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freeradicals,FKUH

freeradicals,FKUH

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11/27/2015

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GERIATRIC SYSTEM BIOCHEMICAL CHANGE

**FREE RADICAL THEORY **TELOMERE

Department of Biochemistry Faculty of Medicine.Hasanuddin Univ. By Rosdiana Natzir

Free Radicals and Antioxidants

Free Radicals (FRs)
‡ These are highly reactive chemical entities that have a single unpaired electron in their outer most orbit. ‡ Under certain conditions can be highly toxic to the cells. ‡ Generally unstable and try to become stable, either by accepting or donating an electron.

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‡ However. they neutralise each other . ± Molecules with which they react are themselves converted to free radicals to propagate the chain of damages. ‡ This characteristic enables the FRs to participate in auto catalytic chain reactions.‡ Therefore if two FRs react. if the FRs react with stable molecules. 4 . there is generation of more free radicals.

But as they do not contain unpaired electrons in their outermost orbit.Reactive Oxygen Species (ROS): These are free radicals derived initially from oxygen. .H2O2. they do not qualify as free radicals and so are referred to separately as ROS. HOCL. Eg. NO. Free radicals are formed in side our body by both PHYSIOLOGICAL (Natural) and PATHOLOGICAL stimuli : 5 .

Physiological Stimuli that Form FRs ‡ Normal respiration ± ± ± ± ± O2 ± Superoxide. H2O2 ± Hydrogen Peroxide HOCL ± Hypochlorous acid NO ± Nitric Oxide ‡ Transition metals present inside our body when are in free form behave as free radicals. Cu+ 6 . Fe2+.

30/08/2002 7 . ‡ Ageing ‡ Phagocytosis or biogenetics ‡ Oxidation of foods and endogenous compounds. ± Macrophages (NO2) ± Neurones (ONOOH ± Peroxy nitrite).‡ Body cells± Endothelium (NO3 ± Nitric Oxide. NO2 ± Nitrous Oxide). ‡ Transportation of substances for energy production.

Pathological Stimuli that Form FRs ‡ Radiation pBreaks the water inside our body: H2O =H+ + OH‡ Metabolism of drugs p CCl3 ‡ Transition Metals p Cu+. Fe2+ ‡ Ultraviolet rays ‡ Emotional stress 30/08/2002 8 .

30/08/2002 9 . ‡ So FRs are also called OXIDANTS.Actions of FRs Mechanism of Action: ‡ They act on the cell membranes and membranes of different organelles of cells and cause cell injury and death by oxidative reactions.

leading to calcium influx and altered PH of the cell. ± These alterations in the enzymes and receptoors inside the cell lead to abnormal cell behaviour.Actions of FRs ‡ FRs cause lipid peroxidation. Methionine. ± FRs cause ± cross-linking of proteins and fragmentation of protein strands. By lipid peroxidation FR increases the permeability of cells. 30/08/2002 10 . oxidation of amino acids like cystene. ‡ FRs alter the enzyme and receptor proteins. ± The PUFA of cell membrane are more vulnerable for this injury.

This oxidative injury may be. 11 . ± Lethal ± Leading to cell death and ultimately removed by phagocytosis. ± Sub lethal . ‡ Mutation of cells.which may result in ‡ Increased cell permeability. ‡ Toxicity.Actions of FRs ‡ FRs cause fracturing on the cell nucleus resulting in single strand DNA damage.

Arteriosclerosis. Rheumatoid arthritis. Obesity. Myocardial reperfusion injury. Shock related injury. some electrons may escape oxidation and become FRs ‡ This chain reaction may produce diseases like: ± ± ± ± ± ± ± ± ± Carcinogenesis. 12 .FRs Induce Chain Reaction ‡ During the process of oxidant damage resulting in tissue destruction & degeneration. Diabetes. Etc. Adult respiratory diseases. Lipid abnormality.

