Accutane, Methylation Block and Glycine N-Methyltransferase

[droit]

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

 

[GenDylan]

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.

 

[Ivmi]

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

 

[*GG*]

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

 

[Ivmi]

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...

 

[*GG*]

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...

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

 

[zzz0r]

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

 

[name]

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

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,

 

[name]

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...

 

[name]

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

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

 

[jamienoble]

I know this is an old post but i have a question.

I have been sick for most likely all my life (since birth), i have had an medical investigation going on for 8 years, pretty much all my tests has been normal so i have no idea what is wrong with me.
I have symptoms on the brain (bad/slow thinking), bad body and urine odour, pale and ill looking skin colour, very dry hair, fatigue.
10 years ago i was temporarly cured by taking Roaccutan (Accutane), i took it for 7 months and then stopped, a few months later all my symptoms went away or was changed for the better, this healthy period lasted for 6 months and then the symptoms gradually came back again.
I haven't found anyone in the world that has been through something similar, Accutane is famous for making bad side effects but for me something completely different happened.

Im pretty sure today that i have some sort of genetic/metabolic disease, and i know from this thread that Accutane affects the GNMT gene.
Lets say you have Hypermethioninemia which means you have elevated methionine and the GNMT gene is bad so you cant break down methionine in the body (which means you have Hypermethioninemia). And then you take Accutane for 7 months which hyperactivates the bad GNMT gene. What could happen then? If a bad gene gets hyperactivated, could it perhaps be repaired then?

 

[Critterina]

Hi @jamienoble,

It seems like an amino acid panel should be able to confirm the methionine level in your blood. It it is elevated and then you take Roaccutan and retest and it's lower, then we could start looking for the Roaccutan-related mechanism.

Faulty genes are rarely repaired (although I've read about using a virus to carry new copies of a gene into people sick with Parkinson's). Changing the DNA of a gene would be risky business, as I would think that as likely as not, you'd turn off something that controls cell growth and end up with cancer. But genes make enzymes and some things beyond the basic structure encoded by the gene can make them more or less efficient.

Many of us on this forum try to help out our less efficient enzyme (made with faulty genes) by supplementing either the product that the enzyme would produce (like taking methylfolate for MTHFR C677T) or by increasing the amount of reactants (like taking methylfolate for MTHFR A1298C or TMG for BHMT-08) so that whenever the enzyme has a free binding site, there's something for it to react with.

In other circumstances, there are other things (vitamins, minerals, and other things) that get depleted and become the rate-limiting thing that slows down the enzyme that is less efficient. Sometimes supplementing these things brings improvement.

I'm happy for your six months of being well. Have you repeated the experiment with more Roaccutan and had the same results? It would be interesting to see if it's repeatable and if the time lag between stopping the Roaccutan and the remission of symptoms is the same or different. Can you think of anything else that might have changed in your life besides the Roaccutan?

Best of health, and best of sleuthing this out so you can repeat the good health!

Critterina

 

[jamienoble]

Thanks alot for the reply

I actually did an amino test earlier this year and all levels was normal, including methionine.. The only levels that were slightly elevated was Isolecuin 92 (40-85) and Tryptofan 71 (30-65).

So this amino test pretty much confirms that i don't have genetic or metabolic disease either?

https://www.dropbox.com/s/mhr8l0zqkvz8vt2/Amino test 1.jpg?dl=0
https://www.dropbox.com/s/73s8c0wz7rt0co0/Amino test 2.jpg?dl=0

Accutane or Isotretinoin can only cure skin problems, cancer, Gilbert Syndrome and some skeleton disease that i don't have.
Vitamin A can cure malaria, HIV, messles and probably other virus disease but i don't think i have an infection. What type of infection is in your body since either birth or when you were like 4-5 years old and then it stays there for all these years without any changes? I dont have lyme disease or anything similar either, i have checked that.

I don't think its wrong with any organ because i have scanned much of my body and all tests has been normal, bowels, thyroid, liver, kidney, adrenal glands, brain... Liver & kidney you can never be 100% sure about but what could Roaccutan have done to those so i suddenly became healthy? It doesn't make any sense...
I think the doctors ruled out an immune system problem because those main levels are normal, IgA and IgG i think they are called.

My plan is to take Accutane again in September because this is the last thing i can do, if this doesn't work i will never find this..
I will visit doctors and different specialists before (now), during my healthy time and afterwards to compare all my symptoms and then i hope someone can puzzle it all together.
A dermatologist for the skin colour and hair, someone for the body odour, someone for the brain capacity, someone for the fatigue (if possible). I will also meet with 3 different doctors during this period so they can follow this closely and i can show to them that something is really happening. But of course, there are no guarantees that the same effect will happen again..
Do you have any suggestions how i should do this?

Best Regards
Daniel

 

[Critterina]

Hi Daniel,

I'm glad you're going to try it again - I do wish you all the success in figuring it out and making that healthy phase permanent!

I am SO not a doctor, and I can't really tell you what the tests mean or what to do. Especially I can't tell you whether you have any genetic or metabolic diseases, but these panels look pretty good to me. The questions I have, looking at them and the Genova Diagnostics Interpretive Guide are:

Have you had your blood sugar checked, so you know you don't have hyperglycemia (diabetes or insulin resistance) or hypoglycemia? Blood glucose would tell you that.

Do your vitamins include B6 in the pyridoxine hydrochloride form? Or do you take the active form, pyridoxine-5'-phosphate (P5P)? If you're not taking P5P, you might consider it, maybe talk to your doctor? (My experience is that my amino acids showed low B6 even though I was taking it for months - I needed to take P5P for it to work.)

Have you had a test on your red blood cells or your hair to determine if you have enough Manganese (Mn)? Do you take a vitamin containing Mn?

So, those are the only things the amino acids suggest to me.

There are diseases that can lay dormant in your body after an infection; I know that. But I'm only familiar with the ones in North America, and mostly only ones that have occurred in my family and friends. So, if you haven't traveled to the US, and in particular the American south/southwest, I probably don't have anything helpful to offer.

In the event that the Roaccutan doesn't result in the same relief, we would need to talk about what happened 10 years ago between the time you stopped taking it and when you felt better. Maybe we should start that now. I'm also thinking that this thread is probably not the best place to chat. Why don't you post your original comments in a new thread with a title of what you are asking for help about? Then we can move these comments there and delete them here. You can ask one of the moderators if you need help.

Cheers!
Crit.