Mitochondrial damage and acetaminophen (paracetamol in the UK)

[skylark99]

This post in the Morgellons Treatment section, as this is where Frito posts her methylation thread, and this, by way of mitochondrial function/disease, is related to methylation.

This thread is not intended to be a hypothesis or a theory. it is my comments on something that has been niggling at the periphery of my thoughts for some time now, and in doing some reading have come across some studies that suggest that I should do further reading. I have been curious to find a reason or a mechanism for calcium being precipitated through the skin in Morgellons (as Mark Darrah has demonstrated with Raman graph analysis of white particles from some patients) -in the absence of kidney stone formation or long-term dialysis, as usually accompanies this odd symptom. In the process of finding that mechanism, I have been looking at what events or exposures that may have an impact on mitochondrial illness or dysfunction. What I discuss here regards acetaminophen and mitochondrial damage came as a complete surprise to me.... a big "hmm".
There is a growing base of evidence that indicates the merit of a closer look.

I have observed that many of the symptoms of exhaustion, malise, joint, muscle, and bone pain of Morgellons are strikingly similar to that of Chronic Fatigue Syndrome or Myalgic encephalitis. I have also observed that some people with Morgellons have been diagnosed with CFS/ME. (Some with Morgellons have also been diagnosed with other co-infections such as Lyme Borreliosis etc, but I am not addressing those infections here, as I do not have good understanding of the link between those infections and mitochondrial illness.)

I have read much new literature and studies concerning defects in mitochondrial function in patients with CFS/ME. There is substantial scientific data supporting the theory that mitochondrial function is indeed impaired or damaged in those with CFS/ME.

At the present time it is unknown if the same impairments in mitochondrial function seen in patients with CFS/ME are also seen in patients with symptoms of Morgellons. However, in addition to the physical symptoms listed above, the labs results of patients with both CFS and Morgellons are strikingly similar as well, especially elevated inflammatory markers (cytokines) and low CD 56 and 57 (T-killer cells) counts. Too, our own Frito has postulated that there is a biochemical basis for Morgellons symptoms, including but not limited to, disruptions or faults in the methylation portion of the Krebbs cycle, impaired nutrient assimilation and blocked cellular detoxification pathways. Having read her work, I have to agree with her hypothesis.

Damage to mitochondrial function has been attributed to exposure to toxins both environmental and endogenous (within the body), genetic defects, and long-term emotional, physical, and nutritional stress, to list a few.

I find the implication that environmental toxins cause damage to the cell's mitochindria interesting. One of the commonalities of people with symptoms of Morgellons is exposure to pesticides and chemicals; the information collected in Franky's poll indicates that the vast majority of those with these symptoms have been exposed to topical insecticides as well as insecticides used in residential and agricultural settings. But what of those that have not? What other exposures -on a large scale-- might people have encountered that causes impaired function of mitochondria or damage to it? What are some of the symptoms that all of these patients have in common, and how might the symptomatic treatment of one such commonality have an impact on mitochondrial function?

I began looking at one single commonality seen in a vast number of patients with symptoms of Morgellons and CFS/ME -- pain.

How is pain medicated in western countries where allopathic medicine is the norm for the vast majority of patients?

With the understanding of Rhys syndrome in 1963 by R. D. K. Reye of Australia, and, a few months later G. M. Johnson in the United States, there was a move away from the use of aspirin to treat infection-associated fever and inflammation. It was later revealed that many patients that developed Reye syndrome were noted to have an underlying inborn error of metabolism (IEM).

(as an aside) It is an interesting observation that IEM's that may mimic Reye syndrome include fatty-acid oxidation defects, amino and organic acidopathies, urea-cycle defects, and disorders of carbohydrate metabolism. Too, other etiologies that may mimic Reye syndrome include viral infections, neuromuscular diseases, adverse drug reactions, and toxic exposures to chemicals and plants that cause hepatocellular damage and encephalopathy.

