The Glutathione Depletion Cascade

[Kimsie]

I have revised my theory again, so I will try to share it in an understandable way. I am calling it the Glutathione Depletion Cascade, because I think that it starts when a person has stress, often from more than one source, that overcomes the body's ability to produce enough glutatione (and catalase) to deal with the hydrogen peroxide, or H2O2, produced by oxidative stress. H2O2 levels build up and affect other enzymes by interfering with iron-sulfur clusters (used in the electron transport chain to make energy, and for other things, too) and TCA cycle (energy cycle) enzymes and sulfite oxidase isn't able to get rid of sulfite and that builds up and causes more problems and a whole cascade of enzyme inhibition is started which creates a vicious cycle which continues even if the original stress goes away.

This all leads to disruptions in the energy producing cycle and low levels of catalase and norepinephrine, and high H2O2 and sulfite and a lot of messed up metabolic pathways.

We have figured out some very helpful ways of treating it, but not how to overcome the vicious cycle and put an end to it. I think it could be stopped if there was a way to lower the sulfite levels, but I can't find anything to do that yet.

I am working on a blog to explain all this so if anyone is interested, it is here. I have graphics that I hope will help people to understand what I am taking about, plus a Powerpoint about it.

I really think this is probably the main cause of ME/CFS, and a number of other chronic illnesses involving mitochondrial dysfunction. Some of my ideas about treatment are different than what are usually talked about, such as high dose niacinamide (essential), and an alternative source of acetyl groups for the TCA cycle (but not ketones!), particularly in the brain. (also essential)

 

[Kimsie]

Actually, in the case of extreme fatigue, catalase and norepinephrine are probably not low, but enzyme pathways including the energy producing pathways are still messed up.

 

[undcvr]

its not the whole story otherwise just treating it with glutathione wud solve everything, there have been pple here on Glu IV for awhile and it really didn't help much. I agree Glu is crucial in cells either way and w/o it we wud be dead but it does not take part in ATP generation in the mitochondria and the acids in the krebs cycle are not really affected by oxidation. But I agree with you that NIacin is essential, that whole pathway that starts from Niacin all the way down to cholesterol and bile is screwed up, i don't know why nobody has figured this out yet, it is a real shame. Here again Niacin itself is not enuf and the enzyme steps from Niacin to NADH cud be broken down or poisoned.

 

[alex3619]

the acids in the krebs cycle are not really affected by oxidation.

It depends on the kind of oxidation in the mitochondria., and the extent. Mitochondrial oxidative bursts can cause cell death. Indeed, one model of alcohol poisoning holds this is the case. Peroxynitrite destroys aconitase and probably other iron containing enzymes. Any of them can cause mitochondrial DNA damage. There is a lot of resistance to oxidative damage in the mitochondria, but its not perfect. If those mechanisms fail in enough mitochondria then there could be issues.

One thing almost nobody comments on but I have been saying from maybe 2000 or 2002 is that sufficient depletion of glutathione in the cell can lead to poor protein folding. Enzymes like aconitase are nuclear proteins, imported to the mitochondria. If GSH is low the mitochondria may have lots of aconitase but its not working as its not folded right. I have not checked other mitochondrial proteins but I suspect there would be a few more with this vulnerability, not just aconitase.

 

[caledonia]

Rich Van Konynenburg covered this in his papers a couple of years ago. Methylation treatment will overcome the vicious cycle. High dose niacinamide with soak up methyl groups, slowing down methylation, the opposite of what you want.

 

[undcvr]

I actually disagree, methylation is not as crucial as getting Niacin to convert to NADH to ATP to power the cells. Methylation is just a minor player. No ATP u die and that is the crux of what CFS cells are experiencing. I still don't know what the pathways are that demethylise, everyone keeps telling me that Niacin soaks up methyl groups but I don't know what the path ways are.

 

[Kimsie]

its not the whole story otherwise just treating it with glutathione wud solve everything, there have been pple here on Glu IV for awhile and it really didn't help much. I agree Glu is crucial in cells either way and w/o it we wud be dead but it does not take part in ATP generation in the mitochondria and the acids in the krebs cycle are not really affected by oxidation. But I agree with you that NIacin is essential, that whole pathway that starts from Niacin all the way down to cholesterol and bile is screwed up, i don't know why nobody has figured this out yet, it is a real shame. Here again Niacin itself is not enuf and the enzyme steps from Niacin to NADH cud be broken down or poisoned.

