Oxidative Stress and Free Radical Damage
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Free Radicals
The Body's Natural Antioxidants
Overview
Superoxide Dismutase (SOD)
Glutathione Peroxidase
Peroxynitrite Formation
Excessive free radical (oxidative) damage to the mitochondrial membrane
Markers for Oxidative Stress and Damage
Free Radicals:
Free radicals are those particles and molecules that cause damage to the body's cells and essential fatty acids (e.g. EPA) by their ready reactivity and oxidising ability. This characteristic is defined by their unpaired electron. Oxidative damage is often associated with premature ageing and biochemical and DNA damage. Some examples of oxidative damage to cells can be found on the Identification page. Oxidative stress may not be a primarly cause of CFS or related conditions in most sufferers, but it is often a contributary factor. Oxidative damage is often much higher in those suffering from impaired liver function, heavy metal toxicity or who are heavily detoxifying the body (releasing heavy metals from the tissues).
http://en.wikipedia.org/wiki/Antioxidant#Oxidative_stress_in_disease
'Oxidative stress is thought to contribute to the development of a wide range of diseases including Alzheimer's disease, Parkinson's disease, the pathologies caused by diabetes, rheumatoid arthritis, and neurodegeneration in motor neurone diseases. In many of these cases, it is unclear if oxidants trigger the disease, or if they are produced as a consequence of the disease and cause the disease symptoms...The brain is uniquely vulnerable to oxidative injury, due to its high metabolic rate and elevated levels of polyunsaturated lipids, the target of lipid peroxidation. Consequently, antioxidants are commonly used as medications to treat various forms of brain injury.'
Free radicals damage the mitochondria (that produce the body's energy). Free radical damage shorts the life of our bodies cells and contributes to premature ageing. The number of times our somatic cells can replicate or divide are fixed or rather limited. The protective telomeres present at the end of chromosomes become shorter each time a cell divides. The telomeres maintain the viability of body/somatic cells. When they are too short they can no longer protect the chromosomes or provide the cell with the ability to divide. When the telomeres of the chromosomes that make up a cell are lost, the cell undergoes apoptosis or perish. Thus, increasing the length of the life of each cell prior to division (by consuming enough antioxidants and minimising the number of oxidants consumed/breathed in) contributes to increasing one's overall life expectancy and delays the onset of ageing.
Indeed, oxidative stress seen in various diseases is probably itself a symptom of poor liver function. It is likely that impaired liver function is in fact closely associated with these diseases.
Oxidants and free radicals, including inflammatory and pro-oxidant cytokines of the immune system, have an adverse effect on blood vessel management and can promote the formation of atherosclerotic plaque.
Dr Ray D. Strand's web site below contains articles on oxidative stress. Below is also a link to an article about oxidative stress and CFS and FMS.
www.bionutrition.org/default.asp
http://www.brillianthealth.net/reports/pdf/ChronicFatigue.pdf
Oxidative stress should be obvious from a variety of different blood tests and blood analyses, for example, blood serum vitamin levels (A, C, E), live blood microscopy, and many others. For more information on Oxidative Stress and their effect on blood cells, please see the Identification page.
Dr Martin Pall has theorised that triggers of CFS and Fibromyalgia such as viral and bacterial infections (amongst others) actually cause an increase in Nitric Oxide levels, greatly increasing the oxidative stress on the body and worsening symptoms, in a body that may well have been under considerable oxidative stress anyway because of dietary, lifestyle and other environmental causes. Please see the Viri page for more information.
Free radicals come from a wide variety of sources, from pollution in the air we breathe, heavy metals (which also multiply the numbers of free radicals), air molecules ionised by radiation, smoke (cigarettes, drugs or fires), chlorine in tap water, but mainly our diet. The biggest source of ingested free radicals is probably fried foods and heated cooking oils, e.g. potato crisps/chips, french fries, onion rings etc. (fried in vegetable oils which oxidises readily on account of the high Omega 3 and 6 fatty acid content, into free radicals). Heated oil also tastes rather unpleasant compared to its unheated counterpart if one excludes the food taste from the equation. Please see the Nutritional page for more information.
