Uric acid

[Kimsie]

I was looking at a study about the ability of methylfolate to scavenge peroxynitrite and I noticed that they used uric acid as the peroxynitrite scavenger that they compared with the folate. So I have been doing some studying long these lines and I have come up with some interesting things.

Some studies have found that uric acid levels are low in certain illnesses that are associated with mitochondrial dysfunction, which I believe are all caused by the same underlying vicious cycle that causes ME/CFS, such as MS and Alzheimer's. The symptoms of psychosis in schizophrenia were found to correlate inversely with uric serum uric acid levels. Some of the mitochondrial illnesses don't have a lower level of uric acid, and some are higher.

There have also been some studies that have found a lower level of Alzheimer's in people with gout, and another study that didn't find that to be the case.

I wonder if the body decreases the excretion of uric acid in response to high levels of peroxynitrite in order to use it to detoxify it? Maybe the body only excretes the uric acid if it has already been used to scavenge peroxynitrite and holds on to the activated form. Only the active form can be used as an antioxidant and acorbate is what reactivates it, and glutathione reactivates C and NADPH reactivates glutathione, and so maybe a lot of it gets excreted in some people who can't reactivate the uric acid, but other people keep holding on to it even if it isn't reactivated, and those are the people who have fibro, which is associated with high serum levels.

Another thing that sprang into my mind regarding this is that perhaps this is why urine therapy can help people - if they are low in uric acid. But I would think that it would only help much if they are excreting a lot of the active form.

I can't help wondering if taking uric acid could be a help in these illnesses. It would be a lot nicer if you could take it as a supplement in a pill, but I don't know if it gets degraded and I can't find any information about anyone using it.

Just some things to think about.
Kim

 

[Ema]

Inosine raises uric acid levels.

 

[Kimsie]

Yes, but I just realized that uric acid is formed by xanthine oxidase, and according to my hypothesis of how these illnesses are caused, the molybdenum cofactor, which is required by xanthine oxidase, is affected which would lower synthesis of uric acid.

So there must be a problem converting any purines, including inosine, to uric acid.

 

[Ema]

I think it could be different for everyone.

A few months of inosine brought my uric acid levels up into range nicely. So obviously that part of the purine pathway is working and my malfunction is higher up. My theory is adenosine deaminase deficiency.

 

[alex3619]

I have extremely high uric acid levels. At one point I was (incorrectly) diagnosed with gout.

 

[Kimsie]

Yes, as I am reading it seems that the levels are either high or low in a lot of affected people, with one or the other predominating in several of the illnesses, but some illnesses going either way, and sometimes the CSF levels are contrary to the serum levels. Whether the levels are high or low probably depends on genetics, but raising the levels in people who are low might be a good therapy, along with all the other things. I don't think it would do a lot by itself, because you need the C, GSH and NADPH to keep it activated.

Alex, do you have any symptoms of fibro? Just wondering because the high levels might be associated with it.

Yes on the inosine, I was thinking about it, and even if xanthine oxidase is inhibited taking inosine will raise the levels. Taking the ingredients for purine synthesis can help, too, but inosine would be better.

 

[Kimsie]

I think it could be different for everyone.

A few months of inosine brought my uric acid levels up into range nicely. So obviously that part of the purine pathway is working and my malfunction is higher up. My theory is adenosine deaminase deficiency.

That's an interesting thought. My son with schizophrenia is high in adenosine.

 

[adreno]

@Kimsie, I believe many of the issues you are finding could be related to gut dysbiosis. Prebiotics, such as resistant starch, can increase uric acid. See this quote for example:

So let's say we increased your purine metabolism, or at least the activity of xanthine oxidases which generates uric acid. One absolute consequence would be the increased production of superoxide and peroxynitrite. An increase in this part of the metabolism likely signifies that there is an increase in the ability to suppress superoxide radicals and peroxynitrite simply because ONOO levels will inhibit this reaction. Put another way, as peroxynitrite levels rise this down-regulates xanthine oxidase activity and all the byproducts of this reaction, including uric acid, are suppressed. This serves to reduce the demands on the entire antioxidant network and the dehydrogenase enzymes, in particular. The increased activity of XO would seemingly suggest that the prebiotics have reduced ONOO levels.

