Cheney: "There’s a reason to be methylation blocked..."

[alex3619]

If glycine and glutamate are low its almost always due to bad diet. These aminos are in all protein foods. Strict vegetarians, or those on severely limited diets due to MCS, may have problems there. There may also be disorders in which the availability may be modified, but I know little about those. One other issue that can arise is glycine and glutamate may be converted to other forms, the body does this all the time.

PS glycine to serine, glutamate to glutamine

 

[LaurieL]

We are missing something from the Cheney discussion, too much information was not reported. Reading between the lines, and coming up with at best a speculative explanation, I think the problem he is refering to is NOT about how much glutathione we have, but how much of it is reduced or oxidized. If you have more glutathione, then the reduced GSH to oxidized GSH ratio will get worse. Personally I don't think that matters, but, again speculatively, I think Cheney does think it matters. Now in terms of biological processes there could be issues if oxidized glutathione is at too high a level.

Now to me this shouldn't be an argument against methylation protocols even if you believe it. it should instead be an argument for combining an antioxidant support protocol with a methylation protocol. For a start this would include lipoic, C, E and CoQ10, plus extra NAC to make sure glutathione levels stay high. It would also probably emphasize a wide range of food sourced organic antioxidants (organic as in chemistry, not growing practices).

The only way to get to the bottom of this is not to rely on an imcomplete reporting source, but to go get some information proactively. I do not have contact with Cheney, but some do.

I am all for the concurrent antioxidant protocol alongside methylation. Whats the sense in getting methylation going if you cannot detoxify, methylation creates metabolites as well, and especially if you consider "limiting factors" and other SNP's in those related pathways. Methylation was very helpful, but it wasn't until I started addressing my detox issues/SNP's, that improvements went through the roof for me.

As for the reporting on Dr. Cheney's conversation with this poster, I am not one to put much stock in patient doctor conversations. For two reasons, patient understanding, and doctors modifying and there for leaving out a bunch of info so as to not overwhelm the patient. This same conversation would be different in context if published or in conversation to his peers. More detailed info and a different exchange would ensue. I am a realist, and that is just the way of it.

Quite frankly, I think Dr. Cheney deserves the respect enough amongst us to at least clarify the statement prior to making any assumptions. I am not saying he is always right, no one is, but he still deserves that consideration. I like your last sentences. These mirror what I am saying.

 

[LaurieL]

If glycine and glutamate are low its almost always due to bad diet. These aminos are in all protein foods. Strict vegetarians, or those on severely limited diets due to MCS, may have problems there. There may also be disorders in which the availability may be modified, but I know little about those. One other issue that can arise is glycine and glutamate may be converted to other forms, the body does this all the time.

PS glycine to serine, glutamate to glutamine

I will be linking to this thread in creating my own so as to not hi-jack the current thread. I think you will find that there are indeed other causes of low glycine and glutamate besides a diet lacking protein.

LaurieL

 

[alex3619]

I will be linking to this thread in creating my own so as to not hi-jack the current thread. I think you will find that there are indeed other causes of low glycine and glutamate besides a diet lacking protein.

LaurieL

I am interested in reading about that.

 

[LaurieL]

I am interested in reading about that.

I am quite interested in your input.....and I have some questions for you.

 

[dannybex]

It's my understanding that glycine is can be low due to salicylate issues (glycine is one of the aminos that helps handle sals/phenols), and also in general because while glycine may be in a lot of foods, it's usually in much lower ratios than the other aminos in those foods that it has to compete with (i.e. most foods are substantially higher in glutamine/glutatamate and/or methionine). Also, we (in general) don't eat the foods (like gelatin from bones) that are naturally very high in glycine) or make broths, stocks from them, as our parents or grandparents used to do, so that may be creating an imbalance or deficiency. ???

And yes, the body does convert glutamate to glutamine and gaba, but needs other nutrients to do so, so if those are in short supply (and/or perhaps other things might inhibit this conversion) then there's no conversion. At least that's my understanding.

My glycine was low -- and has been for since it was first tested in 2002 -- and my cysteine was/is high. And yes, I have salicylate/phenol issues, although they're a little bit better than a year or so ago.

 

[Dufresne]

I believe you have it right, Alex. Cheney claimed he had evidence indicating the amount of glutathione was normal, but that the cell was suffering under the weight of free radicals and so much of the glutathione was oxidized.

Cheney believed (and I assume he still does) that the problem was in something stimulating the NMDA receptor. Moreover the problem was really with superoxide dismutase not being able to keep up. This is where the artesunate came in. Apparently his patients were testing on average 50% higher in SOD while on artesunate, and this corresponded to the wiping out of ‘oxygen toxicity’ as gauged by his ETM. It was his belief that this was the mechanism that needed to be addressed.

We’re all different, but his findings match up perfectly with my own disease. Yet I'm in a small minority. Most PWC’s who try his protocol experience very little improvement. What most people do derive benefit from is methylation supplements.

