Peroxynitrite.....one of the 'bad guys'
Peroxynitrite is considered to be the angry gorilla in the room! This gorilla doesn't look so angry right now. But let's find out what that statement means and why that's important in relationship to our genetic variants.
‘Peroxynitrite’ is a short lived oxidant species that is a potent inducer of cell death (or, cell danger response; CDR.) Along with superoxide, this is formed when L-arginine is not turned into nitric oxide. Recent evidence indicated that most of the cytotoxicity attributed to NO is rather due to peroxynitrite (produced from the diffusion controlled reaction between NO and superoxide anion.) Thus, when L-Arginine is not turned into nitric oxide it turns into peroxynitrite and causes inflammation! (Think, erectile dysfunction.)
Peroxynitrite affects mitochondria function and triggers cell death via oxidation and nitration reactions. So, peroxynitrite is formed in any cell or tissue where both the superoxide and nitric oxide radicals exist simultaneously. These dangerous free radicals trigger ‘microglial activation’ (the nervous system’s personal immune system), increased NMDA receptor stimulation, excessive glutamate production and eventually neuronal degeneration. That’s very important, let’s read it again. If you are not making super oxide dismutase (SOD), you may need the SOD/Catalase supplement and the Nutrition and Antioxidant Accelerator to dampen those super oxide free radicals. (Ask us about these supplements.)
Because if its oxidizing properties, peroxynitrites interact with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanism. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis (cell death.)
Peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as:
-stroke
-myocardial infarction
-chronic heart failure
-diabetes
-circulatory shock
-chronic inflammatory diseases
-cancer (colorectal and breast)
-neurodegenerative disorders (Parkinson's, Alzheimer's, ALS, etc.)
A key regulator of peroxynitrite production is the concentration of NO, and the reaction proceeds when the concentration of NO increases and can overcome dismutation by superoxide dismutase. An advantage of the oxidant-mediated deleterious effects of peroxynitrite is that it has been suggested to contribute to the host-defense response to bacterial invasion.
iNOS inhibitors, superoxide scavengers, NADPH oxidase inhibitors and broadly effective antioxidants (e.g., vitamin E, ascorbate, melatonin, etc.) may be in part protective by preventing the formation of peroxynitrite or repairing damage initiated by it. Because the rate of peroxynitrite formation rises 100-fold for each 10-fold increase in superoxide and NO production, the production of superoxide offers a dynamic mechanism to redirect NO from being of host-defense and innate immunity.
Peroxynitrite is a dangerous and damaging molecule that is created in NOS uncoupling. It will deplete glutathione, and weaken the immune system. NOS uncoupling involves the 'loss of function' of several genes in the Biopterin Pathway. The Biopterin pathway is connected to the Folate Pathway which is connected to the Methionine Pathway, and so on. Some specific variants to look for in the Biopterin Pathway might be DHFR, PAH, IDO1, COMT, and SULT1.
*So, to keep it simple; peroxynitrites deplete glutathione, create hydroxyl radicals, increase inflammation, lowers immune function and adds to our toxic burden. That's why we call it the 'angry gorilla' in the room!
Let’s look at some examples of conditions associated with peroxynitrites:
Alzheimer’s- ‘In brain tissue from cases of Alzheimer’s disease, we found increased protein nitration in neurons, including but certainly not restricted to those containing neurofibrillary tangles (NFT’s.) Conversely, nitrotyrosine was undetectable in the cerebral cortex of age-matched control brains. These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer’s disease.’ http://www.ncbi.nlm.nih.gov/pubmed/9092586
Arthritis- ‘In collagen-induced arthritis, significant staining for nitrotyrosine, a marker of peroxynitrite formation, was found in the inflamed joints’ Peroxynitrite, a cytotoxic oxidant formed from nitric oxide (NO) and superoxide, induces DNA strand breakage, which activates the nuclear enzyme poly (ADP-ribose) synthase…’ ‘Massive ADP-ribosylation of nuclear proteins by PARS (activation) then results in cellular energy depletion and injury, reminiscent of necrosis…’
Asthma- ‘potent peroxynitrite may contribute to airway obstruction and hyper responsiveness and epithelial damage in asthma. It also enhances inflammatory cell recruitment, inhibits pulmonary surfactant.’ Airway hyper responsiveness, increased mucus secretion and vascular permeability, edema and epithelial cell damage are common manifestations of asthma.’
