This is a really good article!
Here are some quotes that I was hoping that Rich (or others) might comment upon:
>If Phase I detoxification is highly active and Phase II detoxification is lethargic, the individual is referred to as a "pathological detoxifier," a condition which increases sensitivities to environmental poisons.
> Excessive amounts of toxic chemicals such as pesticides can disrupt the P-450 enzyme system by causing over activity or what is called 'induction' of this pathway. This will result in high levels of damaging free radicals being produced.
> Patients with underactive phase I detoxification will experience caffeine intolerance, intolerance to perfumes and other environmental chemicals, and an increased risk for liver disease.
>A significant side-effect of phase I detoxification is the production of free radicals as the toxins are transformed--for each molecule of toxin metabolized by phase I, one molecule of free radical is generated. Without adequate free radical defenses, every time the liver neutralizes a toxin exposure, it is damaged by the free radicals produced.
> The most important antioxidant for neutralizing the free radicals produced in phase I is glutathione. When high levels of toxin exposure produce so many free radicals from phase I detoxification that the glutathione is depleted, the phase II processes dependent upon glutathione stop.
> Many substances inhibit cytochrome P450. This situation can cause substantial problems as it makes toxins potentially more damaging because they remain in the body longer before detoxification.
> Curcumin, the compound that gives turmeric its yellow color, is interesting because it inhibits phase I while stimulating phase II.
>In order to work, these enzyme systems need nutrients both for their activation and to provide the small molecules they add to the toxins. In addition, they utilize metabolic energy to function and to synthesize some of the small conjugating molecules. Thus, mitochondrial dysfunction, such as found in chronic fatigue syndrome, a magnesium deficiency or physical inactivity, can cause phase II detoxification to slow down, allowing the build-up of toxic intermediates.
I'm not sure if I'm understanding this correctly, but this is what I'm thinking.
It looks here like many/most/all of us with ME/CFS might be naturally inclined to be "pathological detoxifiers" (with too much Phase I and not enough Phase II).
The main reason for this seems to be the sluggishness of Phase II.
This in part is related to the mitochondrial dysfunction, which (per this thread) seems due to the presence of XMRV and/or exposure to biotoxins and/or something else.
http://www.mecfsforums.com/index.php/topic,3241.0.html
Another part is because we have a hard time methylating (due in part to the inability to properly convert folic acid into activated folate).
I would like to posit that perhaps certain mold toxins induce Phase I detox. Thus, if people are constantly exposed to too much mold toxin, Phase I naturally goes wild.
This is a bad thing, if we don't have enough Phase II going on. The partially metabolized forms of many toxins are more damaging than the unmetabolized forms. In addition, if not enough glutathione or other antioxidants are present, free radicals build up and create damage.
It looks like when this happens, glutathione is naturally shifted to neutralize the free radicals (which I believe are deadly) in Phase I. If the supply of glutathione is limited, this means that none is left for Phase II (meaning that damaging toxins are present). If it's really limited, free radicals aren't neutralized and create super damage.
It's always my inclination to think that the body is designed to operate in as functional a way as its resources will allow. Insofar as we are "pathological detoxifiers" and don't somehow speed up Phase II, the body may be inclined to decrease Phase I (meaning that many toxins are not broken down at all and -- I believe -- not eliminated from the body except in unmetabolized form, e.g. through sweat).
However, insofar as Phase I is insufficient to counter all the toxins that are taken into the body, the dysfunctions mentioned above (intolerance for caffeine, perfume and environmental chemicals as well as liver disease) may manifest.
As you suggest, it sounds like more glutathione would be a really good thing for us. It would reduce the damage in Phase I as well as speed up Phase II.
Magnesium, often thought to be beneficial to ME/CFS patients, seems useful as well. This seems to have the potential for explaining where the huge amounts of magnesium that some of us take (e.g. in Myers Cocktails) go.
Interesting here is physical activity. This is a loaded topic that I hesitate to bring up, because it is clear that exercising too much is extremely bad for ME/CFS patients. But this suggests that insofar as ME/CFS patients can exercise in a way that doesn't cause the harm, they may benefit from it in terms of stimulating Phase II.
