Mechanisim and generation of free radicals

AIJAZ AHMAD DAR FROM PANDUSHAN SHOPIAN J&K

1. introduction A free radical is defined as any chemical species that contains unpaired electrons, b ecause of these free radicals are highly reactive and readily take part in chemical reactions leading to tissue injury They are produced either from normal cell metabolisms in situ or from external sources (pollution, cigarette smoke, radiation, medication ). When an overload of free radicals cannot gradually be destroyed, their accumulation in the body generates a phenomenon called oxidative stress. This process plays a major part in the development of chronic and degenerative illness such as cancer etc    Endogenous and exogenous antioxidants act as “free radical scavengers” by preventing and repairing damages caused by ROS and RNS and enhance immune defence pham-Huy.LA & et.al,free radical,antioxidants in disease and health,int j biomed sci ,2008 jun,v.4(2) :p 89-96

2. Free radical-targets Free radicals attack three main cellular components . Lipids:- Peroxidation of lipids in cell membranes can damage cell membranes by disrupting fluidity and permeability. Lipid peroxidation can also adversely affect the function of membrane bound proteins such as enzymes and receptors. Proteins:- Direct damage to proteins can be caused by free radicals. This can affect many kinds of protein, interfering with enzyme activity and the function of structural proteins . DNA:- Fragmentation of DNA caused by free radical attack causes activation of the poly (ADP-ribose) synthetase enzyme, splits NAD+ to aid the repair of DNA. if the damage is extensive, NAD+ levels may become depleted to the extent that the cell may no longer be able to function and dies . When a cell membrane or an organelle membrane is damaged by free radicals, it loses its protective properties . This puts the health of the entire cell at risk. Abheri Das Sarma et. al. Free Radicals and Their Role in Different Clinical Conditions ,International Journal of Pharma Sciences and Research (IJPSR),Vol.1(3), 2010, 185-192

3. Formation of free radicals Normally , bonds don’t split to leave a molecule with an odd, unpaired electron. But when weak bonds split, free radicals are formed . Free radicals are very unstable and react quickly with other compounds, trying to capture the needed electron to gain stability. When the "attacked" molecule loses its electron, it becomes a free radical itself , beginning a chain reaction , resulting in the disruption of a living cell. Some free radicals may arise normally during metabolism and by immune system’s cells purposefully to neutralize viruses and bacteria .

4. Steps involving free radical generation free radicals take part in radical addition and radical substitution as reactive intermediates. Chain reactions involving free radicals can usually be divided into three distinct processes: initiation, propagation, and termination. Initiation reactions are those, which result in a net increase in the number of free radicals. They may involve the formation of free radicals from stable species or they may involve reactions of free radicals with stable species to form more free radicals. Propagation reactions involve free radicals in which the total number of free radicals remains the same. Termination reactions are those reactions resulting in a net decrease in the number of free radicals. Radicals may also be formed by single electron oxidation or reduction of an atom or molecule. An example is the production of superoxide by the electron transport chain. Abheri Das Sarma et. al. Free Radicals and Their Role in Different Clinical Conditions ,International Journal of Pharma Sciences and Research (IJPSR),Vol.1(3), 2010, 185-192

5. CAUSES OF FREE RADICALS Pollution   and   other   external   substances:- The pollutants produced by modern technologies often generate free radicals in the body. The food most of us buy contains farm chemicals, including fertilizers and pesticides, that produce free radicals when we ingest them. Prescription drugs often have the same effect, their harmful side-effects may be caused by the free radicals they generate . Processed foods frequently contain high levels of lipid peroxides, which produce free radicals that damage the cardiovascular system. Cigarette smoke generates high free-radical concentrations , much of the lung damage associated with smoking is caused by free radicals. Air pollution , Alcohol is a potent generator of free radicals Stress:- T he body's stress response creating free radicals in abundance. The stress response races the body's energy-creating apparatus, increasing the number of free radicals as a toxic by-product T he hormones that mediate the stress reaction in the body - cortisol and catecholamines - will themselves degenerate into particularly destructive free radicals

6. CAUSES OF FREE RADICALS Production of free radicals in the body is continuous and inescapable The basic causes include the following : The immune system:-   The body tries to harness the destructive power of the most dangerous free radicals - the oxy radicals and ROS - for use in the immune system and in inflammatory reactions . Certain cells in these systems engulf bacteria or viruses, take up oxygen molecules from the bloodstream, remove an electron to create a flood of oxy radicals and ROS, and bombard the invader with the resulting toxic shower. This aggressive use of toxic oxygen species is remarkably effective in protecting the body against infectious organisms . Energy production:- The energy-producing process in every cell generates oxy radicals and ROS as toxic waste, continuously and abundantly Oxygen is used to burn glucose molecules that act as the body's fuel . The cell includes a number of metabolic processes   with the constant creation of oxy radicals and ROS. Abheri Das Sarma et. al. Free Radicals and Their Role in Different Clinical Conditions ,International Journal of Pharma Sciences and Research (IJPSR),Vol.1(3), 2010, 185-192

7. FREE RADICAL DEFENSES Given the many sources of free radicals, it is not surprising that all aerobic forms of life maintain and elaborate anti-free-radical defense systems, also known as antioxidant systems . Enzymes:- Every cell in the body creates its own "bomb squad"-antioxidant enzymes whose specialty is defusing oxy radicals and ROS. superoxide dismutase (SOD), takes hold of molecules of superoxide - a particularly destructive free radical and changes them to a much less reactive form. SOD and another important antioxidant enzyme set, the glutathione system, work within the cell. Nutrients:- second line of defense body makes use of many standard vitamins and other nutrients to quench the oxy radicals' thirst for electrons Among the many substances used are Vitamins C and E, beta-carotene, and bioflavonoids. Abheri Das Sarma et. al. Free Radicals and Their Role in Different Clinical Conditions ,International Journal of Pharma Sciences and Research (IJPSR),Vol.1(3), 2010, 185-192

