Methylation, the no/onoo cycle, and porphyria

by: Denton Coleman

Denton Coleman, Satori Institute Founder

Bachelor of Science in Human Performance.

Certified Exercise Physiologist: ACSM.

Certified Strength and Conditioning Specialist: NSCA.

Certified Orthopedic Exercise Specialist: ACE.

Certified Holistic Fitness Specialist: AHF.

Certified Personal Trainer: ACSM.

www.satoriinstitute.info

Methylation

• Methylation = the donation/removal of a methyl group (an organic compound comprised of one carbon atom and three hydrogen atoms) to/from a substrate (such as a protein, nucleotide, enzyme, heavy metal, etc.), catalyzed by a methylating enzyme.

• Methyl donors can be viewed as “worker bees” which help to power a very large array of physiological processes concerned with tissue healing, generation of energy, genetic expression, neurological function, detoxification, immunity, and others.

Methylation

• The maintenance of a high capacity for methylation, and the sustainment of a proper and orderly operation of methylating action, allows for a correct and healthy organization of bodily functionality that follows one’s genetic blueprint.

• A lack of methyl donors (from depletion due to persistent stress in any form or due to inadequate nutrition) can easily lead to widespread dysfunction, breakdown, and disease manifestation.

DNA methylation

• With regard to methylation of human DNA, the methylation of nucleotides and the acetylation of histones (proteins which help to compact and package DNA into smaller units) allow for epigenetic modulation of gene activity in which specific genes may be either activated or repressed (basically “turned-on” or “turned-off”) [1].

DNA methylation

• The methylation of DNA also provides a means by which heritable information for genetic expression may be imprinted into the genome. This information can include the silencing of retroviral genes which have found their way into the human genome.

• Furthermore, I believe the silencing of retroviral genes via methylation could, potentially, thwart or protect against the activation of retroviral genes by pathogens such as Epstein-Barr virus [2]. This thwarting may aide in blocking the development of autoimmune conditions (like multiple sclerosis) that are linked to viral or retroviral proliferation [3].

DNA methylation and cancer

• Aberrant patterns of DNA methylation (too much, too little, or simply disorganized methylation) have been seen to decrease the stability of the human genome and facilitate the development of cancerous conditions [4].

• Oftentimes, this facilitation is due to an increase in the “turning-off” of genes associated with tumor suppression and an increase in the “turning-on” of genes associated with tumor formation [5].

Methylation

• Because of the toxicity of today’s world (food, water, air, and electromagnetic pollution), methylation capacity has become more important than ever. The protection against and healing of damaged nuclear and mitochondrial DNA (from toxins, inflammation, and radiation) requires an abundance of methyl donors.

• Persistent stress imposed upon the body in virtually any form can deplete methyl donors, as a hierarchy exists for the utilization of methyl groups according to immediate survival needs.

Methylation

• If one does not replenish their depleted methyl reserves, they can become locked into a prison of cellular inflammation termed the “no/onoo cycle” [6]. Once an individual becomes locked into this cycle, any of a myriad of symptoms and conditions may arise as a downward spiral of catabolism ensues and spreads throughout the body.

Methylation

• Proper nutrition from healthy, organic foods provides our cells with the resources they need (including methyl donors) to cleanse and heal themselves, with methylating actions serving as an intermediary in many of such processes.

• Methylation cofactors and synergists (such as folate, vitamin B12, zinc, magnesium, selenium, etc.) are needed to power methylating actions, as is ATP – which requires other nutrients and oxygen in order to be manufactured. Moreover, healthy, organic foods provide the antioxidants needed to protect mitochondria and mitochondrial DNA from damage (damage which would short-circuit ATP production).

• Therefore, proper nutrition is at the heart of maintaining a high methylation capacity and preventing the rampancy of the no/onoo cycle.

The no/onoo cycle

• The no/onoo cycle can be defined simplistically as a self-perpetuating cycle that yields increasing concentrations of nitric oxide (NO), peroxynitrite (ONOO), and other elements, leading to high levels of oxidative and inflammatory stress [7].

