Why do PWCs crash? was Re: Pricing of Lipoceutical Glutathione

[Guest guest]

Hi, CS.

In my opinion, PWCs " crash " because they are operating right at the

ragged edge of having enough glutathione to keep functioning, at least

at the level they are able to function. If they do anything or are

subjected to anything that lowers their glutathione below what is

needed to keep funtioning at that level, they " crash. " There is a

wide variety of factors that can lower the glutathione level--

physical, chemical, biological and psychological/emotional factors can

all do it.

Your second question requires a more involved answer.

Here's a brief overview of my current hypothesis for the etiology

(root causes) and first part of the pathogenesis (development of the

disease process) in one subset of chronic fatigue syndrome:

It starts with genetic variations (or single nucleotide polymorphisms)

that a person inherits and has from conception. I suspect that they

involve certain aspects of the sulfur metabolism, particularly the

methionine cycle and/or glutathione synthesis or use. These

polymorphisms cause the sulfur metabolism to operate in a suboptimum

manner, but the person is still able to function relatively normally

unless/until they encounter other factors that place a major demand on

glutathione. In that case, the sulfur metabolism can be thrown into a

dysfunctional state from which it has been very difficult to recover,

because of the development of positive feedback (vicious circles) and

interactions due to toxin buildup and infections.

The sulfur metabolism is highly integrated and interdependent. When

one part of it has a problem, the other parts experience it as well.

Most of the sulfur that comes into the body is in the form of two

sulfur-containing amino acids (methionine and cysteine), found in

proteins in the diet. These amino acids are used to make proteins in

the body, but some of them are also processed through the sulfur

metabolism to make other sulfur-containing substances that have very

important roles in the body. Some of these substances are S-

adenosylmethionine (SAMe), cysteine, taurine, and sulfate. Sulfur

leaves the body principally in the forms of sulfate and taurine, in

the urine.

The overall sulfur metabolism includes the methionine (or methylation)

cycle and the transsulfuration pathway. These are linked together at

homocysteine. Homocysteine can either be converted back to

methionine, thus closing the methionine cycle, or it can be processed

to form cysteine. Cysteine can either be used to make proteins, or to

make glutathione, or it can be converted to taurine, or can be

oxidized to sulfite and then to sulfate.

In autism, and I suspect in many cases of CFS, there is a problem in

the genetic basis for the enzymes that convert homocysteine to

methionine. These enzymes use methyl-B12, folate, and

trimethylglycine, and in many cases of autism (and I hope of CFS) it

is possible to make up for their genetic variations by increasing the

intake of methyl-B12, folinic acid, and trimethylglycine.

If homocysteine cannot be converted to methionine at normal rates,

there is a built-in regulatory system that attempts to direct more

homocysteine toward methionine, which decreases the production of

glutathione. On the other hand, if there is a shortage of

glutathione, the regulatory system attempts to move more homocysteine

down the transsulfuration pathway, and less toward conversion to

methionine. The result of this is that if one of these does not

proceed well, the other will also be diminished. If the conversion to

methionine is diminished, the methionine cycle will slow down, and

there will be less production of SAMe. SAMe is responsible for

performing methylation reactions in the body, involving the production

of creatine, neurotransmitters, DNA and RNA among other things. So

these functions will suffer.

One thing I learned at the DAN! autism meeting is how closely these

two are linked. Methylation dysfunction gets a lot of attention in

autism, because it is necessary for development of the brain, and

autism strikes children before their brains are fully developed. In

CFS, on the other hand, the lack of glutathione is what caught my

attention, and what I have been emphasizing for several years. But

both are present in both autism and many cases of CFS. And I've

become convinced that you can't fix one without fixing the other.

You asked about the Krebs cycle. In the red, slow-twitch skeletal

muscles, most of the ATP is generated by the use of the Krebs cycle

and the respiratory chain within the mitochondria of the muscle

cells. The ATP is what powers the relaxation and contraction of the

muscle fibers. Anything that interferes with the operation of the

mitochondria in these cells will interfere with the operation of the

muscles, and will manifest in the form of physical fatigue or weakness

or both.

I believe that glutathione depletion affects the red, slow twitch

skeletal muscles early on in the depletion. When the glutathione

level drops in the mitochondria of the skeletal muscle cells, the

hydrogen peroxide level rises, because glutathione is not available to

quench it. The rise in hydrogen peroxide causes a slowing of the

superoxide dismutase reaction by product inhibition. The superoxide

concentration rises, and more of it is then available to react with

nitric oxide, to form peroxynitrite. Peroxynitrite reacts with the

enzymes aconitase and cytochrome oxidase in the Krebs cycle and the

respiratory chain, respectively, and this gives rise to partial

blockades, which lower the rate of production of ATP from ADP.

When a PWC " crashes, " the glutathione level drops further in the

skeletal muscle cells, and this causes a further drop in the rate of

conversion of ADP to ATP. The level of ADP then rises, and one

molecule of ADP reacts with another molecule of ADP, producing ATP and

AMP. However, the AMP breaks down to adenosine and is lost from the

cell. In a profound crash, this loss of AMP makes it much more

difficult to climb back out. That's where ribose is helpful. It

speeds up the process of reforming ATP, then ADP, which can be used to

make ATP again.

I think you may experience some benefit in coming out of a crash from

the combination of substances you listed. However, if my hypothesis

fits your case, I don't think these substances will prevent you from

undergoing another crash, if you either do too much or are subjected

to too much of the factors I mentioned ealier, because I believe that

the process of going into a crash results from glutathione depletion,

and I don't think this combination of substances will prevent that.

To prevent glutathione depletion, I think we have to compensate for

the problem that I believe is at the root of CFS in many cases, which

I believe is the genetic variations in the genes that affect the

enzymes in the sulfur metabolism. This is at the cutting edge of what

is currently known in CFS, but I am hopeful that we will soon know a

lot more about this. I believe that has been learned by the DAN!

project in autism in this area will lead the way for CFS.

Rich

Id like to have your thoughts on why you think people are

> crashing despite getting rid of alot of their toxins from there

sytem - how

> does the kreb's cycle relate to Glutathione and methylation?

>

> I m looking into Creatine / D-ribose / Co Q10 / NADH to help with

this

> " crashing " .

>

> Regards

> CS