‡ In normal healthy state a balance is maintained between FRs & AOs ‡ The µAO¶ activity of serum is measured as % inhibition of lipid peroxidation in a standardised brain homogenate. derived from oxygen. ‡ Moreover we can as well supplement these from outside (in vitro Antioxidants). 13 .Antioxidants (AOs) ‡ These are substances.

Blood. Mucus membrane Kidney. bone marrow.In Vivo Antioxidants: I.Enzymes Name SOD (Superoxide dismutase) CATALASE Acts against Super oxide Present in cytosol mitochondria. membranes of lipids. Liver. Haemoglobin and erythrocytes 14 H2 O 2 GOP (Glutathion H2 O2. lipid peroxidase) peroxidation .

Eg.-Transferin for Fe.II. Preventive AOs AOs These are binding proteins. they break the catalytic chain propagated by FRs. Ceruloplasmin for Cu III. Scavenger AOs AOs Also called chain breaking enzymes. They keep the free ions of plasma in a binding form. 30/08/2002 15 . so prevent oxidation injury.

In the form of Medicines: Vitamin A. Grape. Cystine. Bioflavines.In Vivo Antioxidants: . Food sources:  Green & yellow vegetables  Herbs: -Turmeric/kunyit. Carrot. Berries. Kidney. Spinach. II.Source I. C & E. Zn. Tea. Se. Glutathion. Melthionine. Liver & Lipoic Acid 16 . Broccoli. Garlic.  Red Meat.

30/08/2002 17 . ‡ When this equilibrium breaks. due to o FR formation or q AO system. a state called oxidation stress arises with in.Oxidative Stress: ‡ Under normal conditions body maintains an equilibrium between its own FR¶s and Antioxidants.

18 . ± Because of the rapidly growing foetus there is increased cellular activity.Example: AO Status in Normal Pregnancy: ‡ There is increased need for AOs as there is increased production of FRs due to ± Pregnancy being a stressful condition.

‡ drugs that lead to µFR¶ formation must be avoided. 30/08/2002 19 . ± o Activity of GOP(glutathione peroxidase) ± o Serum ceruloplasmin & transferring level.‡ Thus AO activity during normal pregnancy progressively increases as demonstrated by ± o Serum tocopherol.

± o lipid peroxidation in cell membranes in diabetic pregnancies ± Periods of maternal hyperglycaemia & hypoglycemia may cause marked changes in the availability of glucose to the foetus.AOs & Diabetic Embryopathy: ‡ Oxidative stress has been suggested to contribute to the increased risk of foetal malformations in poorly controlled diabetics. notably the ketone bodies and branched chain amino acids in the maternal circulation contribute to altered nutrition for the embryo. of lipids. ± o conc. 30/08/2002 20 .

30/08/2002 21 . ± This leads to o production of FR in embryonic tissues to cause congenital malformations.‡ During later part of pregnancy ± o load of glucose in the mitochondria may accelerate the flow of electrons through respiratory chain including mitochondrial leakage of free radicals.

maintenance of blood glucose level at euglycemic level is always important for prevention of Diabetic embryopathy .‡ Thus maintenance of normal concentration of metabolites of all nutrient class may be important for prevention of adverse foetal outcome. ‡ However. 22 .

‡ So FRs play a role in pathogenesis of Down¶s syndrome. ‡ Administration of AOs may help in preventing this disease.AOs & Down Syndrome: ‡ Free radicals being the hallmark of aging. are greatly increased with omaternal age. 23 .

± FRs are promoters of maternal vasoconstriction. ± Produce peroxynitrate. E. ‡ O2 .8 times higher in comparison to normal placenta. 24 . ± Severity of hypertension has been found to be inversely proportional to concentration of Vit.‡ Increased activity of free radicals promote maternal uterine vascular malformations. H2 O2 & NO2 in combinations ± Inactivate the NO (a vasorelaxant) ± Causes o PG synthatase activity. a potent oxidant ± Lipid peroxide in pre-eclamptic placenta is about 1.

Carcinogenesis: ‡ Basics of cancer formation: ± A normal cell can undergo malignant transformation in presence of procarcinogens and carcinogens. ± Without immune system detection a normal cell is converted to malignant cell in stages ±> ‡ Initiation p Promotion p Progression 25 .