• The cycle can be initiated by the body’s experiencing of one or more of a variety of stressors (e.g. microbial infection, toxin exposure (including thimerosal from vaccinations), psychological/emotional stress, physical trauma, etc.) which triggers the release of nitric oxide and the signaling of the immune response [8].

The no/onoo cycle

• Nitric oxide is normally a necessary and beneficial molecule that serves many roles. However, if there is a lack of the antioxidants superoxide dismutase, catalase, and glutathione (due to a dietary lack or due to the body using these defenders elsewhere), then the no/onoo cycle can be kick-started and a large number of harmful free radicals can be created [9].

• If the body is continually bombarded with toxins, microbial infections/overgrowths, and/or hurtful radiation while there is insufficient nutrition onboard to combat these threats, then the no/onoo cycle can be repeatedly invoked.

The no/onoo cycle

• A flaming of the no/onoo cycle fire is often synonymous with mitochondrial dysfunction, as mitochondria and mitochondrial DNA are quite susceptible to the damaging free radicals and inflammation procured by the cycle.

• Because the body depends tremendously upon the energy and functionality offered by the mitochondria, mitochondrial ill-health can quickly grow to equal global ill-health. In essence, mitochondropathies (word of the day) can stand behind the development of just about any chronic disease.

The no/onoo cycle

• Note that a continuation of the no/onoo cycle’s destruction can promote the development of amyloidosis variations in which amyloids (fibrous protein aggregates) form and disrupt the health, communication, and functionality of nearby cells [10]. A few diseases in which amyloids may be featured include Alzheimer’s disease, type 2 diabetes, Parkinson’s disease, Huntington’s disease, atherosclerosis, and rheumatoid arthritis.

• Credit is due to Dr. Martin Pall for his elucidating of the no/onoo cycle’s nature and its stance in the etiology of disease (especially chronic fatigue syndrome/myalgic encephalomyelitis, fibromyalgia, and multiple chemical sensitivity).

Porphyria

• A condition strongly related to the issues we’ve discussed thus far is that of porphyria, the name given to one of eight disorders involving dysfunction in the body’s production of heme. Heme is an iron-containing compound that is used in the construction of multiple “hemoproteins” such as hemoglobin, myoglobin, cytochrome P450 enzymes, and catalase (remember catalase as one of the very important antioxidants from earlier).

• Porphyria (or a predisposition for its development) most often stems from an inherited gene mutation that results in a lack of one or more of the eight enzymes used in manufacturing heme.

Porphyria

• A deficiency in any of these enzymes creates two immediate problems. The first of which being a depletion of oxygen due to a dearth of hemoglobin and myoglobin (which require heme).

• The second problem is the accumulation of heme precursors, termed porphyrins, which can become very toxic in high concentrations.

• Note that four of the enzymes employed in making heme reside in the mitochondria, and the other three reside in the cytosol. So if the no/onoo cycle is running wild or there has been damage to the mitochondria, even less heme and even more porphyrins may be produced.

Porphyria

• Porphyric conditions may also be acquired from exposure to heavy metals (especially mercury), pesticides (which can ruin the body’s P450 enzymes), pharmaceuticals, microbial infection/overgrowth, or other toxins.

• For example, some pharmaceuticals and xenobiotics are capable of uncoupling the steps of oxidative phosphorylation and the electron transport chain, resulting in mitochondrial damage and a drop in ATP crafting.

• This should illumine the strong three-way relationship between methylation capacity, the no/onoo cycle, and porphyria.

Porphyria

• I want to particularly point out that autism, in some cases, may be functionally relabeled “chronic porphyria,” induced by thimerosal poisoning in an individual carrying a porphyric predisposition or mutation/defect. The fact of autism being largely a disorder of neurotoxicity is incontrovertible.

• Underlying porphyria can be a common thread in individuals who become chronically-ill after infection by or proliferation of a microbial species (like Candida albicans, Borrelia burgdorferi (responsible for Lyme disease), or Epstein-Barr) [11]. Just like methylation inadequacy and the no/onoo cycle, porphyria can invoke an ongoing, downward spiral of catabolism and breakdown.

