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    Free Radicals

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    Mashyem Ahmed
    Free radicals are unstable chemical species with unpaired electrons that can damage cells. They are produced during normal metabolism but also by environmental factors like radiation and pollution. While low levels play some beneficial roles in immune function, high levels can cause lipid peroxidation, protein and DNA damage linked to diseases. The body has antioxidant defenses including enzymes like superoxide dismutase, catalase and glutathione peroxidase as well as non-enzymatic antioxidants from diet and endogenous synthesis that scavenge free radicals and limit oxidative damage. Maintaining adequate antioxidant levels is important for health but excessive antioxidants may also have negative effects.

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    Free Radicals

    Uploaded by

    Mashyem Ahmed
    30 views67 pages
    Free radicals are unstable chemical species with unpaired electrons that can damage cells. They are produced during normal metabolism but also by environmental factors like radiation and pollution. While low levels play some beneficial roles in immune function, high levels can cause lipid peroxidation, protein and DNA damage linked to diseases. The body has antioxidant defenses including enzymes like superoxide dismutase, catalase and glutathione peroxidase as well as non-enzymatic antioxidants from diet and endogenous synthesis that scavenge free radicals and limit oxidative damage. Maintaining adequate antioxidant levels is important for health but excessive antioxidants may also have negative effects.

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    Free radicals are unstable chemical species with unpaired electrons that can damage cells. They are produced during normal metabolism but also by environmental factors like radiation and pollution. While low levels play some beneficial roles in immune function, high levels can cause lipid peroxidation, protein and DNA damage linked to diseases. The body has antioxidant defenses including enzymes like superoxide dismutase, catalase and glutathione peroxidase as well as non-enzymatic antioxidants from diet and endogenous synthesis that scavenge free radicals and limit oxidative damage. Maintaining adequate antioxidant levels is important for health but excessive antioxidants may also have negative effects.

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    Download as pdf or txt
    30 views67 pages

    Free Radicals

    Uploaded by

    Mashyem Ahmed
    Free radicals are unstable chemical species with unpaired electrons that can damage cells. They are produced during normal metabolism but also by environmental factors like radiation and pollution. While low levels play some beneficial roles in immune function, high levels can cause lipid peroxidation, protein and DNA damage linked to diseases. The body has antioxidant defenses including enzymes like superoxide dismutase, catalase and glutathione peroxidase as well as non-enzymatic antioxidants from diet and endogenous synthesis that scavenge free radicals and limit oxidative damage. Maintaining adequate antioxidant levels is important for health but excessive antioxidants may also have negative effects.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PDF, TXT or read online from Scribd
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    of 67

    Free Radicals

    Objective
    What are they? What are their source ? What damage do they cause ? How we can prevent their effects ?

    What is free radical?

    Definition
    Any chemical species (can be atom, ions, molecule)with one or more unpaired electrons Tend to reach equilibrium, plucks an electron from the nearest intact molecule. Eg 1. Superoxide O2 2. Nitrogen oxide NO .

    ROS (reactive oxygen species)


    Free radicals Particals which are not free radicals Superoxide O2 Hydroxyl radical OH Hydrogen peroxide H2O2 Hypochlorous acid HClO Peroxyl ROO Ozone O3 Alkoxyl RO Hydroperoxyl HO2

    RNS (reactive nitrogen species)


    Particals which are not Free radicals free radicals Nitrogen(II) oxide, NO . Nitrosyl NO+ Nitrogen(IV) oxide, NO2 . Nitrous acid HONO Nitogen(III) oxide, N2O3 Peroxynitrite ONOO Alkylperoxinitrite ROONO

    Formation of Free Radicals


    1. Hemolysis of covalent bonds A:B A. + B. 2. Addition of a single electron to a neutral atom A+e A-. 3. Loss of a single electron from a neutral atom A A+. + e

    Mechanism of radical reactions


    1. Initiation (homolytic covalent bonds cleavage) 2. Propagation (chain propagation) 3. Termination

    Source Of Free Radicals


    Body uses oxygen in metabolic reactions. Sometimes oxygen reacts with body compounds and forms unstable molecules called free radicals. Free radicals can also be formed by environmental factors:
    Ultraviolet radiation Air pollution Tobacco smoke.

    Where are radicals produced ?