It should be noted that most tap water is not neutral in pH. My local tap water is between 6.25 and 6.50, i.e. slightly acidic, on account of the chlorine that is added to it. Chlorine is an anti-microbial agent that kills off bacteria and other microbes that might cause illness and infection otherwise. It achieves this because it is an oxidising agent. When Chlorine gas dissolves in water, it produces hydrochloric acid and hydrochlorous acid (the oxidising agent). This oxidising power is taken into the body and can add to the free radical burden of the body as well as lowering one's pH. Pure water has a pH of 7. Some water authorities also add Fluoride to water, as described above, to 'help with tooth decay'. As already mentioned, it is possible to remove Fluoride and Chlorine from tap water as well as other potential contaminants and heavy metals, using a sophisticated water purification and ionisation system. This can elevate the pH from slightly acidic to slightly alkaline, i.e. above pH 7. Please see the Acidosis page for more information.
As well as from external sources, free radicals also derive from the partial detoxification products produced in the liver, as toxins are processed prior to excretion. In addition, free radicals are produced inside the mitochondria of our cells, and their prouction is directly related to metabolism, i.e. the rate of respiration and amount of energy we produce. The more energy we produce, the more free radicals we produced. However, under normal, healthy circumstances, the body has its own mechanimsms to deal with these. As oxygen and other compounds are broken down to be utilised by the body (as part of metabolism), certain molecules become unbalanced, creating free radicals or oxidants. When free radicals or oxidants are produced in excess, cells may suffer from oxidative damage. One of the most harmful of these free radicals is the anion Superoxide.
http://en.wikipedia.org/wiki/Superoxide
Superoxide is the anion O2-, i.e. the dioxygen O2 or O=O molecule with an additional electron, different from the Oxygen anion O--. It is important as the product of the one-electron reduction of dioxygen, which occurs widely in nature. With one unpaired electron, the superoxide ion is a free radical, and, like dioxygen, it is paramagnetic.
It should be noted that some treatments for dysbiosis include hydrogen peroxide and ozone, both of which are powerful oxidising agents. Of course, they may well oxidise harmful bacteria and yeasts etc., but they are not selective in what they oxidise and will cause oxidative damage/stress to everything they come into contact to varying extents. If consumed orally, then they will have a detrimental effect on one's probiotic gut flora and also may well oxidise some of the tissues as well. Acidophilus bacteria do produce hydrogen peroxide, but in very small quantities and locally within the colon.
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The Body's Natural Antioxidants
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Overview
http://en.wikipedia.org/wiki/Antioxidant
Antioxidants are molecules that protect the body against oxidative damage, which are themselves oxidised rather than bodily tissues being oxidised. They also help to reduce the build up of atherosclerotic plaque in the arteries and help to protect the liver. A lack of antioxidants as described above will result in an increased level of oxidative damage, the build of up atherosclerotic plaque, premature ageing and put an excessive stress on the liver.
Antioxidants protect the cells from damage from free radicals or oxidising agents and particles. Antioxidants in general, and in particular the Superoxide Dismutase (SOD) enzyme (discussed below) have the ability to break down Superoxide. They also help to reduce plaque that builds up inside our artery walls from high LDL cholesterol blood levels. Some people have reported huge life changing benefits from consuming high levels of antioxidants (e.g. drinking Xango juice), but it is likely that such individuals were simply suffering from excessive free radicals and not more complex biochemical problems. In general terms, the capacity to respond to oxidative stress has the potential to positively impact energy levels, vitality, health and the ability to cope with the physical and psychological stresses of modern life.
www.netdoctor.co.uk/focus/nutrition/facts/oxidative_stress/oxidativestress.htm
For an examination of good sources of external antioxidants, please see the Nutritional Deficiencies page.