The mechanism by which glyconutrients or resistant carbohydrates could result in an increase in uric acid likely involves the provision of SCFA's, particularly butyrate, where it is needed. Increases in butyrate would seemingly have the ability to influence every single consequences of enhanced purine metabolism that comes to mind. In fact, I think it perfectly fits this equation. I think it is also notable that while butyrate is taken up by the colonocytes, it is also principally utilized in the liver. It is certainly not coincidental that in humans, xanthine oxidase, which creates uric acid, is chiefly and almost exclusively expressed in the liver and intestinal tract.

 

[Kimsie]

@Kimsie, I believe many of the issues you are finding could be related to gut dysbiosis. Prebiotics, such as resistant starch, can increase uric acid. See this quote for example:

Well, they could be related to gut dysbiosis, and for over a year I was following that line of thinking with my son who has alternating fatigue and depression but that was a dead end.

My son who has schizophrenia does have gut dysbiosis (from having so many antibiotics after a ruptured appendix followed by an abscess in his abdomen when he was 13), and I think that probably contributed to his getting sick, but he had the dysbiosis for 3 years before he got the mono that started his schizophrenia symptoms. The problem is that we can't deal with the dysbiosis because he really isn't going to cooperate with dietary measures.

I actually am pretty sure now that the schizophrenia and the depression are both caused by using the folate cycle for ATP synthesis. I have very strong reasons for believing that this is the case. The tendency to get these symptoms and probably to use the folate cycle so heavily for ATP when the ETC is inhibited must be genetic. I think most of the people here at PR probably have a strong tendency to use the glycolysis pathway for ATP more than the folate pathway, but they might use both pathways to some extent, especially if they take much folate.

 

[adreno]

I think most of the people here at PR probably have a strong tendency to use the glycolysis pathway for ATP more than the folate pathway, but they might use both pathways to some extent, especially if they take much folate.

On tests I have seen high pyruvate and high lactate in my case. So I guess glycolysis is ok for me, but pyruvate is not been sufficiently metabolized to acetyl-coenzyme A. As I understand, this is carried out by pyruvate dehydrogenase, which uses B1, B2 and lipoic acid as co-factors. So perhaps this is what I need rather than more B3/NAD. If the krebs cycle isn't running, I can't reduce NAD+ to NADH, right?

 

[Kimsie]

Well, according to my hypothesis, which may or may not be correct, your NAD/NADH ratio is most likely low, because the electron transport chain is inhibited, so if you make more NAD, that will raise the NAD/NADH ratio and push the ETC. The Pyruvate dehydrogenase complex is inhibited when this ratio is low. Raising the NAD/NADH ratio by increasing NAD will help this enzyme work better, but there might be something else that inhibits it, too, however I'm not sure about that part.

I think the main reason why you have a lot of pyruvate and lactate is simply because your electron transport chain is inhibited and that slows the TCA cycle so it can't use as much pyruvate, but the glycolysis pathway keeps going anyway to make ATP, because the TCA cycle isn't making enough, and you must not be using the folate pathway much. Don't worry about that, you don't want to use the folate pathway for ATP because that brings its own set of problems. Have you ever tested low in B6? I think if you use folate for ATP it can lower your B6.

Taking more lipoic acid can push the TCA cycle and the ETC, because the pyruvate dehydrogenase complex and alpha keto-glutarate dehydrogenase both use lipoic acid but in our experience that only works for a few hours. I think that it only helps for a few hours is because it just pushes the NAD/NADH ratio a little lower and then the TCA cycle becomes more inhibited. The pyruvate dehydrogenase complex and alpha keto-glutarate dehydrogenase both use lipoic acid.

 

[adreno]

Well, according to my hypothesis, which may or may not be correct, your NAD/NADH ratio is most likely low, because the electron transport chain is inhibited, so if you make more NAD, that will raise the NAD/NADH ratio and push the ETC.

Is there any way to test your hypothesis and establish if the ETC is inhibited?

 

[Sidereal]

Taking more lipoic acid can push the TCA cycle and the ETC, because the pyruvate dehydrogenase complex and alpha keto-glutarate dehydrogenase both use lipoic acid but in our experience that only works for a few hours. I think that it only helps for a few hours is because it just pushes the NAD/NADH ratio a little lower and then the TCA cycle becomes more inhibited. The pyruvate dehydrogenase complex and alpha keto-glutarate dehydrogenase both use lipoic acid.

In that case it may be worth taking ALA around the clock as Dr Cutler recommends in his mercury chelation protocol - small dose every three hours, including nighttime dosing. It is possible that some people who have benefitted from this approach actually benefitted from ALA's effect on the PDH complex as opposed to its mercury chelating properties.

