|Year : 1997 | Volume
| Issue : 9 | Page : 319-336
The free radicals - The hidden culprits - An update
M.L.N. Medical College, Allahabad-211 001., India
K N Ansari
M.D.D-13, G.T.B. Nagar (Karelii), ANahabad-211016. (U.P.)
|How to cite this article:|
Ansari K N. The free radicals - The hidden culprits - An update. Indian J Med Sci 1997;51:319-36
"A free radical is any species capable of independent existence, that contains one or more unpaired electrons."  A related term reactive oxygen species used to describe collectvely not only the oxygen derived free radicals but also the non-radical oxidants like hydrogen peroxide (H 2 0 2 ) and Hypochlorous acid (H+ocl) which are not unpaired electrons .  The essential prerequisite for stability of any atom or molecule is that the electrons in its outermost orbit may carry a positive or negative charge or may be electrically neutral but it should be paired.  In presence of any unpaired electron, the atom or molecule gets unstable and shows high reactivity in order to gain an electron from other atoms/molecules [Figure 1]. The salient features of free radicals are- 1. It contains an unpaired electron. 2. Unstable in nature. 3. Try to gain stability by snatching electrons from neighbouring entities, hence are reactive in nature. 4. In doing so, they initiate a chain reaction, which fits into the definition of oxidation. 5. The free radical oxidation moves from molecule to molecule, cell to cell, organelle to organelle, causing immense damage to the human body. 6. Implicated as culprits in a host of disorders.
Physiological Background: Oxygen is required to transform various substrates for the release of energy to oxidize endogenous compounds and to detoxify xenobiotics. During these metabolic processes oxygen acts as a terminal 4 electron acceptor and it is transformed through various stages to a stable chemical product water. However electron reduction of oxygen is frequently incomplete under normal condition and a series of chemical intermediate products are produced  [Figure 2]. However in human physiology, superoxide and hydroxyl redicals (also known as oxygen derived free radicals) togather with hydrogen peroxide and hypocholorous acid are important ones  Free radicals subserve the following functions:  1. They control mitochondrial oxidation. 2. Oxygen transport. 3. Cytochrome p45 activity for cellular metabolism. 4. Prostaglandin cascade through self deactivation of cyclooxygenase activity to modulate inflammatory process. 5. Free radical intermediates in neutriophils and macrophages initiate respiratory burst unrelated to mitochondrial electron transport at the onset of phagocytosis of invading bacteria to check infection. 6. Maintain the vascular tone by controlling the production of endothelium derived factor (EDRF). 7. Helps in detoxification process.
Sources of free Radicals: The production of free radicals is from two sources. 
I. Endogenous: (Produced during cellular metabolism).
1. Prostaglandin synthesis. 2. Mitochordrial electron transport. 3. Endoplasmic reticulum oxidation. 4. Enzyme activity. 5. Oxyhaemoglobin. 6. Autooxidation. 7. Phagocytosis.
1. Pesticides. 2. Air Pollutants (Industrial Pollution). 3. Smoke (Tabacco smoking). 4. Radiation. (Ionizing radiation and sun-light). 5. Drugs. It has been reported that generation of free radical is associated with side effects of many drugs. This may take three forms. (a) Toxin is a free radical e.g. Nitrogen dioxide (b) It is metabolised to a free radical e.g. carbon tetrachlorde. (c) It depletes antioxidant defence e.g. paracetamol.
Free radical production may also be increased during various disease states.  The details of biological sources of free radicals are depicted in [Table 1].
Important free Radicals: Although a large number of free radicals are formed, the following are responsible for inducing disease and hence need to be combated at all costs. 
1. Superoxide Radicals (0 2 ): This radical is the most important factor in oxygen toxicity. It is mainly derived from the electron transport chains of mitochondria and endoplasmic reticulum. It is responsible for damage associated with cardiac and intestinal ischemia.
2. Hydroxyl Radical (OH): This is derived from ionising radiations, iron and hydrogen peroxide. This is the most reactive radical and capable of damaging every type of molecules found in living cells-carbohydrate, amino acids, phospholipids, nucleicacid. It is also responsible for damage done to cellular DNA and to membranes.
