Methylation

[fritolay66]

METHYLATION

Multiple factors absolutely influence an individuals susceptability to disease. Environmental toxins including mold exposures, exposure to infectious agents and the endotoxins they can create, as well as underlying genetic susceptibility to disease, or genotypes. There are varying genotypes by which expression or suppression occurs within the genetic make up of an individual and confers their susceptibility or resistance to differing diseases. (1)

The precise combination of components that interact to cause multifactorial diseases can be very different from individual to individual. There may be slight or enormous changes in the relative contributions of each of the factors to disease. I believe this is the explanation for the differences between those of us with Morgellons.

I also believe that many of us are suffering from toxicity or biotoxin issues. Varying but none the less, by looking at the MRF’s testing and the commonalities found in those published on it site, those tests reflect biotoxin disease and the abnormalities associated with it. See link here for the common abnormalities found in Morgellons patients.

Case Definition of Morgellons - Morgellons Research Foundation

Due to those common lab abnormalities found in their case studies, I also believe methylation may have a definitive role in our disease but I have yet to hear it talked about on Morgellons boards. I’d like to introduce it here today and the information I have found on it.

Methylation is not just one specific reaction as there are hundreds of “methylation” reactions in the body. Methylation is simply the addition or subtraction of a methyl group to a compound or element within the body and the systems within the body that depend on this reaction. A methyl group is one carbon connected to three hydrogen atoms and can be written as CH3. (1) You will find some sources cite re-methylation and that specific terminology refers to the addition of a methyl group to a substrate or element.

In general, when some compounds receive a methyl group, this starts a reaction, such as turning on a particular gene or activating an enzyme which is incredibly important in the body detoxification mechanisms. When the methyl group is "lost" or removed, the reaction stops, or a gene is turned off or the enzyme is deactivated. (3) This can be bad when we lose our ability to detoxify. I believe this is what some of us are experiencing, the loss or removal of methyl groups through our illness in the cytokine responses I have previously posted on. And if loss of methylation is occurring, this would have huge ramifications on our health, immunity, and genetic traits.

Follow the links I have provided. There are one or two on the techy side, the rest are what I call easy reading.

Enzymes & Methylation

Nutrigenomic testing and the methylation pathway | Townsend Letter for Doctors and Patients | Find Articles at BNET

Folic Acid | HOPES - A guide to the science of Huntington's disease

A Histone Methylation-Dependent DNA Methylation Pathway Is Uniquely Impaired by Deficiency in Arabidopsis S-Adenosylhomocysteine Hydrolase -- Mull et al. 174 (3): 1161 -- Genetics

http://www.ncbi.nlm.gov/pubmed/16729250

Alternative Treatments for Depression, Anxiety, and Stress From Dr. Podell

PWSDots

Folic acid - PWSDots

An Integrative Approach to the Prevention and Treatment of Postpartum Depression (PPD) and Postpartum Anxiety Disorder (PPA) (Print Ready)

Methylation - Wikipedia, the free encyclopedia

This has everything to do with gene expression, gene deletion, rNA, detoxification systems in the body, enzymes, amino acids, proteins, prions, MCS, and the many diseases they are finding these commonalties in. Fibromyalgia, CFS, MS, Alzheimers, Lyme, Depression disorders, etc. I feel this is most definately a contributor in our disease as well and very dependent on our own genetic codes.

Frito

Edited to include:

Rich Van K: Methylation and MSH

[Gator]

Thanks Frito,

I have been learning what I can about this topic for it is a basic cause of MCS/EI. I spoke with Cynthia at the Chemical Injury, Information Network CIIN this week and she said the reason we suffer from MCS/EI is not that our detoxification pathways are blocked, they have been destroyed by the chemical exposure, ack of production of the enzymes needed to detox chemicals and toxins in our world. One of the enzymes is p450.

The lead article in this months Toxic Times from CIIN is entitled "Chemical Hell On Earth".

I t speaks of the pharmaceutical, GMO foods and Personal care and other products.

