion of those factors/nutrient for detox purpose will stop because methylation will be ok(there is encogh of the factor for it action from regular protocol or even just food) and will downregulate GNMT to normal level.
    maybe the problem isn't realy epigenetic, i mean it is. but it is not the core cuase, maybe the core cause is just the toxiciy that maybe casued by the drug accutane that need to get detox, and it is normal that the enzyme is hyperactive.
    i wonder how much the toxic affect exist ,hence how much of those factors will be nedded, and of course what are those factors exept for folate.

    i realy not an expert i need help here, dont know what is sam e and other stuffs like this.
    but i will try guss and hope someone can answer here who have more knowledge than me.

    I read in these forum http://www.acne.org/messageboard/topic/295030-repairing-the-long-term-damage-from-accutane/page-286
    somewhere study that says the drug is out of the system after short time and not years,
    but maybe it leaves some other unbalacne in the body that need to be correct via the gnmt enzyme
    this enztme use to reduce methionine and homocystine i read also. and that accutane upper the level of those.
    could i have excess
    methionine? stop eating meat?
    http://180degreehealth.com/diet-inflammation-part-4/
    ''

    There is only one metabolic pathway that exists in the human body to get rid of excess methionine. That pathway—via the enzyme glycine-N-methyltransferase (GNMT)—uses up glycine in the process.
    ''



    If indeed giving gnmt enzyme some factores needed for it to operate will also help to finish its job and then downregulate it- please help me figure out what are those factors:

    quoting droit
    ''
    As Rich explains Glycine N-Methyltransferase which regulates the ratio of SAMe to SAH. If hyperactive in the way that the cited research says, SAMe is quickly converted to SAH, losing its methyl group to glycine.
    ''

    eating glycine(gelatin) can help the process?


    maybe this will help you to help me
    http://en.wikipedia.org/wiki/Glycine_N-methyltransferase
    ''
    In enzymology, a glycine N-methyltransferase (EC 2.1.1.20) is an enzyme that catalyzes the chemical reaction


    S-adenosyl-L-methionine + glycine [​IMG] S-adenosyl-L-homocysteine + sarcosine

    Thus, the two substrates of this enzyme are S-adenosyl methionine and glycine, whereas its two products are S-adenosylhomocysteine and sarcosine.
    ''

    so to i need the substrates or the products or maybe both is better.

    the substrates:
    S-adenosyl-L-methionine
    http://en.wikipedia.org/wiki/S-Adenosyl_methionine
    It is made from adenosine triphosphate according to wilki is that what found in adenosylcoblamin supp?

    glycine is i guess what i find in gelatin from bone broth or powder you buy.

    the products:
    S-adenosylhomocysteine
    http://en.wikipedia.org/wiki/S-Adenosyl-L-homocysteine
    i guess this need to be made in the body if i understand the wiki page

    sacrosine
    http://en.wikipedia.org/wiki/Sarcosine
    ''Sarcosine is formed from dietary intake of choline and from the metabolism of methionine, and is rapidly degraded to glycine''
    choline as i understand it. so to take extra choline? if yes than how much

    Also if you think that it is a bad idea to help this enzyme and good idea to avoid it's operating factors and just to focus on folate and/or the regular protocol (deadlock quarter) alone , please tell me .


    other things:
    http://forums.phoenixrising.me/inde...ed-depression-isotretinoin.12117/#post-206039
    quoting rich who quote from a stude
    ''In support of this, SAM-dependent synthesis of creatinine was significantly reduced 21% following all-trans-retinoic acid treatment.''
    is this might mean something regarfing to L-carnitine fumarate bigger need in me?

    according to b12 active protocol
    Glutathione and glutathione precursors shold be avoid becasue they deplet b12.
    are those liver helpers herbs -milk thistle,Dandelion root,Artichoke (Cynara scolymus) leaf,curcumin/turmeric,black pepper, are in that reagard?

    Thanks very much to whoever will try to help,
     
    Last edited: Nov 14, 2014
  9. name

    name

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    This is also from rich about the accutane causing GNMT hyperactivation (result depleted SAMe and folate for sure from what i know til now)
    http://forums.phoenixrising.me/inde...-block-and-glycine-n-methyltransferase.26042/
    ''If the mechanism I discussed is going on, you will see low SAMe, high SAH, low glycine and high sarcosine. If you have ME/CFS, you will likely also have low glutathione.''
    so is if i want GNMT enzyme to keep on working-
    eating glycine(gelatine/bone broth) can help that?
    SAMe product can help that? can i increase SAMe naturally through food?
    getting one of the end products- sacrosine, fom choline?