At that time (in the 1960's) the use of acetaminophen (paracetamol) for fevers in children became more common. I was one such child who was given acetaminophen for repeat bouts of tonsillitis and strep throat (nearly monthly); it is experimental the doctors told my parents, but being used in many military hospitals to good effect. It worked surprisingly well and because aspirin upset my stomach it became a medicine cabinet standard in our home.

Today, acetaminophen (in the US) or paracetamol, as it is called in the UK, is probably the most commonly used and prescribed non-steroidal inflammation reducer and fever reducer. Historically, it has been thought to be safe when taken within recommended parameters, but it has not been recognized until fairly recently, that it is toxic to the liver when taken with alcohol, even at recommended doses. I have wondered with some concern why patient instructions accompanying the product do not give more severe warnings about this, and have noted with great concern that no warning about using it to relieve alcohol-associated hangovers are given, considering that blood alcohol levels are still quite high 'the morning after'.

For decades throughout my life, I used a well-known brand of acetaminophen for headaches, fevers, flu, and pain in general -until I learned about homeopathy a couple of decades ago. But later, I had a severe permanent back injury and was advised to take acetaminophen/paracetamol in large doses, this time with codeine. I was seeing a homeopath and getting Bowens Technique all of which helped... but the damage to my vertebrae meant that they were pressing on my spinal cord and the pain it caused was incapacitating. Within a short amount of time the acetaminophen with codeine did not work very well and gave me headaches and I switched to plain acetaminophen. That, too, ceased to relieve pain after a short while, and I felt ill when taking it. So I stopped. But this is relevant to my experience with the onset of my Morgellons symptoms, because within a few weeks of no longer taking acetaminophen, the Morgellons symptoms began in earnest.

In retrospect, some of my symptoms of Morgellons began while I was taking large amounts of acetaminophen: itchy scalp, difficulty sleeping, feeling exhausted, intermittent stinging sensations on my skin, blood in the stools, hair turning wiry, brittle and falling out. But within weeks of stopping the use of acetaminophen my Morgellon symptoms were dramatic and distressing, especially the crawling sensations and the white and black specks in and on my skin and in my environment.

I am not making an assumption that taking acetaminophen caused my Morgellons symptoms. No one knows what causes Morgellons. But I am highly suspicious that taking bucket loads of this seemingly-innocent pain and fever reliever has contributed to my being ill, and when I couple my current improvement from using the supplementation protocol that is recommended for CFS, and the recent research that supports a link between CFS/ME and mitochndrial illness, my suspicion is deepened that use of this over-the-counter medicine has damaged my mitochondria -especialy in light of the articles below.

I have also been puzzling over why CFS patients hyperventilate or why I, in reverse, tend to hold my breath for no apparent reason. As I read this paper, I began to see some mechanisms of mitochondrial illness that may have an association with this odd symptom(s).

Burcham and Harman in the paper cited below, note that toxic changes have been reported to occur during exposure to large doses of acetaminophen, including calcium dyshomeostasis, oxidative stress, lipid peroxidation, and protein thiol oxidation --problems that have been mentioned by several members of this forum, Frito among them.
The mention of calcium dyshomeostasis associated with acetaminophen toxicity has my attention because it has been suggested that my spinal problems are due to degenerative bone disease.

Elsewhere in this first paper the authors demonstrate a reduction in mitochondria glutathione in acetaminophen hepatotoxicity, a findiing that the other papers mentioned below reiterate. (Low glut levels have been demonstrated in both CFS and Morgellons patients by other research).

This thread is not an attempt to implicate the use of acetaminophen as causation of Morgellons. However, the fact that mitochondrial illness has been seen in studies of mice with liver toxicity associated with toxic doses of acetaminophen, and mitochondrial illness is now understood to be implicated in CFS/ME, and since many labs results of CFS/ME and Morgellons patients are similar, the question of whether acetaminophen had anything to do with my own onset of Morgellons symptoms is one that occurs to me.

Because this is extremely long, the references to which I am referring follow separately.