I am very MS/EI. since I wrecked my truck and have been trying to get another vehiclew I am being exposed daily to the toxic clelaners that have been used in the two vehicles I bought.

I will read the articles as I can, I am very interested

gator

[janedoe]

Originally Posted by aliester

any thoughts on inhibiting p450 cyp 3a4? Could someone please clarify; should upright walking hominids seeks to inhibit 3a4 and cox-2, not cox -1 enzymes. If so, would this not suggest a diet with grapefruit and ginger? Please don't sling that ciap around about "what my pill bottle says"; cut the damn thing in half. They're shooting darts with blind folds on for the most part, and the conferences and perks are great too!

ok, shall i pretend to understand that? will anybody else pretend to understand that? lol...funny

[fritolay66]

"any thoughts on inhibiting p450 cyp 3a4? Could someone please clarify; should upright walking hominids seeks to inhibit 3a4 and cox-2, not cox -1 enzymes. If so, would this not suggest a diet with grapefruit and ginger? Please don't sling that ciap around about "what my pill bottle says"; cut the damn thing in half. They're shooting darts with blind folds on for the most part, and the conferences and perks are great too!"

Ali,

I don't necessarily understand your post either, but I am willing to try. Why do you want to block just the CYP3a4 pathway?

For those that do not understand the P450's, the p450's are enzyme pathways found all over the body but are commonly found in the liver in which is responsible for metabolizing the pharma and herbs we ingest.

As far as Cox-2, COX 2 is also an enzyme and a pathway in which have everything to do with inflammation and pain. COX 2 is currently what I am trying to supress with use of Tumeric. But Ali, I wouldn't want to inhibit the P450, CYP3a4 as it would have a very large affect on the detox or metabolism of many drugs, herbs, and the downstream effects of the enzymes being inhibited which would then inhibit other pathways by depleting those enzymes. So again, why the CYP3a4?

As far as slinging around crap, if you were talking to me, I don't sling crap. And if by "they" are shooting darts and the conferences and perks, you mean the doctors, then fine.

Frito

[fritolay66]

"Thanks Frito,

I have been learning what I can about this topic for it is a basic cause of MCS/EI. I spoke with Cynthia at the Chemical Injury, Information Network CIIN this week and she said the reason we suffer from MCS/EI is not that our detoxification pathways are blocked, they have been destroyed by the chemical exposure, ack of production of the enzymes needed to detox chemicals and toxins in our world. One of the enzymes is p450. "

Thank you Gator and your welcome.

I want to support your observation about the destruction aspect, but I do want to clarify. Its the receptors in which with continual exposure are destroyed or damaged so they cannot function appropriately, and there for the entire pathway is destroyed or compromised to such a state that it cannot function. Which is why the information here is so damn important, so as to facilitate the stopping of toxin exposure, the detoxification to minimize the damage, and a hopeful recovery, whether full or partial.

As far the P450, there are literally hundreds of those enzymes denoted with the CYP followed by numbers. Usually when a reference refers to the P450 system, they are simultaneously referring to the liver and all its metabolic pathways, but P450's can be found in all tissues.

Frito

[jonsi]

frito, Thank you for taking the time to post all of the info on Methylation.

I am reading and trying to absorb! I'm glad Gator found this thread.

Back to reading.

In the white light,
~jonsi

[fritolay66]

"I simply have some observations, and these observations have suggested to me that inhibition of specific cyp enzymes is beneficial..."

Those enzymes do not function alone but in a pathway, so by inhibition of one enzyme, you essentially inhibit a pathway to some degree. Inhibition or the depletion of one enzyme over another would be difficult as the one enzyme within the pathway can be sometimes substituted for by another enzyme within the same pathway or another pathway. A borrowing system if that makes it easier for others to understand, and a domino affect. Rob Peter to pay Paul and so Peter is now broke and Paul soon to be, and pretty soon all their friends, and then there is no one to rob to pay. So essentailly, other important enzymes are then depleted to ill effect.

"I'd suggest that by inhibiting 3a4 you are enabling nutrients to remain bioactive, as well as enabling one's own biodefenses to remain vigilant."