3. Transition Metals: These are in a position to transit between two different states on the basis of electron transfer. These metals are iron copper and zinc. Amongst these iron has been shown to be a precursor of OH radical which is formed as a result of fenton reaction (reaction with H 2 0 2 ). This reaction is responsible for consequences of iron overload seen in thalassemic patients given blood transfusion. The reaction are as under:[Additional file 1]
Contrary to this, copper and zinc do not lead to the formation of hydroxyl ions since they are found in bound form. These free radicals are responsible for widespred and indiscriminate oxidation and peroxidation of lipid, denaturation of proteins, depolymerization of polysaccharides and break to modify DNA and any other cell causing cell death or organ damage because of huge chemical reactivity, autocatalytic potential and low chemical specificity, and low steady concentration of free radicals. The outcome of these indiscriminate and extensive oxidative damage will be cell membrane disruption, enzymatic inactivation, altered antigenicity and carcinogenesist. 
| ¤ Pathological Consequences of Free Radical Formation|| |
i. Lipid Peroxidation: This is the most common and dangerous type of free radical oxidation. As a consequence of interaction of free radical and lipid to form peroxide (intermediate free radicals) which subsequently lead to autocatalytic radical chain reactions, resulting in membrane damage for example carbon tetrachloride induced liver damage. Lipid peroxidation leads to majority of human diseases, such as atherosclerosis,  ischaemic perfusion injury  and hypertension. In tissue iscaemic hypoxia ATP is transformed through intermediate stages by hypoxanthines. This enzyme xanthine dehydrogenase, which is abundant in the gut and liver normally catalyses the-reaction. 
Hypoxanthine + H 2 O + NAD = Xanthine + NADH+H.
But in conditions of suboptimal oxygen concentration, such as ischaemia, activation of a Ca 2 +dependant protease induces a transformation of enzyme leading to predominantly oxidase activity. During ischaemia, xanthine oxidase will use any available oxygen as an electron acceptor and convert xanthine or hypoxanthine to uric acid with the production of superoxide radical. The production of this radical is greatly increased when the oxygen supply is restored producing extensive free radical mediated tissue damage - ischaemia reperfusion injury. lschaemia also releases iron from stored ferritin and via fenton reaction produces reactive hydroxyl radical. 
2. Other Pathological Consequences
(i) Free radical inhibits the production of, vasodilators namely endothelium derived relaxing factors which control micro-circulation. This may contribute to the genesis of pulmonary shock syndrome and postischaemic coronary vasocontriction.  (ii) Free radicals are released by activation of macrophage/kupffer cell activation. This process is triggered by immune complexes, endotoxin and activated complement causing damage in cases of resuscitation of critically ill patient resulting in multisystem organ failure characterized by failure of hepatic, renal and pulmonary systems.  (iii) Further it has been reported that tocopherols and beta carotene are the antioxidants that protect LDL molecule.  Alpha tocopherol is the principal lipid soluble chain breaking antioxidant in tissues and plasma. Betacarotene effectively scavenges oxidising radicals particularly singlet oxygen. Ascorbic acid is the first line defence against oxygen radicals in the water soluble compartment. The antioxidants may have a useful therapeutic role with cardioprotective potential to reduce endothelial damage and atheroma formation. 
(iv) Mediators of Inflammation  : Free radicals are important mediators of acute and chronic inflammatory reactions. During phagocytosis they are released into the extracellular space where they cause direct tissue injury and alter structural macromolecules such as elastin, collagen and hyaluronic acid. In addition they may react with a plasma component to produce a chemotactic substance that attracts more neutrophils to the site if inflammation, such as in rheumatoid arthritis where free radical mediated destruction of hyaluronic acid causes synovial fluid to lose its viscosity and joint cartilage to become eroded.
(v) Other common diseases where free radicals have been implicated are connective tissue disease, inflammatory bowel diseases, immune deficiency. and arthritis. Recently  Helicobacter pylori causing peptic ulcer has been reported to have powerful superoxide dismutase and extracellular catalase action of producing severe inflammation.