[skylark99]

http://www.jbc.org/content/266/8/5049.full.pdf

(emphasis mine)

THE JOURNAL OF BIOLOGICAL CHEMISTRY
Copyright 1991 by The American Society for Biochemistry and Molecular Biology, Inc.
Vol. 266, No. 8, Issue of March 15, pp. 5049-5054, 1991

Philip C. Burcham and Andrew W. Harman
From the Department of Pharmacology, Queen Elizabeth II Medical Centre, The University of Western Australia, Nedlands 6009, Western Australia

Acetaminophen Toxicity Results in Site-specific Mitochondrial Damage in Isolated Mouse Hepatocytes

(from this paper):
A number of toxic changes have been reported to occur during acetaminophen hepatotoxicity, including calcium dyshomeostasis (4, oxidative stress and lipid peroxidation (49), and also protein thiol oxidation (50). It may be that one or more of these toxic mechanisms contributes to the damage to respiratory complex I during acetaminophen hepatotoxicity in addition to direct attack by the toxic metabolite.

Discussion

The contention that acetaminophen toxicity results in inhibition of electron transport by site-specific damage to the mitochondria was supported by experiments that examined the effect of NAPQI on respiration in isolated mitochondria. While addition of NAPQI in a bolus dose may not completely model its sustained generation by cytochrome P-450 in the cell, the characteristics of mitochondrial inhibition produced are qualitatively similar. Previous exposure of isolated mitochondria to NAPQI resulted in inhibition of respiration at energy-coupling sites 1 and 2 but had no effect on respiration stimulated at site 3. This confirms recent reports of an inhibitory effect of NAPQI on respiration supported at complexes I and I1 in hepatic mitochondria from rats (9) and mice (10).

We observed a similar pattern of site-specific respiratory inhibition in intact hepatocytes after exposure to acetaminophen. Hence, the lesions produced by acetaminophen in hepatocytes were qualitatively the same as those produced by NAPQI in isolated mitochondria. Furthermore, exposure of submitochondrial particles to NAPQI inhibited NADH dehydrogenase and succinate dehydrogenase activities, associated with respiratory complexes I and 11, respectively, while having no effect on the activities of either ubiquinol-cytochrome c oxidoreductase (complex 111) or cytochrome oxidase (complex IV). Again, this is consistent with the effects observed in hepatocytes. Energy-coupling site 1 is associated with respiratory complex I (NADH dehydrogenase) (42).

Hence, the decrease in NADH dehydrogenase activity in submitochondrial particles exposed to NAPQI is consistent with the reduced respiratory rates with NADH-linked substrates observed in acetaminophen-poisoned hepatocytes and in mitochondria exposed to NAPQI. Site 2 is associated with respiratory complex 111, but in these experiments it was assayed using succinate as the electron donor. This substrate donates reducing equivalents to complex I11 via the nonproton- translocating complex I1 (43). The finding that succinate-supported respiration was decreased both in hepatocytesexposed to acetaminophen and in mitochondria exposed to NAPQI could thus be due to damage at complex I1 or 111. However, the fact that NAPQI did not affect ubiquinolcytochrome c oxidoreductase activity in submitochondrial particles indicates that NAPQI's effect was at complex 11.

The concentrations of NAPQI that inhibited succinate dehydrogenase were comparable with those that interfere with respiration in intact mitochondria. Succinate dehydrogenase is known to contain a number of cysteine-rich sulfur clusters (44) and can be inhibited by a number of agents that modify sulfhydryl groups, such as aklylating agents, oxidizing agents, arsenicals, and metal ions (45). It seems feasible that NAPQI may directly interact with sulfhydryl groups on succinate dehydrogenase, causing the loss of activity. This proposal may be consistent with the finding that significant covalent binding of the reactive metabolite to mitochondrial proteins occurs during paracetamol hepatotoxicity in mice in vivo (46, 47). It may well be that such interactions between NAPQI and the mitochondria are of relevance to the toxic process. It was shown recently that the increased level of covalent binding to mitochondrial proteins was one of the main differences between the subcellular binding pattern produced by acetaminophen and that produced by its nontoxic regioisomer 3" -hydroxyacetanilide (3.