But at the same time, by inhibiting 3A4 especially in those that interact on the substrate level with 3A4, could also prove to be very toxic. Which is the basis for my original question.

With the P450's, you have a substrate, the inhibitors, and the inducers. Pharma or herbs, other chemicals including xenobiotics, yadi ya, are metabolized by CYP3A4 and are called CYP3A4 substrates. Substrates are compounds in which are acted upon by the enzyme or pathway, in this case we are referring to CYP3A4. Keep in mind that many drugs are metabolized by more than one CYP450 enzyme and its associated pathway, and CYP3A4 may represent only one pathway. Unfortunately, many CYP3A4 substrates have substantial toxicity, and some patients may develop severe toxicity when CYP3A4 inhibitors are taken concurrently.

"It seems to me if one was taking an herb/medication/food item, one would seek a dose that would be effective for a long duration. So, by stimulating/inducing the 3a4 pathway, it seems to me you'd be gobbling up the very chemicals/reactions you are trying enable. "

Yes, but I am not seeking to induce the 3A4 pathway and your observation is correct. It is my assumption that some of these pathways have been up-regulated and must be down-regulated and normalized. It is my assumption that the up-regulation has there for depleted other enzymes or pathways in the process. The Peter and Paul story and the domino effect. And there for depletion of other important enzymes or pathways resulting in a positive feedback loop and further downstream effects leading to further and more complicated disease.

"Look up the pill drugs on the market that induce the 3a4 pathway, then look at their side effects and associated diseases. "

I have.

"I'm suggesting that inhibition of the 3a4 pathway is of paramount importance in enabling one's body's healing process. "

I am most willing to look and learn further.

"Would inhibition of 3a4 disable or enable the therapeutic properties of turmeric?"

Not only would it be dose dependant, but also dependant on what other pathways have been up-regulated or inhibited, and there for depleted as I explained earlier.

Also by inhibiting COX 2 specifically you would be enabling the affected organs or body to produce more COX1, decrease inflammation and stop the cytokine cascades, and be able to normalize the CYP's?

"So, food directs gene expression, among other things....... ? Damn I want a pizza, I guess after an apple."

But how does food direct gene expression? For those whom do not know the answer, it is the nutrients within the food, in which are then either used as is in the body, or turned into something the body can use by reactions within many pathways in the body.

Make mine a pepperoni, thin crust with extra meat, and a few green peppers please.

And I love the info about apples and your references. I know about the power of apples and its capability to detox the body and supply needed nutrients. I have recommended for sometime to others about supplementing apple pectin fiber.

Ali, this stuff wasn't easy for me to learn, especially when I was so ill at one time. I do appreciate the dialoge, and would like to continue. I am always game to know more about this stuff.

Frito

[fritolay66]

"While it has long been known that inflammation and infection reduce expression of hepatic cytochrome P450 (CYP) genes involved in xenobiotic metabolism and that exposure to xenobiotic chemicals can impair immune function, the molecular mechanisms underlying both of these phenomena have remained largely unknown. Here we show that activation of the nuclear steroid and xenobiotic receptor (SXR) by commonly used drugs in humans inhibits the activity of NF-κB, a key regulator of inflammation and the immune response. NF-κB target genes are upregulated and small bowel inflammation is significantly increased in mice lacking the SXR ortholog pregnane X receptor (PXR), thereby demonstrating a direct link between SXR and drug-mediated antagonism of NF-κB. Interestingly, NF-κB activation reciprocally inhibits SXR and its target genes whereas inhibition of NF-κB enhances SXR activity. This SXR/PXR–NF-κB axis provides a molecular explanation for the suppression of hepatic CYP mRNAs by inflammatory stimuli as well as the immunosuppressant effects of xenobiotics and SXR-responsive drugs. This mechanistic relationship has clinical consequences for individuals undergoing therapeutic exposure to the wide variety of drugs that are also SXR agonists."