Porphyria

• Because the cytochrome P450 enzymes play a role in the synthesis of various steroid hormones (such as estrogen, testosterone, and cortisol), the presence of porphyria can lead to a deficiency in one or more of these hormones. If the body is unable to make enough cortisol for example, its ability to put out the “fires” of inflammation will be diminished as cortisol is a potent anti-inflammatory.

• On the other hand, porphyria can exacerbate PMS, PCOS, endometriosis, or other conditions associated with estrogen dominance as the P450 enzymes are needed to inactivate the estrogens [12].

Porphyria

• It’s worth mentioning that multiple antidepressants can conjure or activate strong porphyric attacks, so those with porphyria (or suspected porphyria) should be very careful with the use of such medications [13].

• If you’re interested in a little more information regarding antidepressants, I’ve written a short article on their potential dangers that can be accessed here: http://www.satoriinstitute.info/...

Porphyria

• Lastly, the resolution or amelioration of porphyria will require an individualized program, and a highly knowledgeable and competent Naturopathic physician or Functional Medicine practitioner should be able to help you.

• Speaking generally, such a program would likely involve a thorough detoxification protocol, a plan for restoring the microbiome, and the adoption of a highly nutritious diet tailored for your current needs.

• In diagnosing porphyria, porphyrins can be screened for through blood, urine, or stool samples, but I feel genetic testing remains the gold standard.

Questions?

References

1. Feng, J., & Fan, G. (2009). The role of DNA methylation in the central nervous system and neuropsychiatric disorders. International review of neurobiology, 89, 67-84.

2. Sutkowski, N., Conrad, B., Thorley-Lawson, D. A., & Huber, B. T. (2001). Epstein-Barr virus transactivates the human endogenous retrovirus HERV-K18 that encodes a superantigen. Immunity, 15 (4), 579-589.

3. Haahr, S., & Munch, M. (2000). The association between multiple sclerosis and infection with Epstein-Barr virus and retrovirus. Journal of neurovirology, 6 (2), S76-S79.

4. Chen, R. Z., Pettersson, U., Beard, C., Jackson-Grusby, L., & Jaenisch, R. (1998). DNA hypomethylation leads to elevated mutation rates. Nature, 395 (6697), 89-93.

5. Gonzalo, S. (2010). Epigenetic alterations in aging. Journal of Applied Physiology, 109 (2), 586-597.

References

6. Tips, J. (2011). Methylation: The molecule that unlocks the body’s healing response (p. 5). Austin, Texas: Apple-A-Day Press.

7. Pall, M. L. (2013). The NO/ONOO-cycle as the central cause of heart failure. International journal of molecular sciences, 14 (11), 22274-22330.

8. Pall, M. L. (2006). The NO/ONOO–cycle as the cause of fibromyalgia and related illnesses: etiology, explanation and effective therapy. New research in fibromyalgia, 2, 39-59.

9. Tips, J. (2011). Mitochondrial Dysfunction and the NO/ONOO Cycle: Featuring the paradigms of medicine (p. 3). Austin, TX: Apple-A-Day Press.

10. Kadowaki, H., Nishitoh, H., Urano, F., Sadamitsu, C., Matsuzawa, A., Takeda, K., ... & Ichijo, H. (2005). Amyloid β induces neuronal cell death through ROS-mediated ASK1 activation. Cell Death & Differentiation, 12 (1), 19-24.

References

11. Rochlitz, S. (2010). Porphyria: A cause of chronic illnesses. Nexus magazine, 18 (1), 31-36, 78.

12. Tsuchiya, Y., Nakajima, M., & Yokoi, T. (2005). Cytochrome P450-mediated metabolism of estrogens and its regulation in human. Cancer letters, 227 (2), 115-124.

13. Lambrecht, R. W., Gildemeister, O. S., Pepe, J. A., Tortorelli, K. D., Williams, A., & Bonkovsky, H. L. (1999). Effects of antidepressants and benzodiazepine-type anxiolytic agents on hepatic porphyrin accumulation in primary cultures of chick embryo liver cells. Journal of Pharmacology and Experimental Therapeutics, 291 (3), 1150-1155.