Atherosclerosis- ‘Our results suggest that the reaction of O2- with NO is involved in the development of atherosclerotic disease by yielding a potent mediator of lipoprotein oxidation, as well as by limiting NO stimulation of vascular smooth muscle guanylate cyclase activity.’ (Think erectile dysfunction, high blood pressure, and circulation issues.) Superoxide and peroxynitrite in artherosclerosis, proceedings of the National Academy of Sciences of the US of America, 91, 10044-1048. Retrieved May 8, 2014, from http://www.pnas.org/content/91/3/1044
Bipolar Disorder- ‘Nitric oxide can react with superoxide, leading to the formation of peroxynitrite, which has the ability to nitrosylate free tyrosine and tyrosine residues in proteins, forming 3-nitrotyrosine. Our results indicate that patients in the early and late stages of bipolar disorder have increased levels of 3-nitrotyrosine.’ ‘Given that 3-nitrotyrosine is commonly measured as a biomarker of reactive nitrogen species generation, our results suggest that the nitration process may play an important role in the pathophysiology of bipolar disorder.’
Cancer- ‘Peroxynitrite plays a major role in carcinogenesis and tumor progression leading to peroxynitrite-dependent modification of proteins, in particular in patients with colorectal and breast carcinoma.’ ‘Interestingly, recent data have expanded the concept that the inflammation and generation of peroxynitrite are critical components of cancer progression.’ ‘Reactive nitrogen species and, in particular, peroxynitrite have been shown to play a major role in carcinogenesis, affecting diverse processes including inflammation, proliferation, apoptosis, tumorigenesis, and metastasis.’ http://www.ncbi.nlm.nih.gov/pubmed/12878219http://www.jbc.org/content/279/9/7708.abstract
Celiac Disease- As stated earlier, nitrated tyrosine is an indication of peroxynitrite involvement. ‘Elevated nitrotyrosine levels were paralleled by an increase in plasma concentrations of NO-oxidation products (NOx), peroxynitrites, nitrite and nitrate form 15.1 =/- 6.1 uM in controls to 61.0 +/- 28.2 uM in celiac disease patients.’ In summary, many celiac patients have genetic variants for gluten, plus histamine variants leading to zonulin,and the opening of tight junctions, combine w/ peroxynitrites, then you have the perfect storm!
COPD- ‘PN is an extremely powerful and cytotoxic oxidant in biological systems, released predominantly by inflammatory cells at the site of injury in inflammatory disease and involved in tissue damage and airway inflammation.’ ‘PN alters the function of certain proteins such as superoxide dismutase (SOD), glutathione s-transferase, metalloprotteinase, p38MAPK, histone deacetylase 2, and transcriptional factors via nitration of tyrosine residues. These result in amplified inflammation and corticosteroid insensitivity, which are seen in COPD patients.’
Depression- is associated with decreased levels of Serotonin which is made by using BH4 and the amino acid, tryptophan. However, peroxynitrite oxidizes tryptophan, thereby inactivating it. This causes decrease levels of Serotonin. http://www.ncbi.nlm.nih.gov/pubmed/3045111
Fibromyalgia- ‘FM is multi-organ pain and it is known that both excessive NMDA activity and excessive nitric oxide levels can generate pain. Nitric oxide is known to stimulate some but not all of the nociceptors, the neurons that generate the sensation of pain, providing an explanation for the pain generation. Peroxynitrite is implicated in generating pain responses, as well.’ ‘It is known that when NMDA receptors are hyperactive, they produce excessive nitric oxide and peroxynitrite.’ http://www.ncbi.nlm.nih.gov/pubmed/11461161
Kidney Disease- ‘…iNOS-generated NO mediates damage in I-R (ischemia-reperfusion) injury possibly through ONOO-formation.’ ‘…peroxynitrite is involved, at least part, in cisplatin-induced nephrotoxicity and protein nitration.’