I didn't say that glutathione was the whole problem, I said that it started with glutathione depletion and that lead to a cascade of enzyme inhibition which creates a vicious cycle. The most difficult problem is actually the inhibition of sulfite oxidase and the high sulfite to cysteine ratio, which I didn't mention in my post because I was trying to keep it simple. I haven't figured out any way around that, but I think you can supplement to overcome the symptoms caused by it.

Several of the enzymes in the TCA cycle and the electron transport chain produce H2O2, particularly alpha-ketoglutarate dehydrogenase, which is also inhibited by H2O2.

Rich Van Konynenburg covered this in his papers a couple of years ago. Methylation treatment will overcome the vicious cycle. High dose niacinamide with soak up methyl groups, slowing down methylation, the opposite of what you want.

Yes, I know that Rich proposed the idea of the Glutathione/Methylation Depletion theory. He was a great man, and I admire him very much. I first heard about him shortly after he died and I wish he was still alive so I could discuss my ideas with him. I differ with him on the idea that this is a methylation problem. Methylation is affected, because folate is affected, but this is principally a problem in the energy producing machinery of the body. Pyruvate availability, the TCA cycle and the electron transport chain are all affected. I have been working on my blog to make the explanations better if anyone is interested.

When I gave my son methylfolate, sure, it cured his problem with extreme fatigue that he had been having for over a year, but after a few months he began to be severely depressed. This is the catch 22; if you overcome the fatigue with methylation instead of dealing with the underlying cause, you can end up with a new set of symptoms.

About high dose niacinamide: niacinamide uses up methyl groups because it has to be methylated in the breakdown process. If you think that your problems are caused by a lack of methylation, then this might worry you. However, I think that methylation is not the cause of the problem (I know it can be affected, though, it just isn't the cause of the problem). I think that whole view is wrong and I am trying to show that a different view sheds a different light on everything.

The treatment protocol I have come up with involves using high dose niacinamide, high dose P5P (B6), folate, pantethine, coconut oil (for ketones) and some other supplements in more usual amounts.

 

[Gondwanaland]

@Kimsie considering the importance of magnesium for ATP activity, reducing glutamate release, synergism with B2 and B6, antagonism from B1, B3 and B9, besides the catalase production as mentioned in your blog, and many other functions, I ask you if magnesium would not deserve higher emphasis in your protocol.

Do you know this book Magnesium in the Central Nervous System (free download at http://www.adelaide.edu.au/press/titles/magnesium/ )? What do you think about the schizophrenia study (chapter 22)?

Please do not take my ignorance for presumptuousness.

Respectfully,

izzy

 

[undcvr]

I agree with @Kimsie methylation is not the problem. I appreciate RVK contribution to CFS and ME but he is wrong. I agree tho that Glutathione is a big part of the problem but the same can be said too for SOD and Catalase, it is just that we cannot actually nutritionally manipulate SOD and Catalase the way we can Glutathione. (Side: there is Glisodin but that is SOD wraped up in the Gliadin (wheat) protein. That is a no-no for CFS or most people for that matter. U can take as much NAC and cofactors to convert to Glutathione intracellularly as you want but if the reaction does not go then it just won't. The issue is why do cells not have the energy to do the converting, what is jamming up the energy processes.

The pathway I am aiming at is the pentose phosphate pathway that runs parallel to glycolysis in generating ATP. It has broken down. The glycolysis pathway dominates in cells causing an imbalance and an environment where pathogen can easily stay in and thrive. Cellular conditions are so poor that pathogens can stay in it and use it to hide from the immune system.

Correct me if I am wrong but altho methyl groups are used up to to process Niacinamide they are rescued at the end steps. There is no net loss, my biochemistry here is a little rusty.

 

[jepps]

Kimsie, this is a post from Rich van K : http://forums.prohealth.com/forums/...fide-and-the-methylation-cycle-in-cfs.204387/

He describes that toxic sulfites not only come from the methylation cycle (CBS upregulation) but from a dysbiosis in the gut. SRBs (sulfate-reducing bacterias like the streps, enterococcus or prevolta) use sulfate for their metabolism, and make toxic H2S (hydrogen sulfide). H2S (toxic itself) interacts with heavy metals, and this makes heavy metals much more toxic.

