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What Are Free Radicals ?
A free radical is an atom or group of atoms that have one or more unpaired electrons. Free radicals can have positive, negative or neutral charge. They are formed as necessary intermediates in a variety of normal biochemical reactions, but when generated in excess or not appropriately controlled, free radicals can wreak havoc on a broad range of macromolecules. A prominent feature of free radicals is that they have extremely high chemical reactivity, which explains not only their normal biological activities, but how they inflict damage on cells.
Oxygen Free Radicals
There are many types of free radicals, but those of most concern in biological systems are derived from oxygen, and known collectively as reactive oxygen species (ROS). Oxygen has two unpaired electrons in separate orbitals in its outer shell. This electronic structure makes oxygen especially susceptible to radical formation. Sequential reduction of molecular oxygen (equivalent to sequential addition of electrons) leads to formation of a group of reactive oxygen species:
• • •
superoxide anion peroxide (hydrogen peroxide) hydroxyl radical
Formation of Reactive Oxygen Species
Oxygen-derived radicals are generated constantly as part of normal aerobic life. They are formed in mitochondria as oxygen is reduced along the electron transport chain. Reactive oxygen species are also formed as necessary intermediates in a variety of enzyme reactions.
Examples of situations in which oxygen radicals are overproduced in cells include:
White blood cells such as neutrophils specialise in producing oxygen radicals, which are used in host defense to kill invading pathogens. Cells exposed to abnormal environments such as hypoxia or hyperoxia generate abundant and often damaging reactive oxygen species. A number of drugs have oxidizing effects on cells and lead to production of oxygen radicals.
Ionizing radiation is well known to generate oxygen radicals within biological systems. Interestingly, the damaging effects of radiation are higher in well oxygenated tissues than in tissues deficient in oxygen.
Biological Effects of Reactive Oxygen
It is best not to think of oxygen radicals as "bad". They are generated in a number of reactions essential to life and, as mentioned above, phagocytic cells generate radicals to kill invading pathogens. There is also a large body evidence indicating that oxygen radicals are involved in intercellular and intracellular signalling. For example, addition of superoxide or hydrogen peroxide to a variety of cultured cells leads to an increased rate of DNA replication and cell proliferation - in other words, these radicals function as mitogens.
Free radicals in disease
Despite their beneficial activities, reactive oxygen species clearly can be toxic to cells. By definition, radicals possess an unpaired electron, which makes them highly reactive and thereby able to damage all macromolecules, including lipids, proteins and nucleic acids. One of the best known toxic effects of oxygen radicals is damage to cellular membranes (plasma, mitochondrial and endomembrane systems), which is initiated by a process known as lipid peroxidation. A common target for peroxidation is unsaturated fatty acids present in membrane phospholipids.
Reactions involving radicals occur in chain reactions. Note in the figure above that a hydrogen is abstracted from the fatty acid by hydroxyl radical, leaving a carbon-centered radical as part of the fatty acid. That radical then reacts with oxygen to yield the peroxy radical, which can then react with other fatty acids or proteins. Peroxidation of membrane lipids can have numerous effects, including:
• • • •
increased membrane rigidity decreased activity of membrane-bound enzymes (e.g. sodium pumps) altered activity of membrane receptors. altered permeability
In addition to effects on phospholipids, radicals can also directly attack membrane proteins and induce lipid-lipid, lipid-protein and protein-protein crosslinking, all of which obviously have effects on membrane function.
Alcohol, oxidative stress, and free radical damage
Alcohol promotes the generation of ROS and/or interferes with the body's normal defense mechanisms against these compounds through numerous processes, particularly in the liver. For example, alcohol breakdown in the liver results in the formation of molecules whose further metabolism in the cell leads to ROS production. Alcohol also stimulates the activity of enzymes called cytochrome P450s, which contribute to ROS production. Further, alcohol can alter the levels of certain metals in the body, thereby facilitating ROS production. Finally, alcohol reduces the levels of agents that can eliminate ROS (i.e., antioxidants). The resulting state of the cell, known as oxidative stress, can lead to cell injury. ROS production and oxidative stress in liver cells play a central role in the development of alcoholic liver disease
Oxidative stress and aging
Oxidative stress, originating from reactive oxygen species and free radicals provides a constant challenge to eukaryotic cell survival. While implicated in a number of degenerative diseases, some associated with aging and with aging itself, the manner and extent to which oxidative stress contributes to the initiation or implementation of programmed-cell death is problematic. If oxidative stress is an important modulator of programmed-cell death, any ability intentionally to augment or inhibit it might ameliorate diseases in which the process is abnormally underactive or overactive Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL in the endothelium is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade due to oxygen deprivation. This includes Stroke and Heart attack
Free radicals and neurodegenerative diseases
There is significant evidence that the pathogenesis of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, Friedreich's ataxia (FRDA), multiple
sclerosis and amyotrophic lateral sclerosis, may involve the generation of reactive oxygen species (ROS) and/or reactive nitrogen species (RNS) associated with mitochondrial dysfunction. The mitochondrial genome may play an essential role in the pathogenesis of these diseases, and evidence for mitochondria being a site of damage in neurodegenerative disorders is based in part on observed decreases in the respiratory chain complex activities in Parkinson's, Alzheimer's, and Huntington's disease. Such defects in respiratory complex activities, possibly associated with oxidant/antioxidant imbalance, are thought to underlie defects in energy metabolism and induce cellular degeneration.