Free Radical Induced Diseases: Free radical entity is well proven cause of a vast , number of pathological disorders/diseases affecting various systems of human body.  [Table 2]. The following are the important ones:
1. CARDIOLOGY: The following two are important:
(a) Atherosclerosis: The free radicals are capable of damaging lipid (as LDL) through lipid peroxidation according to the following events:
LDL à Attacked by free radicals à sticky LDL (cannot be digested) à will act as nucleus for growth of atheroma à Athero-sclerosis. (b) Ischaemic Perfusion  : Lack of oxygen will cause extensive damage to ATP and lead to accumulation of hypoxanthines as per the following mechanism:[Additional file 2]
2. Endocrinology: The role of free radicals in causing clinical and experimental (Alloxan and streptozotocin induced) diabetes is established.  Lipid peroxidation generates lipid peroxides and peroxy radicals which will aggravate long standing diabetes according to the following mechanisms  :[Additional file 3]
The weakness of the antioxidant defence system may be the biochemical background for the pathogenesis of diabetes because they directly scavenge free radicals. 
3. Autoimmune Disease (Rheumatic Disease): In rheumaloid arthritis role of mediators of inflammation like prostaglandins and leukotriens has been established. In such patients neutrophils migrate into the synovium and release free radicals that attack and damage hyaluronic acid and cartilage of synovial fluid thus contributing to the contributing to the destruction of joints.
4. Ophthalmology: Two distinct pathological changes occur due to free radical generation -
(a) CataracF 6 : The free radicals could bind to many normal cellular compounds including proteins, nucleic acid and unsaturated fatty acid in the cell membrane. The eye is continuously exposed to sunlight and is therefore vulnerable to photo damage. Increased prevalence of cataract has been associated with increased exposure to sunlight. Exposure of the lens to ultraviolet light can enchance the process of opacification. Methionine is an aminoacid found in human lens. Free radicals act on methonirie giving rise to the formation of methionine suiphoxide according to the following reaction:[Additional file 4]
(b) Diabetic Retinopathy: The following reaction occurs as a consequence of free radical generation:[Additional file 5]
(c) Macular Degeneration: The mechanism of macular degeneration is as under :[Additional file 6]
(5) Hepatology:- Liver is damaged due to free radical generation causing majority of hepatic disorders such as cirrhosis, jaundice, drug induced and carbon tetrachloride induced liver toxicity. These are:
(a) Membrane Damage:- Free radicals (OH react with Phosphotidyl choline (lecithin) of the membrane damaging it according to the following mechanism:[Additional file 7]
(b) Carbon Tetrachdorlde Induced Liver Injury:- It occurs due to lipid per oxidation damaging the structure and function of endoplasmic reticulum and liver cell.
6. DERMATOLOGY:- Skin is very sensitive to attack by a variety of insults including free radicals, e.g. Porphyria . In this porphyrins accumulate in the skin and act as photo-sensitizers leading to formation of oxygen free radicals. Exposure to light causes local damage associated with unpleasant eruption, scarring, thickening according the following reaction:[Additional file 8]
Psoriasis: This occurs due to increased production of free radicals by phagocytes, which accumulate in the epidermal lesions.
7. Respiratory Disorders:- Two disorders occur due to increased free radical production. (a) Adult respiratory distress syndrone-This may manifest as acute respiratory failure due to pulmonary oedema leading to severe shock. Tissue damage may occur due to burns/ accidents or massive infections. In this neutrophil turnover and H 2 0 2 concentration are increased.
(b) Emphysema The following is the chain of reaction:[Additional file 9]
8. Gastroenterology: In Crohn's disease and ulcerative colitis, antibodies are formed in these patients due to increased neutrophil related oxidant activity.
9. Oncology:- The free radicals induce chain of reaction leading to initiation of carcinomas, due to DNA damage and mutagenesis.
10. Inflammation:- In any inflammatory process neutrophils and macrophages are involved which produce free radicals at the site of injury according to the following mechanisms:[Additional file 10]
11. Ageing:  It is established that anti-oxidant defences of human tissues are capable of protecting from day to day oxidative stresses. However, with advancing age this anti-oxidant defence becomes weak allowing upper hand to free radical generation causing tissue damage.  Premature ageing is due to excessive production of free radicals.