When you address the gut, and therefore are reducing the SRBs, your body can use sulfur from nutrition for the methionin cycle for energie, glutathion and detoxification instead of using it for the SRBs, which make sulfur toxic.

Konynnenburg refers to a press-conference of Kenny De Meirleir (there are more threads about it in this forum):

http://maartens.home.xs4all.nl/me/RESOURCES/SCIENCE/press-conference-kdm-2.pdf

You can buy a test H2S f.ex. here:

http://www.detoxpeople.eu/index.php?l=product_detail&p=2615


Regards, jepps

 

[undcvr]

@jepps at the end of the day it does not matter how much theory you can come up with, it is on the ground - in the battlezone that it must work. I do not know anyone who has recovered from just the methylation method yet I know many pple who have tried it. I know a few who have recovered but they and I myself didn't exactly treat our methylation too much (i did make sure to take methyl and adenosyl B12).

On top of that methylation processes like everything else needs energy to push the processes forward, if you have a dysfunctional mitochondia it does not matter how much you treat methylation, it has nothing to do with it and cannot help. It is true that methylation is fundamental and so is Glutathione but the breakdown is in generating ATP, that powers both.

 

[Kimsie]

@Kimsie considering the importance of magnesium for ATP activity, reducing glutamate release, synergism with B2 and B6, antagonism from B1, B3 and B9, besides the catalase production as mentioned in your blog, and many other functions, I ask you if magnesium would not deserve higher emphasis in your protocol.

Do you know this book Magnesium in the Central Nervous System (free download at http://www.adelaide.edu.au/press/titles/magnesium/ )? What do you think about the schizophrenia study (chapter 22)?

Please do not take my ignorance for presumptuousness.

Respectfully,

izzy

For a while we were giving a lot of magnesium. But now, seeing that we all test normal on magnesium, I think that the reason magnesium was helping because it was "pushing" the reactions, not because we really need so much of it. I do think that everyone should get their magnesium up to normal levels if they are low. In fact, I think everyone with chronic illness should have a mineral RBC test that covers all the essential minerals and work on correcting any balances. In our family this problem doesn't really drain magnesium, but it might for some people, that's why testing is important.

I'll take a look at the schizophrenia study and comment later.

My 2 year old granddaughter is just waking up (I'm baby sitting today!) so I don't have time for more except I would like to mention that B6 is of more importance that I had thought.

How many of you have vivid dreams? If you don't you might want to consider trying 250-500 mg of P5P a day for a while and see how you feel. Glutathione won't do you any good if you don't have enough B6 (P5P) to make selenoprotein for glutathione peroxidase.

Kim

 

[Kimsie]

I agree with @Kimsie methylation is not the problem. I appreciate RVK contribution to CFS and ME but he is wrong. I agree tho that Glutathione is a big part of the problem but the same can be said too for SOD and Catalase, it is just that we cannot actually nutritionally manipulate SOD and Catalase the way we can Glutathione. .

Actually, according to my Cascade hypothesis, catalase synthesis is affected by low B6 and low succinyl-CoA, so you can nutritionally manipulate it. Large doses of magnesium will raise catalase, but only temporarily. B6 in very large doses should help, but for some reason this takes a week or two to come gradually into effect. If you take large doses of B6 you will probably have to take quite a lot of folate. I am going to write about this on my blog because it is too much for this thread right now.

.... U can take as much NAC and cofactors to convert to Glutathione intracellularly as you want but if the reaction does not go then it just won't. The issue is why do cells not have the energy to do the converting, what is jamming up the energy processes.

Well, another thing about taking NAC is that for glutathione to work, you have to have enough B6, because glutathione peroxidase requires a selenocysteine and selenocysteine requires B6

Correct me if I am wrong but altho methyl groups are used up to to process Niacinamide they are rescued at the end steps. There is no net loss, my biochemistry here is a little rusty.

I don't know if the methyl groups are used up, but I don't think there is a problem with having enough methyl groups; I think that the idea is that too much SAMe gets used for it. That might be a problem, if making SAMe was where a person's problem really was coming from.

 

[Kimsie]

Kimsie, this is a post from Rich van K : http://forums.prohealth.com/forums/...fide-and-the-methylation-cycle-in-cfs.204387/

He describes that toxic sulfites not only come from the methylation cycle (CBS upregulation) but from a dysbiosis in the gut. SRBs (sulfate-reducing bacterias like the streps, enterococcus or prevolta) use sulfate for their metabolism, and make toxic H2S (hydrogen sulfide). H2S (toxic itself) interacts with heavy metals, and this makes heavy metals much more toxic.