    Maybe i get this all wrong and i need to avoid supporting this enzyme and thus avoid glycine and choline ???

    more regarding SAMe and accutane:
    this helped me understand SAMe role
    from rich
    http://forums.phoenixrising.me/inde...-block-and-glycine-n-methyltransferase.26042/
    ''SAMe is produced in the methylation cycle and is the main supplier of methyl (CH3) groups for a large number of methylation reactions in the body, including the methylation of DNA and the biosynthesis of creatine, carnitine, coenzyme Q10, melatonin and epinephrine''

    i found this stuy from 2013:
    http://lib.dr.iastate.edu/cgi/viewcontent.cgi?article=4063&context=etd
    ''oral s adenosyl methionine (SAM) MEDIATES DISTRUPTIONS in methyl group metabolism due to retonic acid therapy and alters neurotransmitter metabolism: implications for major depressive disorder''

    from someonr who took accutane anf found SAMe helpful:
    http://forums.phoenixrising.me/inde...h-can-you-pitch-in-on-this.16078/#post-257280
    ''SAM-e: As soon as i started taking i had massive energy fix, which has lasted - 400mgs a day or 1 tab each of TMG 500mgs & l-methionine 500mgs.''


    I still wonder if this GNMT enzyme hyperactivation serves as a beneficial thing to the body in accutane users
    or
    is it just a consequense of the drug causing random erors in the body and so this enztyme hyperactivation dont have any benefit and it unwanted...
     
  10. name

    name

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    A summary of my two recent messeges(but more detels in them), so if someone will read this he could ''digest'' what i mean more easily and answer.
    so far this is what i was able to grasp about this:
    Glycine N-Methyltransferase enzyme becoming hyperactive from accutane.
    NORMALLY folate can downregulate it.
    here, it(folate) is also depleted in overactivating the Glycine N-Methyltransferase enzyme that we want it to downregulate.
    It was suggested that potentially (but only theoretically so far), unknown large ammount of folate might downregulate this enzyme after accutane.
    The enzyme deplete our importent SAMe also.

    from that I wonder if:
    1)this GNMT enzyme hyperactivation serves as a beneficial thing to the body in accutane users(to correct something that the drug done)
    or
    2)GNMT enzyme hyperactivationis from accutane is just a consequense of the drug causing random erors in the body and so this enzyme get hyperactivate for no good.

    I have a reason to suspect no.1 because according to wiki this enzyme participates in the detoxifiaction pathway in liver cells .

    so IF no.1 is true i also wonder:
    maybe supporting this enzyme to keep working can help to eventually downregulate it(it will finish some job it has to do in the body and then it will come down) . after it's downregulation the importent SAMe will stop to deplete along with the folate(and maybe more things)-problem solved.

    folate is suggested to do all this but i wonder if some other factors are needed along with it to help the enzyme work( and to eventually slowly become downregulate -as more job by him get done there is less to be done so it can come down )
    http://en.wikipedia.org/wiki/Glycine_N-methyltransferase
    ''
    In enzymology, a glycine N-methyltransferase (EC 2.1.1.20) is an enzyme that catalyzes the chemical reaction
    S-adenosyl-L-methionine + glycine [​IMG]S-adenosyl-L-homocysteine + sarcosine

    Thus, the two substrates of this enzyme are S-adenosyl methionine and glycine, whereas its two products are S-adenosylhomocysteine and sarcosine.
    ''
    Does taking any of the substrates or the products can help? if so what are they in food or supps exactly?
    other factors to help this enzyme work?

    if 2) is more likely, avoiding supporting this enzyme (some foods and supps)is advised?

    somoenoe here post accutane got checked folate levels?
    Thaghts on milk thistle dandelion root and other liver supoorting herbs is welcome, my wonder about them is that they raise glutathione which i read that in it production deplete b12 and folate, and how this might connect to this GNMT enzyme problem and low methylation in genral, but if it will help the liver maybe it will help the GNMT to downregulate more quickly.

    ANY THOUGHT IS WELCOME
     

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