12. Drug & Chemicals:- Any substance leading to increased 0 2 and H 2 0 2 levels at normal oxygen concentration can damage cell. These are -
1. Herbicide Poisoning (paraquat) 2. Pesticide Poisoning (Carbontetrachloride) 3. Alloxan and Streptozotocin induced pancreatic damage. 4. Cigarette smoking. 5. Air Pollutants (Sulphur dioxide, Ozone) 6. Drugs (Antimalarials, Paracetamol) 7. Others (Alcohol, Chlorofurocarbons).
Antioxidant System of the Body: In healthy conditions subtle balance exists between free radical generation and antioxidant defence system by enzymes, vitamins and minerals at cellular level which prevent the occurrence of disease. However, factors tilting the balance in favour of free radical generation will lead to widespread oxidative tissue damage and disease [Figure 3]. The degenerative processes occurring in our body are unseen by human eyes. The free radicals are invisible silent killers at work. It has been estimated that the DNA in each cell of human body receives about 10,000 oxidating hits (oxidative stress) per day. However, human body makes use of certain substances that counter the process of free radical oxidation. This defence system of the body is known as antioxidants system. This system consists of substances that provide the much needed stability to free radical by allowing the pairing of electron. This Antioxidant defence can conveniently be classified into two groups: Defence by Enzymes and defence by Micronutrients. 
Defence by Enzymes: These enzymes are known as free radical scavengers which remove free radicals directly irrespective of their source. The primary intracellular enzymes which scavenge free radicals include the following:
1. Catalase:- This is a haem centred enzyme responsible for decomposition of hydrogen peroxide
2H 2 0 2 à 2H 2 0+0 2 to water and oxygen. This enzyme is associated in its different forms with zinc, copper and manganese, and is a potent antioxidant, specially gainst the superoxide radicals and singlet oxygen. This enzyme keeps the body healthy by mopping up the reactive oxygen radicals and, there by, . protecting the body against oxidative stress of the free radicals. This enzyme catalyses the following reaction called 'Dismutation'.
O 2 0 +O 2 0 + 2H à H 2 0 2 +02
he copper and managanese ions undergo alternate oxidation - reduction reaction, whereas zinc contributes to the stability of the enzyme.
3. Glutathione Peroxidase: The enzyme catalyses the oxidation of reduced glutathione (GSSH) to its oxidised form (GSSG), at the expense of hydrogen peroxide.
H 2 02 = 2 GSH à GSSG + H 2
The active site of the enzyme contains selenium, and in fact, several symptoms of selenium deficiency have been explained due to lack of glutathione peroxidase. The enzyme is found at high activity in liver and moderate activity in heart, lung and brain. It is predominantly present in cytosal and mitochondrial matrix.
4. Methionine Sulphoxide Reducatase: The aminoacid methoionine can be oxidised by free radicals to methionine sulphoxide. The protein within the lens of cataract patient contains significant amount of this substance. This is removed by the enzyme methionine sulphoxide reductase.
Defense by Micronutrients: These include vitamins and other micronutrients ,
Vitamins: These include beta carotene the precursor of Vit A and tocopherols (Vit E). Both are lipid soluble oxidant scavengers that protect biomembrane. Ascorbic acid (VitC) and GSH are important water soluble antioxidants. It has been reported that people who took supplements of Vit A or betacarotene, Vit E, Vit C, Copper and selenium were 37% less likely to develop cataract and blindness.
1. Betacarotene: This is precursor of Vit A. There is controversy as to only betacarotene is free radical scavenger or betacarotene and Vit. A both. However, the role of betacarotene in protecting cell membrane from inside is an established fact. It forms primary ring of protection in lipid compartment.
2. Vitamin E (Tocopherol): Vit. E is the oldest recognised biological antioxidant. It is hydrophilic and protects cell membrane from outside. It also protects circulating lipoproteins. Its concentration in the membrane of the rods, lipoproteins and adrenal glands is higher as compared to that in the mitochondria and protects these structures against lipid peroxidation by reacting with lipid peroxide radicals and acts as the chain terminator. Vit. E also forms primary ring of protection in the lipid compartment.