 

[Sidereal]

Quote from another thread relevant to the discussion:

I think heavy metal toxicity is in all probability a secondary consequence of dysbiosis, not the other way around. It wasn't until I foolishly integrated the 20 gram carb diet to control my hypoglycemia that I really became ill, and thus decimated my microbiome. I chelated 700 days to great improvement; however, it eventually became very clear that the effects mediated by Lipoic Acid were eventually largely unrelated to its ability to chelate metals. (Although HM toxicity is a very real problem and I don't want to discount the significance of this, I was plainly mercury toxic)

In my opinion, FDC ALA is the most effective method of chelating mercury. Its effects, however, are generally viewed as being carried out by the chelating properties of lipoic acid. In all likelihood, for many this is not at all what is happening. I think, many of the effects are actually created by its abilities to much more broadly influence detoxification/redox balance/heme metabolism, etc. It has a potent ability to influence dehydrogenation and may be the most effective activator of nrf2 known. It is a great compound, but it wore me out over time as my cysteine levels normalized and I started to understand the bigger picture.

 

[Kimsie]

Is there any way to test your hypothesis and establish if the ETC is inhibited?

Sarah Myhill has a test that specifically does that. Here is an example from her test on an actual person with CFS:

2. Oxidative phosphorylation – Kreb’s Citric Acid Cycle and ADP to ATP conversion

This is going very slow at 38.4% (normal range >60%). In order to assess the efficiency with which ADP is converted to ATP, an inhibitor is added and then removed to see how quickly ATP is reformed. Having added the inhibitor one expects levels of ATP and magnesium to drop below 0.3 – if this does not happen this suggests there is blocking of the active sites. The acceptable percentage is up to 14% and (this person's) result is 47.1% (up to 14%). This suggests that there is significant blockage of the active sites (i.e. complexes I,II,III,IV and V on inner mitochondrial membranes). (I made that part bold, she is referring to the ETC complexes.)

Actually, I just took another look at this test, and it probably would not show the use of the folate pathway for ATP, only the glycolysis pathway. This is because the test uses something that completely blocks Complex III, and measures how much ATP is still being produced. Blocking complex III will stop 2 of the main forms of NADPH synthesis - NNT and the NADP dependent isocitrate dehydrogenase enzyme, and the folate ATP pathway depends mainly on NADPH availability.

So I have to conclude that this test will show ETC inhibition only when the glycolysis pathway is used as an alternative ATP production pathway.

 

[Hanna]

If it interests you, Kimsie, there are a few people here on PR that have done the dr Myhill's test. I did it in 2010.
I will post the result tomorrow if you wish, but from memory, the picture was somewhat different : though I got a 30% general score for mito function, there was no blockage of active sites. (nutrient pb, translocator protein??? etc)

 

[Kimsie]

If it interests you, Kimsie, there are a few people here on PR that have done the dr Myhill's test. I did it in 2010.
I will post the result tomorrow if you wish, but from memory, the picture was somewhat different : though I got a 30% general score for mito function, there was no blockage of active sites. (nutrient pb, translocator protein??? etc)

I would love seeing people's test results if they would like to share them. Include a note about how affected you were at the time of the test. I'm particularly interested in the part I showed in the post earlier today.

 

[aaron_c]

Very interesting thread, and well done on the research @Kimsie.

EDIT: The rest of the post has been deleted because I confused urea and uric acid...so it really isn't worth reading.

 

[Kimsie]

Very interesting thread, and well done on the research @Kimsie.

Yall may know this, but here is a link to a company doing a breath test for H.Pylori where you take a urea supplement, and then see how much of the urea is broken down into carbon dioxide and ammonia.

This makes me wonder if taking something to increase urea might risk feeding H.Pylori. It also makes me wonder if the presence or absence of an H.Pylori infection might be one factor in the variation of uric acid levels some diseases. Still, I would guess that in the short term if H.Pylori is a problem, then taking, for example, inosine plus molybdenum in order to produce urea, would cause "ammonia" type symptoms.

We have noted in our family that molybdenum helps symptoms temporarily. I thought it was because it helps sulfite oxidase, but it might be because it helps make uric acid.

That's interesting about the test. We have some reason to think that our son with schizophrenia has pylori.

 

[aaron_c]

@Kimsie See my edit above. I confused urea and uric acid. Sorry for the confusion!