However, the finding that respiratory complex I1 (succinate dehydrogenase) was more sensitive to NAPQI than complex I (NADH dehydrogenase) in our in vitro system suggests that direct interactions between the toxic metabolite and respiratory chain may not solely account for the mitochondrial damage that occurs during acetaminophen hepatotoxicity in vivo. For example, it has been shown by others that the respiratory capacity of hepatic mitochondria from acetaminophen-poisoned mice is more or less equally impaired with both succinate and NADH-linked substrates (4).Thus ict ould (sic) be that events associated with the toxic process may contribute to the damage to the respiratory chain. A number of toxic changes have been reported to occur during acetaminophen hepatotoxicity, including calcium dyshomeostasis (4, oxidative stress and lipid peroxidation (49), and also proteinthiol oxidation (50). It may be that one or more of these toxic mechanisms contributes to the damage to respiratory complex I during acetaminophen hepatotoxicity in addition to direct attack by the toxic metabolite.

In order for NAPQI to damage the mitochondria it must be sufficiently long-lived to have access to the inner membrane. Since the mitochondria are believed to contain a discrete GSH pool in the hepatocyte (1, depletion of this GSH pool may result from its interaction with NAPQI. The results shown in Fig. 3 indicate that NAPQI generated by endoplasmic reticulum mixed function oxidases was capable of depleting mitochondrial GSH. The finding that a loss of mitochondrial glutathione preceded the loss of respiratory function is consistent with the protective role of glutathione in this organelle. It is possible that the mitochondrial pool of GSH may protect critical nucleophilic sites on respiratory chain proteins against toxic electrophilic metabolites such as NAPQI. On the other hand, mitochondrial injury has been associated with mitochondrial GSH depletion per se (51), and this may also be important in the etiology of acetaminophen toxicity.

In summary, acetaminophen toxicity resulted in an impairment of mitochondrial respiration in isolated mouse hepatocytes, which involved an inhibition of respiration supported at energy-coupling sites 1 and 2. The impairment of succinate supported respiration appeared to be due to an inhibition of succinate dehydrogenase, since this enzyme was very sensitive to NAPQI, acetaminophen's putative toxic metabolite. Since mitochondrial dysfunction occurred prior to irreversible cell injury, it is likely that interactions between NAPQI and these respiratory components contribute to the damaging effects of acetaminophen.

[skylark99]

http://psychrights.org/research/Dige...rialDamage.pdf

This is an excellent paper, not too complicated and discusses this problem in depth explaining the process of mitochondrial function and how damage occurs. It also addresses a huge number of commonly prescribed medications that the authors state have been documented to induce mitochondrial damage. Including Tetracycline!
That one of the authors is a board-certified psychiatrist, is a step in a good direction !


DOI 10.1002/mnfr.200700075
Mol. Nutr. Food Res. 2008, 52, 780 – 788
Molecular Nutrition & Food Research - Wiley Online Library

Copyright 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Received: February 28, 2007; revised: November 16, 2007; accepted: November 22, 2007

Review
Medication-induced mitochondrial damage and disease
John Neustadt and Steve R. Pieczenik
Montana Integrative Medicine, Bozeman, MT, USA

(from this paper)

Since the first mitochondrial dysfunction was described in the 1960s, the medicine has advanced in its understanding the role mitochondria play in health and disease. Damage to mitochondria is now understood to play a role in the pathogenesis of a wide range of seemingly unrelated disorders such as schizophrenia, bipolar disease, dementia, Alzheimer's disease, epilepsy, migraine headaches, strokes, neuropathic pain, Parkinson's disease, ataxia, transient ischemic attack, cardiomyopathy, coronary artery disease, chronic fatigue syndrome, fibromyalgia, retinitis pigmentosa, diabetes, hepatitis C, and primary biliary cirrhosis. Medications have now emerged as a major cause of mitochondrial damage, which may explain many adverse effects. All classes of psychotropic drugs have been documented to damage mitochondria, as have stain medications, analgesics such as acetaminophen, and many others. While targeted nutrient therapies using antioxidants or their prescursors (e.g., N-acetylcysteine) hold promise for improving mitochondrial function, there are large gaps in our knowledge.