The most powerful antioxidants are the body's own internally produced antioxidants, known as Primary Antioxidants, which target specific types of oxidative threats in the body, and are the most important down-regulators of oxidative stress in the body. They help to support proper liver function and the immune system. These Primary Antioxidants are the four in the list below. The most important of these are SOD, Catalase and Gpx. They are enzymes that break down oxidants, i.e. antioxidant enzymes. Melatonin is a antioxidant hormone and is also involved in the Circadian Rhythm (awake/sleep cycle).
The external antioxidants (i.e. those consumed and in some cases injected (e.g. Glutathione)), known as Secondary Antioxidants, are relatively less potent in their antioxidant capacity and are antioxidant chemicals. Perhaps the most effective approach is to prime the body to produce its own extra strength internal (primary) antioxidants, including SOD, Catalase and Gpx. These antioxidants provide the primary and most important level of defence against oxidative stress and free radical damage. Of course, a healthy diet and in particular one that is rich in Omega 3 and 6 fatty acids and other nutritious foods sources, with perhaps moderate amounts of green tea and algae, will also be high in antioxidants anyway. It is generally good practice to eat a diet rich in antioxidants and to take additional antioxidant supplement of one form or another.
In general terms, Primary* and Secondary Antioxidants are listed in decreasing order of potency below.
Superoxide Dismutase (SOD)
http://en.wikipedia.org/wiki/Superoxide_dismutase
SOD is in itself not an antioxidant per se, but an enzyme that breaks down Superoxide specifically (i.e. a targetted antioxidant enzyme). Certain nutritional elements (i.e. those metals described above) make up an essential part of the SOD molecule and sufficient levels are essential in those with high levels of oxidative stress or impaired liver function (or indeed those embarking on a detoxification programme). See also the section on liver function on the toxicity page for more information.
http://en.wikipedia.org/wiki/Antioxidant#Superoxide_dismutase.2C_catalase_and_peroxiredoxins
'Superoxide dismutases (SODs) are a class of closely related enzymes that catalyse the breakdown of the superoxide anion into oxygen and hydrogen peroxide. SOD enzymes are present in almost all aerobic cells and in extracellular fluids. Superoxide dismutase enzymes contain metal ion cofactors that, depending on the isozyme, can be copper, zinc, manganese or iron. In humans, the copper/zinc SOD is present in the cytosol, while manganese SOD is present in the mitochondrion. There also exists a third form of SOD in extracellular fluids, which contains copper and zinc in its active sites. The mitochondrial isozyme seems to be the most biologically important of these three, since mice lacking this enzyme die soon after birth. In contrast, the mice lacking copper/zinc SOD are viable but have lowered fertility, while mice without the extracellular SOD have minimal defects. In plants, SOD isozymes are present in the cytosol and mitochondria, with an iron SOD found in chloroplasts that is absent from vertebrates and yeast.'
As discussed on the Identification Tests page, general cell protection from damage by superoxide is provided by intracellular Zinc:Copper SOD (Zn/Cu-SOD). Mitochondria are protected by manganese-dependent SOD (Mn-SOD). Extracellular SOD (EC-SOD - another type of Zn/Cu SODase) protects the nitric oxide pathways that relax vascular smoother muscle tissue. For each form of SOD, genetic variations are known, and mutations and polymorphisms can occur during excessive oxidative stress placed on the DNA. DNA adducts can chemically block these genes however. Zinc, Copper and Manganese are extremely important elements for maintaining healthy SOD levels, and patients should ensure that these mineral levels are supplemented if they drop below their reference ranges. Mitochondrial function is limited in a sense by the available of SOD as without it extensive mitochondrial damage would occur (with elevated respiration rates beyond the available SOD and Glutathione that can be produced.
Sufficient SOD levels, and indeed SOD supplementation, have been linked to the prevention and/or limitation of DNA damage/mutation from UV exposure. Scientific studies carried out during the last decade have shown that oxidative stress is implicated in cell damage. SOD has been shown to dramatically protect against cellular oxidative stress damage in humans. Results include:
- Supporting significantly lower cellular DNA damage when exposed to intensive oxidative stress.
- Supporting skin health against photo-oxidation.
- Priming the natural internal antioxidants capacities of SOD, Catalaseand Gpx.