8. FREE RADICAL DEFENSES Self repair:- The body also has systems to repair or replace damaged building blocks of cells. For example, the system for repairing damage to DNA and other nucleic acids is particularly elaborate and efficient, with various specialized enzymes that locate damaged areas, snip out ruined bits, replace them with the correct sequence of molecules, and seal up the strand once again. Most protein constituents in the cell, for example, are completely replaced every few days. Scavenger enzymes break used and damaged proteins into their component parts for reuse by the cell . Abheri Das Sarma et. al. Free Radicals and Their Role in Different Clinical Conditions ,International Journal of Pharma Sciences and Research (IJPSR),Vol.1(3), 2010, 185-192

9. Role of free radicals in pathogenesis When produced in excess, free radicals and oxidants generate a phenomenon called oxidative stress, a deleterious process that can seriously alter the cell membranes and other structures such as proteins, lipids, lipoproteins, and deoxyribonucleic acid (DNA ) oxidative stress results from an imbalance between formation and neutralization of ROS/RNS Cancer and oxidative stress:- oxidative DNA damage is responsible for cancer development.  Cancer initiation and promotion are associated with chromosomal defects and oncogene activation induced by free radicals Oxidative DNA damage also produces a multiplicity of modifications in the DNA structure including base and sugar lesions, strand breaks DNA-protein cross-links and base-free sites  For example, tobacco smoking and chronic inflammation resulting from noninfectious diseases like asbestos are sources of oxidative DNA damage that can contribute to the development of lung cancer and other tumors  pham-Huy.LA & et.al, free radical, antioxidants in disease and health , int j biomed sci ,2008 jun,v.4(2) :p 89-96

10. Cardiovascular disease and oxidative stress Oxygen free radicals are highly reactive compounds causing peroxidation of lipids and proteins and are thought to play an important role in the pathogenesis of reperfusion abnormalities including myocardial stunning, irreversible injury, and reperfusion arrhythmias . Potential sources of free radicals during ischemia and reperfusion have been identified in myocytes , vascular endothelium, and leukocytes. Injury to processes involved in regulation of the intracellular Ca2+ concentration may be a common mechanism underlying both free radical- induced and reperfusion abnormalities . Kidney Mitochondrial free radical production induces lipid peroxidation during myohemoglobinuria . Iron catalyzed free radical formation and lipid peroxidation are accepted mechanisms of heme protein-induced acute renal failure. In conclusion, the terminal mitochondrial respiratory chain is the dominant source of free radical. Abheri Das Sarma et. al. Free Radicals and Their Role in Different Clinical Conditions ,International Journal of Pharma Sciences and Research (IJPSR),Vol.1(3), 2010, 185-192

11. Neurological disease and oxidative stress Oxidative stress has been investigated in neurological diseases including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis , memory loss, depression. In Alzheimer’s, numerous experimental and clinical studies have demonstrated that oxidative damage plays a key role in the loss of neurons and the progression to dementia . The production of ß-amyloid, a toxic peptide often found present in Alzheimer’s patients’ brain, is due to oxidative stress and plays an important role in the neurodegenerative processes Rheumatoid arthritis and oxidative stress Rheumatoid arthritis is an autoimmune disease characterized by chronic inflammation of the joints and tissue around the joints with infiltration of macrophages and activated T cells  The pathogenesis of this disease is due to the generation of ROS and RNS at the site of inflammation. Oxidative damage and inflammation in various rheumatic diseases were proved by increased levels of isoprostanes and prostaglandins in serum and synovial fluid compared to controls  pham-Huy.LA & et.al , free radical, antioxidants in disease and health , int j biomed sci , 2008 jun,v.4(2) :p 89-96

12. Nephropathy and oxidative stress Oxidative stress plays a role in a variety of renal diseases such as glomerulonephritis and tubulointerstitial nephritis, chronic renal failure, proteinuria, uremia . The nephrotoxicity of certain drugs such as cyclosporine, tacrolimus , gentamycin, bleomycin , vinblastine, is mainly due to oxidative stress via lipid peroxidation . Heavy metals and transition metals act as free radical inducers causing different forms of nephropathy and carcinogenicity Ocular disease and oxidative stress Oxidative stress is implicated in age-related mascular degeneration and cataracts by altering various cell types in the eye either photochemically or nonphotochemically . Under the action of free radicals, the crystalline proteins in the lens can cross-link and aggregate, leading to the formation of cataracts . In the retina, long-term exposure to radiation can inhibit mitosis in the retinal pigment epithelium and choroids, damage the photoreceptor outer segments, and has been associated with lipid peroxidation pham-Huy.LA & et.al, free radical, antioxidants in disease and health , int j biomed sci ,2008 jun,v.4(2) :p 89-96

13. Free radicals in beneficial role Free radicals perform many critical functions in our bodies in controlling the flow of blood through our arteries , to fight infection, to keep our brain alert and in focus. Phagocytic cells involved in body defense produce and mobilize oxygen free radicals to destroy the bacteria and other cells of foreign matter which they ingest. Similar to antioxidants, some free radicals at low levels are signaling molecules, i.e. they are responsible for turning on and off of genes. Some free radicals such as nitric oxide and superoxide are produced in very high amount by immune cells to poison viruses and bacteria. Some free radicals kill cancer cells , In fact certain cancer drugs aim in increasing the free radical amount in body . Abheri Das Sarma et. al. Free Radicals and Their Role in Different Clinical Conditions ,International Journal of Pharma Sciences and Research (IJPSR),Vol.1(3), 2010, 185-192