The most rational approach is to understand the mechanisms underlying mitochondrial damage for specific medications and attempt to counteract their deleterious effects with nutritional therapies. This article reviews our basic understanding of how mitochondria function and how medications damage mitochondria to create their occasionally fatal adverse effects.

* * *

Medscape: Medscape Access

(emphasis mine)

Medscape Reference
Toxicity, Acetaminophen
Susan E. Farrell MD, Chief Editor: Asim Tarabar, MD
Updated: Nov 19, 2010

Pathophysiology

In acute overdose or when the maximum daily dose is exceeded over a prolonged period, metabolism by conjugation becomes saturated, and excess APAP is oxidatively metabolized by the CYP enzymes (CYP2E1, 1A2, 2A6, 3A4) to a reactive metabolite, N -acetyl-p-benzoquinone-imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and is renally excreted. Under conditions of excessive NAPQI formation, or reduction in glutathione stores by approximately 70%, NAPQI covalently binds to the cysteinyl sulfhydryl groups of cellular proteins, forming NAPQI-protein adducts.

An ensuing cascade of oxidative damage, mitochondrial dysfunction, and the subsequent inflammatory response propagate hepatocellular injury, death, and centrilobular (zone III) liver necrosis. Similar enzymatic reactions occur in extra-hepatic organs, such as the kidney, and can contribute to some degree of extra-hepatic organ dysfunction.

The antidote for acetaminophen poisoning is N -acetylcysteine (NAC)*. NAC is theorized to work through a number of protective mechanisms. NAC is a precursor of glutathione and as such, increases glutathione conjugation of NAPQI. NAC also enhances sulfate conjugation of unmetabolized APAP. NAC functions as an anti-inflammatory and antioxidant and has positive inotropic effects. NAC increases local nitric oxide concentrations and promotes microcirculatory blood flow, enhancing local oxygen delivery to peripheral tissues. The microvascular effects of NAC therapy are associated with a decrease in morbidity and mortality even when NAC is administered in the setting of established hepatotoxicity.


NB * NAC, N -acetylcysteine is a precursor to glutathione.

[MeaganM]

Skylark, this is great information. I am interested in your CFS protocol. If it's not too much trouble, could you PM it to me or send me a link.

Also, I am a little confused as to what mitochondrial damage has to do with calcium deposits in the skin. Maybe I missed something?

[fritolay66]

Today, acetaminophen (in the US) or paracetamol, as it is called in the UK, is probably the most commonly used and prescribed non-steroidal inflammation reducer and fever reducer. Historically, it has been thought to be safe when taken within recommended parameters, but it has not been recognized until fairly recently, that it is toxic to the liver when taken with alcohol, even at recommended doses.

Here's the thing......Its not only the consumption of alcohol that would be a contributing factor. It is the endogenous production from metabolic breakdown that would be what I am finding, is the main contributor of alcohol to the body and there for one of the main contributors to the ROS we all seem to experience. And then you add the consumption of alcohol on top of it, and you have a dangerous combination, in the morgellons patient, in which absolutely has trouble with detoxification.

I have also been puzzling over why CFS patients hyperventilate or why I, in reverse, tend to hold my breath for no apparent reason. As I read this paper, I began to see some mechanisms of mitochondrial illness that may have an association with this odd symptom(s).

Absolutely. And it also incorporates high CO2 levels being found.

Too, our own Frito has postulated that there is a biochemical basis for Morgellons symptoms, including but not limited to, disruptions or faults in the methylation portion of the Krebbs cycle, impaired nutrient assimilation and blocked cellular detoxification pathways. Having read her work, I have to agree with her hypothesis.