3. Vitamin C (Ascorbic Acid): This vitamin is hydrophilic and hence forms primary rings of protection in hydrophilic compartment. The primary role of vitamin C is maintaining the phagocytic activity at an optimum level being present in neutrophil in 50 times more concentration than in extracellular compartment. Vit. C scavenges ferociously destructive Hydroxyl radicals. It also potentiates Vit. E. It is one of the important antioxidant of cardiovascular and respiratory systems.
Minerals: Certain minerals revive the natural antioxidant ring of protection. It has been established that these minerals such as zinc, copper, manganese and selenium are essential for efficient functioning of human antioxidant defence specially the enzymes. Copper, manganese and zinc are essential components and subunits of major human natural antioxidant defence, i.e. superoxide dismutase. Selenium activates body's first line antioxidant defence i.e. glutathione peroxidase.
Remedial Measures: The body has well developed endogenous antioxidant defence system like cellular enzymes and viamins which play an important role in protecting cells from the free radical induced damages. However, the measures employed to counter the adverse consequences of excess free radicals are non-pharmacological and pharmacologiacal. ,
Non-Pharmacological: These measure are as under:
1. Change of Life Style : . These measures induce more production of superoxide dismutase and include avoidance of Stress, physical exercise, yoga and transcendental meditation.
2. Diet :  Nutrition supplement rich in vitamins and minerals are necessary to counter the free radical damage. Intracellularly the defence system largely depends on antioxidant enzymes which require certain micronutrients such as selenium, copper, zinc, iron, ribotflavin etc. for efficient functioning.
Antioxidant compound intercept oxidant molecules and terminates the reactions producing harmless end products. Dietary intake of micronutrients with antioxidant capabilities can protect against excess free radical attack. Naturally occurring antioxidant of potential importance include riboflavin, ascorbic acid, tocopherols, carotenoids and glutathione.
Pharmacological: These are further divided into synthetic and natural [Table 3].
Synthetic: These are: 1. Applied chemical nutrition, 2.Hyperbaric oxygen therapy, 3. Chelating agents  such as E.D.T.A. can chelate free radicals. Desferrioxamine is a potent iron chelator. Desferrioxamine is used in the treatment of rheumatoid arthritis.  It can also chelate copper by preventing hydroxyl radicals production.
4. Enzymes: Superoxide dismutase  removes superoxide radicals whereas catalase and glutathione peroxidase decrease the extracellular concentration of hydrogen peroxide. Preparations of superoxide dismutase have been approved for therapeutic  use in sports injuries such as tennis elbow, froen shoulder, tenosynovitis. Recently it has been tried in osteoarthritis of knee joint and other periarticular diseases. It is not absorbed from g.i tract but is effective when injected locally in joint space to reach intracellular sites of free radicals.
Superoxide dismutase has also been tried with limited success in reducing hypoxic damage to lungs in animal models of adult respiratory distress syndrome.
Vitamins: Ascorbic acid (Vit. C) Tocopherols (Vit.E) and Betacarotene (Vit. A). Ascorbic acid converts the free radicals into less harmful and more stable derivatives and also can regenerate the Vit.E into its antioxidant form. The role of ascorbic acid to protect tissues enzymes in their reduced form has been confirmed.
Tocopherols protect the cell membrane and low density lipid from lipid peroxidation. Apart from free radical scavenging effect in the treatment of a variety of disorders, Vit. E has also been tried in retrolental fibroplasia and haemoiytic syndrome of premature babies. Betacarotene, a precursor of Vit. A reacts with singlet oxygen. It is a very important free radical scavenger.
5. Allopurinol:  It is xanthine oxidase inhibitor which has been shown in animal studies to suppress ischaemic injury in the gut, heart, kidney and brain exacerbated by reperfusion. It is worth considering this drug for limiting ischaemic damage.
6. Dimethyl Sulphoxide and Diathiothreitol.  These are free radical scavengers and effective against reducing the radiation induced oxidative damage in experimental animals.
7. ACE Inhibitors.  Captopril an angiotensin converting enzyme inhibitor is a free radical scavenger in vitro which is due to presence of sulphydryl group present in the molecule. This provides a rationale for its use in the treatment of hypertension associated with diabetic nephropathy in which free radical mechanism has been implicated.