Please see the Nutritional Deficiencies page, in particular the sections on Antioxidants and also Vitamin D and UV Light Exposure.
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Glutathione Peroxidase
http://en.wikipedia.org/wiki/Glutathione_peroxidase
Glutathione peroxidase (Gpx) is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid hydroperoxides to their corresponding alcohols and to reduce free hydrogen peroxide to water.
The reduced form of Glutathione (GSH) is one of the most important compounds involved in detoxification and for inter- and extracellular Antioxidant protection in the body. Glutathione levels are frequently low in CFS patients.
For more information about the role of Glutathione in Phase II Liver Function (Conjugation) in the removal of toxins from the body, please see the Phase 1 and 2 Enzymatic Function Summary section on the Liver Function page.
For more information on Glutathione production, through a process called Methylation, which is frequently impaired in individuals with CFS, please see the Glutathione and Methylation section on the Liver Function page.
For more information generally on Glutathione Peroxidase and Superoxide, and their connection to mitochondrial function and cardiac function, please see the Cardiac Insufficiency page.
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Peroxynitrite Formation:
Please see the Nitric Oxide Cycle and Peroxynitrite page for a detailed review of the shift in the Nitric Oxide cycle in many CFS patients, and the effect on overall oxidative stress.
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Excessive free radical (oxidative) damage to the mitochondrial membrane:
Please see the Mitochondrial Dysfunction page for information on free radical damage by excessive Superoxide formation to the inner mitochondrial membranes.
In addition to excessive free radicals damaging the mitochondrial membranes, they may also cause damage to the actual mitochondrial DNA itself. Mitochondrial DNA is completely separate from nuclear DNA. Unlike Nuclear DNA, it is inherited solely from the mother in sexually reproducing organisms, e.g. humans. Mitochondrial DNA, because of its close proximity to the inner mitochondrial membrane's respiratory chain, a primary source of free radical production, and also their limited capacity for self-repair and self-protection, are particularly susceptible to free radical damage. General cell protection from damage by Superoxide is provided by intracellular Zinc:Copper SOD (Zn/Cu-SOD). Mitochondria are protected by Manganese-dependent SOD (Mn-SOD). Extracellular SOD (EC-SOD - another type of Zn/Cu SODase) protects the nitric oxide pathways that relax vascular smoother muscle tissue. For each form of SOD, genetic variations are known, and mutations and polymorphisms can occur during excessive oxidative stress placed on the DNA. DNA adducts (toxins that attach to DNA genes) can chemically block these genes however. Zinc, Copper and Manganese are extremely important elements for maintaining healthy SOD levels, and patients should ensure that these mineral levels are supplemented if they drop below their reference ranges.
http://en.wikipedia.org/wiki/Mitochondrial_DNA
http://ghr.nlm.nih.gov/chromosome=MT
In addition, free radicals can also be produced in excess by the liver. Liver function with regards to clearing undesired compounds from the blood involves a two step process. This is described in detail on the Inefficient Liver function page. The first step is Phase 1 Regulation, using the Cytochrome P450 enzymes, which are largely a set of oxidase reactions, producing a large number of free radicals. Sufficient antioxidant compounds and chemicals are required by the liver in order to keep these from causing too much damage within the liver and outside of the liver, these are both endogenously produced antioxidants and dietary sources of antioxidants. The second step of liver function is the Phase 2 Conjugation step, whereby molecules are added to the toxins in order to make them easier to remove from the body. These processes work in a perfect balance in a healthy liver. If antioxidant and conjugation steps are impaired, then a large number of free radicals will be produced which can cause oxidative damage within the liver and also spill out into the blood stream, flooding it with excessive free radicals.
The role of antioxidants such as Superoxide Dimutase and R-Lipoic Acid are discussed on the Cardiac and Nutritional pages.
Please see the Effects of Heavy Metal Toxicity page for reasons for the increase in free radical production.
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Other Markers for Oxidative Stress and Damage:
Please see the Tests page for information regarding the oxidative stress markers 8-Oxo-2-Deoxyguanosine and F2-Alpha Isoprostane.