The Glutathione Depletion Cascade

[Kimsie]

Sorry, I meant glutamine

Since ribose is required for the purine salvage pathway, just taking ribose along with your current niacinamide might help even without the glutamine and aspartate. Maybe you could start with 500 mg of ribose 3 x a day and if that is going well try gradually raising the dose. Splitting the niacinamide dose should help, too.

 

[undcvr]

You are talking about glutamine intracellularly its mechanism is very tight controlled as compared to ingesting say MSG and getting it into the bloodstream. Also you are recommending him niacinamide and ribose, you do know that they are eventually combined to form NADH and ATP rite? So NADH is not recommended and its components are???

"you are most likely exchanging NADPH for ATP, and so you have to weigh the long term costs of having lower levels of NADPH in order to make a decision about whether and how much and how long you want to use the folate pathway in this manner" - i think this is all based on current assumptions. They reason why they haven't found a cure for CFS yet is because obviously some or many of the theory that have been thought are wrong.

 

[Kimsie]

You are talking about glutamine intracellularly its mechanism is very tight controlled as compared to ingesting say MSG and getting it into the bloodstream. Also you are recommending him niacinamide and ribose, you do know that they are eventually combined to form NADH and ATP rite? So NADH is not recommended and its components are???

"you are most likely exchanging NADPH for ATP, and so you have to weigh the long term costs of having lower levels of NADPH in order to make a decision about whether and how much and how long you want to use the folate pathway in this manner" - i think this is all based on current assumptions. They reason why they haven't found a cure for CFS yet is because obviously some or many of the theory that have been thought are wrong.

Yes, this is based on my own hypothesis, which may certainly not be correct. I just came to that conclusion because of what happened to my son after he took high dose folate for some time for constant extreme fatigue (not CFS).

 

[acrosstheveil]

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.

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.

I have been following the kpu/hpu protocol for a while now (off and on) but it was hard to tell what was happening because I was also playing around with methylfolate and cofactors along with it. how much methylfolate are you taking with those high doses of p5p?

 

[adreno]

What might help is making sure you have some of the amino acids that can help with the changing of glutamate to alpha-ketoglutarate through aminotransferases, such as oxaloacetate, and probably the best way of doing that is to take the branched chain amino acids which can enter the TCA cycle as succinyl-CoA.

Would AKG by itself do any good? I have some lying around.

 

[Kimsie]

Would AKG by itself do any good? I have some lying around.

It's AKG that gets transformed to glutamate, as in this reaction Aspartate (Asp) + α-ketoglutarate ↔ oxaloacetate + glutamate (Glu) so it's the other amino acid in the reaction that you want to take more of, in this case the oxaloacetate, and this will give you some of the aspartate you need, too. AKG in the mitochondria can eventually become oxaloacetate through the TCA cycle, but I think AKG has to be changed to glutamate to cross into the mitochondrial matrix, but I'm not sure about that. Malic acid might help, but it doesn't cross the BBB, however, we have found it to be helpful. Maybe malic acid would be worth a try because it gets changed to oxaloacetate. (It also can help by making NADPH through the malic enzyme.)

 

[Kimsie]

I have been following the kpu/hpu protocol for a while now (off and on) but it was hard to tell what was happening because I was also playing around with methylfolate and cofactors along with it. how much methylfolate are you taking with those high doses of p5p?

My son is no longer taking such high doses of p5p because from a change in his symptoms it seems that his levels are not too depleted any more. He is taking 50-100 mg of p5p a day, and he is now taking only 500 mcg of folate a day, but before he was taking 5-8 mg.

 

[undcvr]

You attach an ammonia group NH3 to AKG to get glutamine NOT glutamate.

 

[adreno]

You attach an ammonia group NH3 to AKG to get glutamine NOT glutamate.

Actually, AKG combines with ammonia to make glutamate.

 

[Kimsie]

It's lifted the fatigue I don't feel like I have chronic fatigue anymore. I feel like I am weak in general but not fatigued. Somehow somewhere someone dropped the ball, i think we are eventually going to find out that mfolate is therapeutic (and safe) in doses much larger that we thought.

I have been reading the ideas of Bill Walsh and I have been revising my hypothesis considerably in some ways.

Now I think that large doses of folate are fine for people who have overmethylated histones as per Walsh's ideas, but bad for people who are undermethylated, which includes my son who got depressed from taking folate. If you are an overmethylator then probably you won't have a problem with such high doses of folate.