 

[alex3619]

dannybex , I doubt that salicylate detox causes glycine deficiency. Its more likely that glycine deficiency makes salicylate detox worse, so there is an association but the other way around as far as causation is concerned.

Glutathione deficiency (not sure if this has to be reduced though, probably it does) makes one more vulnerable too, not just glycine. If something is destroying glutathione you are going to chew through glycine; so far I have not read of this happening, but I do wonder about it. Glutathione is needed for functioning of the desaturase enzymes, the primary targets of salicylate attack. Without sufficient desaturase activity you cannot make much long chain polyunsaturated fats, and so have a decreased capacity to make eicosanoids.

Oxidized glutathione is typically recycled. However I do wonder if that recycling process can be compromised in us, resulting in actual destruction of glutathione. This might cause a drain on glycine, and of course cysteine. I am expecting a decreased capacity to recycle glutathione, but I don't know there has been much research on this in ME or CFS.

 

[LaurieL]

http://forums.phoenixrising.me/index.php?threads/shmt-and-related-pathways.24086/

 

[sianrecovery]

I am finding elements of this hard to follow, through sheer ignorance, but if anyone wants to read a book that discusses why the body up and down-regulates, and blocks methylation, not from a health, but epigenetics viewpoint, I recommend The Epigenetics Revolution by Nessa Carey. The material is too dense to compress into a short post. It is written for the layperson. Layperson with an attention span, mind you. Which means I only got a partial understanding.

 

[dannybex]

dannybex , I doubt that salicylate detox causes glycine deficiency. Its more likely that glycine deficiency makes salicylate detox worse, so there is an association but the other way around as far as causation is concerned.

I don't know of course. All I know is that one of the ways sals/phenols are handled/detoxed is with glycine, so perhaps if one eats a high sal/phenol diet for years, or decades, then glycine may become depleted...but I can see the other possibility as well. However, I don't understand why glycine would be low and cysteine high...

Glutathione deficiency (not sure if this has to be reduced though, probably it does) makes one more vulnerable too, not just glycine. If something is destroying glutathione you are going to chew through glycine; so far I have not read of this happening, but I do wonder about it. Glutathione is needed for functioning of the desaturase enzymes, the primary targets of salicylate attack. Without sufficient desaturase activity you cannot make much long chain polyunsaturated fats, and so have a decreased capacity to make eicosanoids.

Oxidized glutathione is typically recycled. However I do wonder if that recycling process can be compromised in us, resulting in actual destruction of glutathione. This might cause a drain on glycine, and of course cysteine. I am expecting a decreased capacity to recycle glutathione, but I don't know there has been much research on this in ME or CFS.

My glutathione was high, but yes, of course it was oxidized. I have a feeling that environmental toxins (heavy metals, pesticides, fungicides, etc) are the culprits, and that each of us have our own unique levels of exposures, past and present, and our own thresholds...?

 

[dannybex]

Here's a study re glycine and salicylates/phenols -- using aspirin as the salicylate:

http://www.ncbi.nlm.nih.gov/pubmed/2271231

"

Plasma glycine was consistently lower in patients with aspirin overdose than in these healthy volunteers, suggesting depletion of available glycine."​

 

[alex3619]

High doses of salicylates will temporarily cause a decline in free glycine. This was an overdose condition though. Its like taking too much acetaminophen can cause glutathione depletion, but once a patient recovers (presumign they do not die or suffer severe liver or kidney failure) it returns to normal. So eating a super hot spicy Indian curry might induce temporary problems.

There is also the issue that aspirin deliberately overloads the detox system as a drug ... dosage is designed to allow for detox and still have lots of aspirin in the blood to reach the tissues. Its always a deliberate overload issue.

Acetaminophen also requires glycine for activation. Glycine is used to activate it, and glutathione to detox it.

The problem with the idea that salicylates can chronically deplete glycine is that almost everyone eats salicylates, some eat them in very high quantities, yet only a few have salicylate sensitivity or glycine deficiency. Salicylate sensitivity is multifactorial, it starts in the gut (dysbiosis) and gut wall (detox failure), winds up in the liver (detox failure), and then in the tissues (enzyme poisoning). It takes them all to fail for salicylates to be a problem. So the list of possible failures is long, and involves many enzymes and pathways, even bacterial species in the gut.

I think salicylate sensitivity is a sign of oxidative stress or methylation problems, or both. I am salicylate sensitive yet keep eating them at a steady rate when I can: this keeps my body responding to them optimally, and I don't get the severe crashes I used to get when on an avoidance diet. However to do that I need to keep my protein intake adequate. I was at my worst as a vegetarian. I also have a methylation problem but the exact cause has not been identified ... testing is woeful here. I also respond to antioxidants. Finding the exact cause is a major issue, and I think it might be different in different people.

I am however interested in reading about glycine depletion in other conditions. I am particularly interested in conditions that might impair glycine synthesis or mobilization in the body.