Journal of Clinical Investigation -- Mutual repression between steroid and xenobiotic receptor and NF-κB signaling pathways links xenobiotic metabolism and inflammation

So where as some CYP pathways have been upregulated in my assumption, perhaps we both should consider the CYP3A4 may have been down-regulated in all this.

I have also been of the assumption of too much NFkB and prostaglandins, and hence my selectivity for COX 2. And why I developed the assumption of NFkB is due to bacterial translocation. (This disease is absolutely centered around the gut) Activation of NFkB leads to increased IL-1,PG-E2 and also TNF alpha and CRP. And in genetic expression and induction of NFkB leads to the production of cytokines, adhesion molecules and the pro-inflammatory enzymes we have chatted previously about. And also within this particular activation cycle of inflammation, MMP 9 and Nitric Oxide also fit within this pathway profile.

These interactions all coincide with the lab parameters published by the MRF in their common lab abnormalites found within their own study of Morgellons patients and also coincide with my own labs or experiences as well as my own assumptions of biotoxin disease.

Frito

[Katinka]

Frito, great info, as always.

So what you're basically saying here is that our enzyme production is imbalanced which leads to a malfunctional metabolism and therefor decreased detoxification? and that specific drugs (depending on what kind they are) either inhibit or induce CYP3A4? which in the other hand interacts with another enzyme, glutathione?..among other functions, also an important enzyme for the gastrointestinal system?..supporting your research that Morgellons Disease 'originates' in the gut?

Do you think an overuse in antibiotics and other drugs or possibly intake also over water and food could have caused this reaction?

Kat

[fritolay66]

"So what you're basically saying here is that our enzyme production is imbalanced which leads to a malfunctional metabolism and therefor decreased detoxification?'

Yes but you must also remember previous conversations, it also leads to immune system disfunction.

I want to clarify that I also believe this is a response to an exposure, whether infectious or an environmental exposure. Response not necessarily causation. This can be a mitigating factor in the development of disease as well as a result of disease.

"and that specific drugs (depending on what kind they are) either inhibit or induce CYP3A4?"

Yes, but remember how many CYP's there actually are and can be said of them too. The CYP3A4 is one of the big guys.

which in the other hand interacts with another enzyme, glutathione?

Tink, I know you are focused on glutithione for sometime now. I have not specifically named "the other enzymes" nor did I make a reference to glutithione.

It has always been my understanding that one cannot directly supplement glutithione. You can support it by supplementing nutrients or enzymes at certain points in the pathways we have been talking about to either make glutithione directly or break down another different component to make glutithione but you cannot supplement it to any beneficial affect, by mouth.

And further about the enzymes in general and their pathways. What is so important about this particular subject is that disease can be interupted with nutrients combos and such. We, as a group and Lyme as a group support that general statement ( and look at all the cancer groups) and has been proven to some effect, over and over with the herbal protocols and nutritional protocols resulting in an improved condition of the sufferer.

But for improvement and my personal favorite, resolution, this must be accomplished at certain points, and the pathways all mentioned here have to do with discerning those points in which we can mitigate by supplemental and nutritional protocols.

"supporting your research that Morgellons Disease 'originates' in the gut?"

Tink, I am not looking for support per se for my research. I have no "research", I have assumptions, and I am willing to look for supportive information as well as unsupportive. I have found many to negate my assumptions and have addressed them at one time or another.

"Do you think an overuse in antibiotics and other drugs or possibly intake also over water and food could have caused this reaction?"

It would depend under what context you are asking this particular question. Is it what I think is the cause of Morgellons?

Would it have a contributory affect on disease? Absolutely in that it could certainly affect whether we are able to triumph or fail in fighting it.

You and I have two different agendas. You are seeking the cause of Morgellons be it a single entity or a group of entities directly responsible for its manifestation, where as I am chasing the effects of Morgellons.

As far as what I think about the gut. The intestines are the largest house of reactive cells of the immune system and is surrounded by lymphoid tissue in which then has access to the portal blood, the liver, and then the entire body. It is an assumption I can support over and over again with my findings concerning biotoxin exposure. I have found very little in the way to negate my assumption or observations as far as biotoxin disease goes.

Frito