    Sources of free radicals


    Mitochondria, NO, O2 , H2O2 Endothelial Cells, NO, O2 , H2O2 Immune cells (anti-bactericidal) Hypochlorous acid (bleach) NO, O2 , H2O2

    Sources of free radicals


    membranes enzymes and/or coenzymes with flavine structures, hem coenzymes, enzymes containing Cu atom in an active site 1. respiratory chain mitochondria : mainly superoxide and then H2O2 approx 1- 5% O2 entres into resp. chain (mainly complexes I a III)

    4H+ + O2 2H2O (~95% of the time) O2 *O2- H2O2* Only 1-5% generate free radicals

    The main sources of free radicals II


    2. Endoplasmic reticulum superoxide creation (by cytochrome P- 450) 3. Hemoglobin to methemoglobin oxidation (erytrocyte is full of antioxidants)

    Leukocytes superoxide creation by NADP-oxidas

    Fig. 12

    Cellular sources of ROS

    Sources of ROS
    Ionizing Radiation generates OH

    Is free radicals dangerous or beneficial ?

    Free Radicals
    Sometimes free radical attacks can be beneficial. For example, the immune system uses free radicals as an oxidative burst to destroy disease causing viruses and bacteria.

    Positive Effects of Free Radicals


    Immune system: neutrophils and macrophages use ROS to destroy engulfed microorganisms 2O2 + NADPH NADPH-oxidase 2O .- + NADP+ + H+ O2.- can be converted to H2O2 by SOD. The H2O2 can then be transformed to HOCL by myeloperoxidase O2.SOD H2O2 myeloperoxidase HOCl O2.- and HOCL are powerful oxidizing agents that degrade microbes.

    Positive Effects of Free Radicals


    Can serve as second messengers or modify oxidation-reduction (redox) states. Involved in some enzyme activation. Involved in drug detoxification. Play an essential role in muscle contraction.

    Negative Effects of Free Radicals


    Because of their reactive nature free radicals can provoke inflammation or altered cellular functions through: Lipid peroxidation Protein modification DNA modification

    Lipid Peroxidation
    Lipid peroxidation is a complex process and a wide range of products are formed in variable amounts. The major products are: 1. ,-unsaturated reactive aldehydes 4-hydroxy-2-nonenal (HNE) malondialehyde (MDA) 2-propenal (acrolein) 2. isoprostanes

    The lipid aldehydes are relatively stable, but reactive, and can diffuse within or escape from the cell and attack targets far from their site of formation. They can be regarded as second cytotoxic messengers.

    They can react with various biomolecules including protein, DNA and phospholipids generating stable end-products. 1. They react with amino acids, mainly Cys, His and Lys, to modify protein structure and function. 2. They can cross-link lipids in cell membranes interrupting structure and fluidity. 3. They can react with DNA to form a number of DNA adducts having mutagenic and carcinogenic effects.

    Protein Modification
    Proteins are major targets of free radical attack because of their high abundance and because they are primarily responsible for most functional processes within cells. Protein modification may alter every level of protein structure from primary to quaternary causing major structural changes.

    Oxidative damage is induced


    1. 2. 3. 4. Peptide backbone cleavage or fragmentation Peptide cross-linking Proteolytic enzymes susceptibility Modification of the side chains of virtually every amino acid by the formation of new reactive groups (from tyr, cys, his, pro, lys, arg, trp, phe, val) or the formation of protein carbonyls.

    Chemical structures of protein carbonyls arising from direct oxidation of amino acid side chains

    Protein Modification
    Most damage is irreparable and may have a wide range of down steam consequences affecting the function of receptors, enzymes, transport proteins etc and may generate new antigens provoking an immune response. In turn it can result in secondary damage to other biomolecules such as inactivation of DNA repair enzymes and loss of fidelity of damaged DNA polymerase in replicating DNA.

    DNA Modification
    Free radicals induce several types of DNA damage including Strand breaks, DNA-protein cross-links a large range of base and sugar modifications.

    DNA Modification
    Hydroxyl radical (OH) is the most prominent in the development of base and sugar modifications. DNA damage also occurs through reactive nitrogen species undergoing mainly nitration and deamination of purines. The net result is an increased risk of mutagenesis and carcinogenesis.