Not only the methylation portion of the Krebbs cycle. Take a good look at the BH4 cycle and its relation to NOS, SOD, and the Urea cycle. Those will blow your mind. Its the BH4 cycle in which the neurotransmitters come in and are absolutely affected in this disease. Same as CFS, and Lyme and Company. To deny the neurological aspect of this disease is a huge mistake. And it is here, in which they keep us confined to DOP, of which it is not.

The methylation cycles importance lies in the ability to silence what has been activated by lack of methylation. Without methylation capacity, one loses the ability of their DNA to silence sequences like they should be, so they become active, where they most certainly should not be. And this is the DNA damage and mutational culprit.

Good stuff.

Frito

[fritolay66]

Also, I am a little confused as to what mitochondrial damage has to do with calcium deposits in the skin. Maybe I missed something?

Mitochondrial damage results in and from abnormal amino acid metabolism. Abnormal amino acid metabolism can = calcium precip in the skin, with or without kidney precip. Do you ever wonder why so many of us cannot take amino acid complexes or heavy whey protein mixes, and must use branched chain amino acids instead, or specific amino's versus complexes? Some can, many cannot. The difference between the groups, is the genetic aspect of the metabolic pathways.

Frito

[fritolay66]

And for further note:

CFS protocols are individualized and not one protocol works for everyone. Although there are some basic recommendations, it would be extremely difficult for one person to give you a protocol, have you follow it, and have you react in the same way. And again, the reason why is the genetic aspect, and its contribution to the accumulation of illness.

Frito

[fritolay66]

To date: The research I have done would suggest one main culprit common in morgellons sufferers, and that is tetrahydrobiopterin. Methylation is downstream to that cycle.
hint...hint...

Frito

[skylark99]

Megan.... .

I began with Vit C and had amazing results.
Not everyone who has followed in my footsteps has had the same remarkable result, although some have, and others have come close.

(I will soon-ish update my 'white frass' thread about how it is going and what have recently added), but I have not long ago added a lot of other supplements to my daily ration of tablets, some have made me feel better, some have made me feel worse, and I still have yet to include another five or so that are commonly recommended for CFS.... still others are "not allowed" here in the UK.... it is all very expensive and requires much pill popping and organizing....... and really, the whole thing can get frustrating and annoying. Not to mention rapidly wallet thinning!

I MUST get a MFT -- mitchodrial function test done to find out what I need for my individual requirements. It is very expensive here and I might have to get in line as few md's order them and interpret the results.

The supplements used for CFS do vary from person to person, and yes some are standard, but it is a minefield of information and there are so many different versions that one has to wade through a lot of information.. And even as I have done, the "standard" CFS supplementation schedule is not exactly right for me. I will have to get tested and will do that as soon as I am able.
Google: how to fix mitochondrial illness, and you will be reading for a week.


Frito............
Thank you for those replies.
And for your hint hint. I am both tired and laughing. Maybe a good time to try and escape from some japanese room or island paradise..........

[fritolay66]

Here's the thing......Its not only the consumption of alcohol that would be a contributing factor. It is the endogenous production from metabolic breakdown that would be what I am finding, is the main contributor of alcohol to the body and there for one of the main contributors to the ROS we all seem to experience. And then you add the consumption of alcohol on top of it, and you have a dangerous combination, in the morgellons patient, in which absolutely has trouble with detoxification.

Do you remember the lessons we have learned from the work of Dr. Hulda Clark and the connection to parasites?

Her main premise of parasitic infestation is due to the collection of various alcohols in the body, and their presence allowing the parasites to take hold.

What I found interesting about later research and the endogenous alcohols resulting from abnormal metabolism, and it correlations to the lessons learned from Dr. Clark, that help to explain why so many of us test positive for various parasites. The abnormal metabolism being one contributor in addition to the connections she has found to the exogenous sources of various alcohols. Just an interesting aside.

Most of the various forms of alcohol referenced in her book, can also be found to be made endogenously by the body.

Mmmm.....the chinese room sounds peaceful and cool. I am tired of tropical. We are again in the crazy triple digits, and the "windchill" is something akin to an oven on broil......


Frito