8. Calcium Channel Blockers.  Nifedipine and verapamil have been shown to suppress lipid peroxidation and enhance recovery of myocardial contractility in the experimental ischaemic heart of rat model. This has led to its use in the treatment of hepertension where free radicals have been implicated.
9. Pentoxyfylline.  Recently this drug has been reported to block cytokine induced Ieucoyte adherence. chemotaxis and free radical production and to improve survival following experimentally induced haemorrhagic shock.
10. Gabexate Measilate :  It is a leucocyte adhesion inhibitor and has been recommended for free radical induced diseases such as endotoxin shock, acute pancreatits and polyarthritis. The agent is free radical scavenger acting by inhibiting superoxide production by neutrophils.
Probucol:  It is a synthetic iipophilic antioxidant related structurally to butylated hydroxytoluene. It lowers plasma cholesterol in animals and humans. The drug suffers from the drawbacks that it reduces HDL cholesterol even more than LDL cholesterol. However, interest in probucol has been rekindled recently because of the possibility that it may retard- atherosclerosis by antioxidant mechanisms that extend beyond its effects on plasma cholesterol concentration. Dose - 250-300mg. twice daily taken with morning and evening meals.
Herbal Preparations Having Antioxidant Potential: The use of natural substances having antioxidant properties in food presservation is now well established. Antioxidants are also used to prevent oxidative damage during sterilization of food stuffs by ionizing radiations. The natural or herbal substances exists in natural state as a part of larger molecules. Upon ingestion in the stomach in the presence of acidic medium low molecular weight antioxidants are liberated which are well absorbed from the intestine. Such substances are: alphatocopherol, flavinoids, beta carotene, ascorbate, polyphenols, - riboflavin, catechins.
1. Maharishi Amrit Kalash , (MAK 4 & 5): This is herbal food supplement containing antioxidants like tannic acid, flavinoids, catechine, tocopherols, betacarotene, ascorbate and riboflavin. Administration of MAK 4 and 5 during intensive chemotherapy by anticancer drugs decreases the free radicals and reactive oxygen species related cell injury. It is also associated with decrease in the side effects and toxicities of chemotherapy and subjective over all feeling of well being.
2. Clover:  Clove and its active principle Eugenol has been reported to ,have antioxidant activity capable of preventing destruction of membranes, chromosomes and several other organelles leading to several degenerating disorders like cardiovascular diseases, cancer, accelerated ageing and so many others induced by free radicals. Eugenol being a naturally occurring phenolic compound with antioxidant properties could be an ideal agent to confer health benefits. Its antioxidant activity was evaluated in vitro using non-enzymatic and enzymatic lipid peroxidation system. Eugenol was found to be effective in inhibiting peroxidation in all the systems to a varying extent. The intake level of cloves through commonly consumed spice mixture in Indian diet are not only devoid of harmful effects but decisively bestow beneficial properties.
3. Other Antioxidants of Plant Origin:These compounds are phenols such as quercetin, carnosol, thymol, rutin, elleagic acid, vanilline etc.
Mode of Action of Antioxidant: Antioxidants whether from synthetic source or herbal are molecules which give electron to free radical and terminate chain reactions. Antioxidant radicals themselves are least reactive, harmless and quite often quench themselves. Therefore, antioxidants assume utmost importance in the context of disposing of harmful free radical.
Free radicals are normally produced as a by-product of cellular metabolism. Free radicals are capable of killing bacteria, damage biomolecules, provoke immune response, activate oncogens, cause atherogenesis and enhance ageing process. However, in healthy conditions nature has endowed human body with enormous antioxidant potential. Subtle balance exists between free radical generation and antioxidant defence system to cope with oxidative stress by various enzymes and vitamins at cellular level which prevent the occurrence of disease. However, factors tilting the balance in favour of excess free radicals generation lead to widespread oxidative tissue damage and diseases. Therefore, trouble starts when there is an excess of free radicals and the defence mechanism lags behind. Overwhelming production of free radicals in response to exposure to toxic chemicals and ageing may necessitate judicious antioxidant supplement to help alleviate free radical mediated damage.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
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