(I am interested in this because I do think that exercise feels like a good thing for me, if I do it when I'm in a clear environment. Sometimes I even feel like a little bit of inflammation while I'm doing it is worthwhile, in terms of the long term benefits. I wonder if this is responsible for the benefits that have been shown in some studies for Graded Exercise Therapy -- that if you can stay right at threshold of getting too much inflammation, this will increase Phase II and thus allow better detoxifying....thus increasing the ability to tolerate more exercise. Of course, this only would work with mild CFS. Once people get really sick, exercise of the sort that would substantially induce Phase II may be wholly destructive. But those people usually aren't included in GET studies.)
One thing I'm thinking here is that mold toxins must be a big inducer of Phase I. As we've discussed before, just because they can be efficiently removed by the immune system (in people with the "good genes") does not mean that they are not removed by the non-immune system too. So far, we've found in the literature evidence that they are removed, and no evidence that they are not removed, through what you have sometimes called the "main" detox system.
That would explain a lot.
For instance, do you remember when we discussed how when Erik and I have found that our chemical sensitivities go away when we're not being exposed to mold, but come back when we get more mold exposure? (Coffee and alcohol consumption becomes less tolerable with exposures too.)This sounds like what's happening is that the mold exposure is triggering a cascade by which Phase I outstrips Phase II, and then Phase I is decreased as compensation. With not enough Phase I then going on, the chemical and caffeine sensitivities occur.
I'm going to posit here that these shifts occur fast. Sometimes the chemical/caffeine sensitivities emerge within hours of the new mold/biotoxin exposure.
(BTW, I'm no longer getting chemical reactions no matter how much mold/biotoxin exposures I'm getting. Progress!)
I think this also explains why I get so sluggish (sometimes not having enough energy to lift a finger!) when I'm getting a lot of biotoxin exposure. With a lot of exposure, the mitochondria work hard on Phase II (as a prelude to the system punting by decreasing Phase I). Perhaps there's then no energy left for activity?
But it's odd, because insofar as I'm not getting biotoxin exposure, I have apparently unlimited energy. Maybe it's just that mitochondrial production is a super-inefficient way to speed up Phase II, but that use is so important that ALL the production is shunted that way even if it means that there's none left to do anything else.
This is getting better too. It takes a lot more biotoxin exposure to do me in. A bit oddly, the thing that now seems to absorb all the mitochondrial energy is killing pathogens (just with natural products -- Rizols Gamma or Lauricidin, both of which are really strong). I'm not sure why that is. If I understood what the problem is supposed to be with the mitochondria, maybe that would make sense.
Another observation that many of us have made: when we get to a really clear environment, our bodies start to release what seems to be an unmetabolized form of mold toxin (obviously through sweat and breath, sometimes through vomiting or saliva, and possibly through "normal" waste channels). This stuff is toxic in itself (causing skin breakouts or -- in an enclosed space -- headaches). What I am thinking here is that when it's not being broken down, it's sequestered until the body thinks that it's safe enough to release a bit of it.
Again, this leads me to believe that the body is "supposed" to be breaking down mycotoxins. Regardless of their HLA DR genotypes, I never have gotten the sense from anybody except ME/CFS patients that they excrete these types of toxins in unmetabolized form.
Going back to the P450 system.....I can see here why (per Cheney) that system would get shut down in ME/CFS.
What I don't understand here is why (per Cheney) methylation might be a bad thing to promote. It seems here like methylation is Phase II, and thus only a good thing. I must be missing something.
I intuitively feel about curcumin the way that this article seems to suggest that I should. If I'm getting a lot of biotoxin exposure, it feels like it may be somewhat useful for me. (That's the time when slowing down Phase I and speeding up Phase II might be a good thing.) The rest of the time (when Phase I's not being overly induced by mold toxins), it seems like not a good thing at all.
I also wonder about the issue of adding glutathione. Didn't you say you keep going back and forth on that? Keith Berndtson suggests that he's had really good success in giving people high amounts of IV glutathione, but I'm not sure that these are people with clear-cut ME/CFS. I've not found glutathione to be particularly helpful for me (IV Vitamin C and -- now that I can tolerate it -- IV ALA to support my liver seem better). I've not even heard that ME/CFS patients benefit that much from juicing. Why is that?
Does any of this seem right to you? What am I missing?
Thanks much for your help.
Best, Lisa