Reactive oxygen species in arthritis.
A vast amount of circumstantial evidence implicates oxygen-derived free radicals, especially reactive oxygen species and nitric oxide as mediators of inflammation and/or tissue destruction in inflammatory and arthritic disorders. Reactive oxygen species can initiate a wide range of toxic oxidative reactions. These include initiation of lipid peroxidation, direct inhibition of mitochondrial respiratory chain enzymes, inactivation of glyceraldehyde-3phosphate dehydrogenase, inhibition of membrane sodium/potassium ATP-ase activity, inactivation of membrane sodium channels, and other oxidative modifications of proteins. All these toxicities are likely to play a role in the pathophysiology of inflammation. Reactive oxygen species are all potential reactants capable of initiating DNA single strand breakage, with subsequent activation of the nuclear enzyme poly (ADP ribose) synthetase (PARS), leading to eventual severe energy depletion of the cells, and necrotic-type cell death. Recently it has been demonstrated that iNOS inhibitor prevents the activation of poly (ADP ribose) synthetase, and prevents the organ injury associated with inflammation. Although the severity and duration of inflammation may dictate the timing and extent of NOS expression, it is now evident that the up-regulation of NOS can take place during sustained inflammation. Thus, induced nitric oxide, in addition to being a "final common mediator" of inflammation, is essential for the up-regulation of the inflammatory response. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of reactive oxygen species, with them associated toxicities, and indirectly through the amplification of the inflammatory response.
Mechanisms for Protection Against Radicals
Life on Earth evolved in the presence of oxygen, and necessarily adapted by evolution of a large battery of antioxidant systems. Some of these antioxidant molecules are present in all lifeforms examined, from bacteria to mammals, indicating their appearance early in the history of life. Many antioxidants work by transiently becoming radicals themselves. These molecules are usually part of a larger network of cooperating antioxidants that end up regenerating the original antioxidant. For example, vitamin E becomes a radical, but is regenerated through the activity of the antioxidants vitamin C and glutathione.
Three groups of enzymes play significant roles in protecting cells from oxidant stress: Superoxide dismutases (SOD) are enzymes that catalyze the conversion of two superoxides into hydrogen peroxide and oxygen. The benefit here is that hydrogen peroxide is substantially less toxic that superoxide. SOD accelerates this detoxifying reaction roughly 10,000-fold over the non-catalyzed reaction.
Interestingly, SODs are inducible enzymes - exposure of cells to higher concentrations of oxygen results in rapid increases in the concentration of SOD. Catalase is found in peroxisomes in eucaryotic cells. It degrades hydrogen peroxide to water and oxygen, and hence finishes the detoxification reaction started by SOD. Glutathione peroxidase is a group of enzymes, the most abundant of which contain selenium. These enyzmes, like catalase, degrade hydrogen peroxide. They also reduce organic peroxides to alcohols, providing another route for eliminating toxic oxidants.
In addition to these enzymes, glutathione transferase, ceruloplasmin, hemoxygenase and possibly several other enzymes may participate in enzymatic control of oxygen radicals and their products. Nonenzymatic Antioxidants
Three non-enzymatic antioxidants of particular importance are: Vitamin E is the major lipid-soluble antioxidant, and plays a vital role in protecting membranes from oxidative damage. Its primary activity is to trap peroxy radicals in cellular membranes. Vitamin C or ascorbic acid is a water-soluble antioxidant that can reduce radicals from a variety of sources. It also appears to participate in recycling vitamine E radicals. Interestingly, vitamin C also functions as a pro-oxidant under certain circumstances. Glutathione may well be the most important intracellular defense against damage by reactive oxygen species. It is a tripeptide (glutamyl-cysteinyl-glycine). The cysteine provides an exposed free sulphydryl group (SH) that is very reactive, providing an abundant target for radical attack. Reaction with radicals oxidises glutathione, but the reduced form is regenerated in a redox cycle involving glutathione reductase and the electron acceptor NADPH. In addition to these "big three", there are numerous small molecules that function as antioxidants. Examples include bilrubin, uric acid, flavonoids and carotenoids. Researches have found mitochondrial antioxidant therapy to be the most efficacious in reducing pathological changes and in not producing adverse effects in cases of neurodegenerative diseases. Thus, mitochondrial antioxidant therapy is promising as a treatment for neurodegenerative patients. Once in the mitochondria, they rapidly neutralize free radicals and decrease mitochondrial toxicity. Thus, mitochondrially targeted antioxidants are promising candidates for treating these patients.
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