Xenobiotics . which act on cellular targets to cause oxidant DNA damage in form of mutagenesis. 30/08/2002 26 .‡ Free radicals are formed from stimulants like ± Radiation .Inflammatory cells .Respiration etc.

. ‡ Inactivation or loss of tumour suppresser genes.which cause: . which cause promotion and progression of these initiated cells to cancer 30/08/2002 27 .initiation of carcinogenesis by‡ Activation of protooncogens. ± Procarcinogens are metabolically activated by FRs. ‡ Normal cell becomes initiated cell.

Spontaneous p ¡ Ÿn Repair by AOs Premalignant Cell ¡ p FRs p .FRs & AOs in Carcinogenesis: FRs p Activation of procarcinogens & Carcinogens pGenetic Damage Normal cell p Initiation p ¡ Ÿn Repair by AOs Initiated Cell p Promotion FRs p .Dysregulation .Tumour promoters .Greater Cell autonomy .Reduced Growth Factor dependence Progression p ¡ ¡o n Repair by AOs m Malignant Cell ¡ CLINICAL CANCER 28 30/08/2002 .

Eormation of toxic products.AOs in Cancer Prevention: ‡ DEFENCE: . Changes in cell permeability. Metabolic disturbances. ¡ Prevention of initiation of Carcinogenesis 30/08/2002 29 .enzymes with antioxidant property cause first line of defence by: ± Protecting the lipids and enzymes against oxidation p p Creating a balance of µAOs¶ against FRs in the body p PREVENTS : ‡ ‡ ‡ ‡ Cell pathology.

± Simulate oxygen. ± Maintenance of physical stability of membrane & also within cells.‡ INTERVENTION at promotion & progression stages: ± Local deactivation of genotoxins responsible for further nuclear mutations ± Inactivation of tumour promoters eg. 30 . ± Maintenance of proper function of gap junction communication..activation of granulocytes.

‡ Majority of epidemiological data suggest supplementation with antioxidants . C.beta carotene & selenium.. 31 . E. . decreases the incidence of various cancers.Vit.A.

200 IU Features Causing o Req.500 IU Possible Toxicity Level Chronic intake of 125. Heavy metals 32 Selenium None 50-200 mg . Smoking Negligible / 1.000 IU >1. Smoking. 2Gms OCP.Smoking >200mg Aging.RECOMMENDED FOR CARCINOMA PREVENTION Antioxidant RDA Recommende d Dose 12. Smoking Vitamin µA¶ 5000 IU Vitamin µE¶ Vitamin µC¶ 10-20 IU 60 mg 200-800 IU 1000 mg High PUFA intake.Stress. High PUFA intake.

‡ In asthenospermic and oligoasthenospermic males there is increased serum concentration of MDA. ‡ Even in normospermic males if there is o concentration of MDA there is reduced fertility. ‡ Addition of vitamin E causes decreased concentration of MDA and improves fertility. 33 .‡ Various studies have suggested Conc. of Malon ±di-Aldehyde (MDA) is inversely proportional to fertility in case of males.

± an arrest the cell growth (div) at 2. 4. 8 cell stages ± Hamper the regulation of corpus luteum. 34 .FRs & AOs in Infertility . ‡ Addition of µAOs¶ improves the results.Female ‡ FRs cause ± Short luteal phase .

So where there is life there are oxidants. Every O2 atom we breath in . 30/08/2002 35 . H2 O2 & OH are formed along with water. When four electrons are added three µFRs¶.is converted to water inside our body by addition of four electrons sequentially.CONCLUSION Oxidant generation is a part of human life.O2.

will go a long way to find out the exact contribution of oxidants in disease processes and the role of µAOs¶ to prevent it. However. careful use of µAOs¶ and newer and more accurate methods to measure oxidant generation in humans . So our concern should be to q FRs in systemic circulation.CONCLUSION But when produced in excess. 36 . they can cause any disease.

THANK YOU 37 .

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