When you address the gut, and therefore are reducing the SRBs, your body can use sulfur from nutrition for the methionin cycle for energie, glutathion and detoxification instead of using it for the SRBs, which make sulfur toxic.

...

Regards, jepps

I agree that gut dysbiosis can be part of the problem, but I have two son's that I believe are affected by this, one of them had gut dysbiosis for 3 years before his symptoms started, and the other one we have no reason to think he has had gut dysbiosis at all. They both started having symptoms when they had mononucleosis, and I think that was what set it off. The gut dysbiosis just made the one son more vulnerable to oxidative stress, in my opinion. I think the problem with sulfite is that sulfite oxidase is not working correctly. The sulfite is coming from the protein they eat. But it is the ratio of sulfite/cysteine, not so much the amount of sulfite, that is the main part of the problem. Otherwise a good fast would take care of it.

I think that gut dysbiosis makes people more vulnerable, so that when another stressor comes along, like a virus or something, the total oxidative stress can overcome their ability to get rid of H2O2 and this is what starts the vicious cycle. The gut dysbiosis by itself isn't the cause.

I haven't studied the effects of sulfide, so I can't comment on that at this point.
Kim

 

[Kimsie]

Well, I have been thinking a lot about this the past few days and I think it might be helpful. Here is a diagram I made to show part of the relationship of methylation to energy production: (these first few diagrams are large and take a while to load, so be patient.)

When my son was 15 he was very fatigued for over a year after having mono. When I started giving him methylfolate 5 mg a day he improved dramatically, but after 3 months he became very depressed. It might seem that the improvement in his energy was because he was able to make more ATP because the SHMT enzyme, which requires folate, worked better when it had more folate, but I don't think that was why.

It isn't known very well, but there is good evidence that folate is required for synthesis and/or repair of iron-sulfur clusters. The electron transport chain is full of iron-sulfur clusters, so if you have a problem with your iron-sulfur clusters, then you will not produce much ATP. I think the Cascade starts when iron-sulfur clusters are damaged by H2O2, due to problems with glutathione. This blocks energy production. (For some reason, some people with the Cascade don't have a problem with energy production, this must be due to genetics. They can get other problems, though, like depression, MS or Alzheimer's.) When my son started taking large doses of folate, the electron transport chain worked better, and he had more energy, but SHMT started draining B6.

Then problems with the pathway that makes catalase began, because catalase synthesis requires heme, and heme requires B6, glycine, and succinyl-CoA, which is already in limited supply due to the Cascade, which I won't explain why here. And without enough catalase, dopamine beta-hydroxylase is inhibited, leading to higher dopamine and lower norepinephrine.

So I started giving him a lot more B6, and he is feeling better, but twice today after giving him 250 mg of P5P (B6) he started feeling fatigue, but not depression, so the higher levels of B6 are draining the folate, just like the folate drained the B6. So my conclusion is that you have to give both of them in pretty large amounts. When I gave him about 2 mg more folate, the fatigue went away each time.

I hope this is clear enough to make sense!

 

[undcvr]

Deplin is sold in 15 mg and in the trials they used up to 60mg of it. That's a great observation between B6 and B9. What about B12? Do you give him any of that at all? If so which form?

 

[dannybex]

@Kimsie -- interesting about the b6. I'm wondering if you worked up to such a high dose? A lot of us have had issues with B6, even tiny doses, even though tests show we need it. And there's a webpage w/hundreds of people complaining about similar toxicity issues...

I've found that b2 helps convert it, and maybe that's why you're using p5p instead of B6?

 

[adreno]

I think many of the "toxicity" reports, or side effects, with B6/P5P is because it can drain folate. I find that the folate and B6 needs to be balanced. The neurological symptoms with B6 probably happens because folate (and perhaps B12) goes to low. If I get side effects from P5P I take more folate and it usually goes away.

 

[undcvr]

I agree with @adreno this is what I have been observing too. I have been taking really high doses of mfolate for awhile now an average of 90mg a day.

 

[adreno]

now an average of 90mg a day.

You're taking 90mg mfolate daily? Damn.