    DNA Modification
    Oxidative damage to DNA is repaired by cellular repair systems and DNA base damage is thought to be repaired mainly by baseexcision repair.

    Free Radicals and Disease

    Free Radicals and Disease


    If free radical damage becomes extensive, health problems can develop. Oxidative and nitrosative stress has been identified as a causative factor in: Cognitive performance Aging process Development of diseases such as cancer, arthritis, cataracts, and heart disease

    Are you ready to fight the attack of prooxidants?


    O-2, 1O2, .OH, H2O2, Cu, Fe. R, RO, ROO

    Antioxidant
    Prooxidant Jail

    R, RO, ROO,
    1O , 2

    O-2,

    -OH, H2O2, Cu, Fe

    What is Antioxidant?
    A substance when present in trace (small) amounts inhibits the oxidation of the bulk

    Good antioxidants
    Relatively un-reactive (antioxidant) Repaired Rapidly Decays to harmless products

    Levels of antioxidant defence system


    Inhibition of production the abundance of RONS Capture of radicals (scavengers, trappers, quenchers) Correction mechanism of destroyed biomoleculs

    Antioxidants

    Endogennous

    Exogennous Vitamin, trace elements and others

    Enzymes

    Nonenzymatic

    Antioxidants and scavengers review


    1. Endogennous antioxidants Enzymes (cytochrome c, SOD, GSHPx, catalase) Nonenzymatic - out of membranes (transferrin, bilirubin) - fixed in membranes (coenzym Q 10)

    Enzymes defence mechanism

    Superoxid dismutase
    2O2. - + 2H+ H2O2 + O2 SOD - is present in all oxygen-metabolizing cells Different cofactors (metals) an inducible in case of superoxide overproduction 3 isoforms: Cytosol, mitochondria, extracellular

    Superoxid dismutase
    Mn 2+ SOD (SOD1) tetramer matrix mitochondria lower stability then Cu, Zn - SOD

    Superoxid dismutase
    Cu 2+/Zn 2+ SOD (SOD 2) dimer, Cu = redox centr cytosol, intermitochondrial space hepatocyt, brain, erytrocyte high stability, catalysation at pH 4,5-9,5

    Glutathion peroxidases
    Eliminat intracellular hydroperoxides and H2O2 2 GSH + ROOH GSSH + H2O + ROH Cytosolic GSH - glutathionperoxidasa Extracelullar GSH - glutathionperoxidasa Phospholipidhydroperoxide GSH - peroxidase

    Catalasa
    2 H2O2 2 H2O + O2 Have high affinity to H2O2 Peroxisomes hepatocytes mitochondria, cytoplasm of erytrocytes Tetramer with Fe, needs NADPH

    High-molecula endogennous antioxidants


    1. Transferrin

    2. 3. 4. 5.

    Ferritin Haptoglobin Hemopexin Albumin

    6. Uric acid (urates) 7. Bilirubin

    Low-molecule endogennous antioxidats II ubiquinone (coenzyme Q) electron carrier in respisratory chain co-operates with tocopheryl

    Low-molecule endogennous antioxidats IV Lipoic acid (lipoate) PDH cofactor tocopheryl and ascorbate regeneration melatonin lipophilic ; hydroxyl radicals scavenger

    Antioxidants and scavengers review II


    2. Exogennous antioxidants FR scavengers trace elements drugs and compounds influence to FR metabolism

    Trace elements influence to FR metabolism


    Selenium influence to vitamin E resorption, part of selenoproteins of Se = insufficient immun. respons, erytrocytes hemolysis, methemoglobin synthesis Zinc cell membrane stabilisation Fe antagonist

    1. Vitamin E (alpha-tocopherol) 2. Vitamin C (ascorbic acid) 3. -carotene (pre-cursor to retinol)

    Vitamin C (ascorbate)
    Is antioxidant Can donate e- to vitamin E to regenerate Vitamin E
    Water-soluble, circulates blood and fluids to access membranes

    Vitamin E (-tocopherol)

    Phenolic Compounds
    Phenolic acids Flavones, flavonols, flavanones,

    Flavonoids are antioxidants


    May inhibit enzymes responsible for ROS (xanthing oxidase) May chelate Fe and Cu; free-radical scavengers

    Muscle-Antioxidant Defenses

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