What that study did show is that taking glycine can improve salicylate detox. So it makes a vegetarian curry problematic - low in glycine, high in salicylates from both the vegetables and the spices.

 

[dannybex]

Thanks Alex, again I agree in general...it's much more complex and complicated than just one thing causing (or not causing) another issue.

It's my understanding that sals/phenols are also detoxified via glucuronidation. Some folks have reported some improvement using calcium d-glucarate. Have you tried it?

Also I've read that increasing sulfates can help w/salicylate issues...?

(sorry if this is so off topic!)

 

[alex3619]

I haven't tried glucuronidation. I think it might increase drug toxicity, I need to look into this. I don't know much about sulfates and salicylate toxicity. It would be really nice if someone wrote a really good book on all this - I have one but its so old the science is obsolete.

 

[Jarod]

Hey Danny,

Did you ever try/benefit from supplementing glycine directly? It didn't work for me; maybe more spacey (can't remember).

Jarod

 

[dannybex]

Hi Jarod,

I did, but stopped it about six weeks ago when someone said it may increase endogenous oxalate production. Turns out that might not be true...so just ordered more, and will let you know. I can say that I've been worse since stopping it -- a little too on edge at times, and irritable. Also, salicylate symptoms (especially itching) seemed to be worse the past six weeks...

It's ideally supposed to be a calming amino acid, at least that's my understanding.

 

[LaurieL]

The thing about glutithione is that there are two forms. Reduced and oxidized, and it is this ratio that will show oxidative stress. A very high percentage of the glutithione we need is supposed to be in the reduced form. In this form, it draws electrons from others in conjugation. After it gains the electron, it then becomes very reactive and unstable (the process of oxidation). What is supposed to occur, in this form, is that there is supposed to be a high ratio of the reduced form, in which then the oxidized very radical glutithione reacts with to create the reduced form from the oxidized form. But we dont have a lot of the reduced form. So essentially what happens to the oxidized glutithione? It can't regenerate to the reduced form because there isnt any available to do it. So, essentially, oxidized glutithione becomes a free radical of itself.

Danny, if your glycine is low, and your cysteine is high, look at the pathways connected to glycine, as well as toxins that deplete it. If cysteine is high, then it sounds like your body is trying to get glutithione, but one of the three needed, glycine, to make it, is being blocked or depleted somewhere.

 

[Jarod]

Had a random idea this weekend about this whole glutathinone hypothesis ME/CFS illness after reading the quotes Danny and Patrick found from Dr Cheney earlier in this thread.

1) We get a virus somehwere along the way(maybe something similar whatever Dr JM found)

2) we get some stressor that depletes glutathione (as Rich Proposed)

3) We can no longer keep #1 virus in check due to low gluathione.

4) Once this happens, the body shuts down sex hormones and NO to suppress virus(especially in males where testosterone stimulates virus #1) The lower hormones cause all kinds of other dysfunction. Like skin and tissues not healing properly.

6) we get secondary infections and heavy metal posioning, especially in the gut. This causes nutrional deficiencies and poor absorption/balance of amino acids.

7) difficult to recover because low glutathione means we can't suppress virus #1, and with poor NO and hormone balance we can't rebuild gut/tissues or process aminos/nutrients to get glutathione back up(needed to suppress virus #1).

It's a vicious circle that never allows us to get back in balance due to virus #1, and the secondary trigger which leads to low glutathione, which leads to low hormones and NO balance, which never allows us to get back with glutathione levels high enough to keep #1 in check.

 

[Mij]

Rich van Konynenburg's idea is that ineffective methylation is a major cause of fatigue.

• To produce vital molecules such as Co Q-10 and carnitine.
• To switch on DNA and switch off DNA. This is achieved by activating and deactivating genes by methylation. This is essential for gene expression and protein synthesis. Proteins of course make up the hormones, neurotransmitters, enzymes, immune factors and are fundamental to good health. When viruses attack our bodies, they take over our own DNA in order to replicate themselves. If we can't switch DNA/RNA replication off then we will become more susceptible to viral infection.
• To produce myelin for the brain and nervous system.
• To determine the rate of synthesis of glutathione which is essential for detoxification.
• To determine the rate of synthesis of glutathione which is an essential anti-oxidant as glutathione-peroxidase. Furthermore oxidative stress blocks glutathione synthesis - yet another vicious cycle!
• To control sulphur metabolism of the body, not just glutathione but also cysteine, taurine and sulphate. This is an important process for detoxification.
• As part of folic acid metabolism. This also switches on synthesis of new DNA and RNA.
• For normal immune function. The methylation cycle is essential for cell mediated immune function and blockages here will mean that infections will not be adequately dealt with. I know this clinically because many patients tell me that once they get on to their B12 injections (an essential co-factor for methylation) this seems to protect them from getting infectio

The overall effect here is that if the methylation cycle doesn't work, the immune system mal-functions, the detoxification system mal-functions, our ability to heal and repair is reduced and the anti-oxidant system mal-functions.