Liver Disease- ‘In fat-engorged hepatocytes, several vicious cycles involving tumor necrosis factor-a, reactive oxygen species (ROS), peroxynitrite, and lipid peroxynitrite, and lipid peroxidation products alter respiratory chain polypeptides and mtDNA, thus partially blocking the flow of electrons in the respiratory chain. The overreaction of upstream respiratory chain complexes increases mitochondrial ROS and peroxynitrite formation. Oxidative stress increases the release of lipid peroxidation products and cytokines, which together trigger the liver of lesions of NASH.’ http://www.ncbi.nlm.nih.gov/pubmed/17567459
Lyme Disease- In my experience with MethylGenetic AnalysisTM, I have seen that 99.9% of folks with Lyme have the genetic patterns that lead to peroxynitrites which chew up glutathione and suppress the immune system. Nitrotyrosine is a marker for peroxynitrite. ‘High serum levels of total NO, MDA and nitrotyrosine observed in patients with Lyme borrelisis indicate on enhancement of lipid peroxidation and protein nitration, which in consequence may enhance the inflammatory process in patients with Lyme borreliosis.’
http://progress.umb.edu.pl/sites/progress.umb.edu.pl/files/26-32-ratajczak.pdf
Male Infertility- ‘Spontaneous tyrosine nitration occurs in human spermatozoa. This post-translational protein modification is enhanced by an overproduction of peroxynitrite, which is more evident in asthenozoospermic infertile patients when compared with normospermic fertile donors. Motility parameters are negatively affected, suggesting that ONOO-may be involved in defective sperm function.’
Migraines- ‘In the presence of extracellular L-arginine, ONOO-production was significantly greater in patients’ platelets than in those of controls.’ ‘…migraine patients show intercritic changes in platelet membrane fluidity and activity that may be related to the oxidative stress caused by increased ONOO-levels.’
Raynaud’s Syndrome- ‘Nitrite and nitrate, the stable oxidation products of NO and peroxynitrite, respectively, were measured in cerebrospinal fluid samples obtained from MS patients and controls. Levels of nitrate were elevated significantly during clinical relapses of MS. These data suggest that peroxynitrite formation is a major consequence of NO produced in MS-affected CNS and implicate a role for their powerful oxidant in the pathogenesis of MS.’
Osteoporosis- ‘Either authentic PN addition to cultured hOB (human osteoblast-like) cells or its indirect release through SIN-1 affects both hOB proliferation and differentiation. Blockade of ONOO-release in spite of persistent NO generation can efficiently inhibit ONOO-effect on hOB. Thus, this data provides evidence that PN may be a final mediator of NO—induced deleterious effects on hOB metabolism.’
http://onlinelibrary.wiley.com/doi/10.1359/jbmr.2002.17.3.434/abstract
Parkinson’s Disease- Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly (ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy, and neuropathy.’ http://www.ncbi.nlm.nih.gov/pubmed/15723618
Ulcerative Colitis- ‘Nitric oxide and peroxynitrite formation may play an important role in causing irreversible cellular injury to the colonic mucosa in patients with active ulcerative colitis.’ ‘Peroxynitrite formation as assessed by nitrotyrosine staining was frequently observed in the lamina propria of actively inflamed mucosa.’ http://onlinelibrary.wiley.com/doi/10.1359/jbmr.2002.17.3.434/abstract
**Additional information on ONOO can be found in Dr. Martin Pall's book: 'Explaining Unexplained Illnesses.'
Article is an excerpt from MethylGenetic NutritionTM Analysis Pre-Course Session.
Ask us about our 'Peroxynitrite Scavenger'...it's specifically designed to support the scavenging of peroxynitrites.
Peroxynitrites scavenges your tryptophan and melatonin and thus causes difficulty sleeping! Ask us about our Peroxynitrite Scavenger, PM.