Free radicals and cell injury

FREE RADICALS AND CELL INJURY

• Free radicals are chemical species that have a single unpaired electron in an outer orbit. Energy created by this unstable configuration is released through reactions with adjacent molecules , such as proteins, lipids, carbohydrates in membranes & nucleic acid

• Free radicals initiate autocatalytic reactions whereby molecules with which they react are themselves converted into free radicals to propagate the chain of damage  

• Free radicals are generated by

  • The reduction –  oxidation reactions that occurs during normal metabolic process

    • Cells generate energy by reducing molecular oxygen to water

    • During this process, small amount of partially reduced reactive oxygen forms [i,e. Superoxide anion radical (O₂^–), Hydrogen peroxide (H₂O₂), and Hydroxyl ions (OH^–)] are produced in which different numbers of electrons have been transferred from O2

  • Absorption of radiant energy (UV rays , x-rays)- ionizing radiation can hydrolyze water into Hydroxyl (OH^–) and hydrogen (H) free radicals

  • Rapid bursts of Superoxide production occurs in the activated polymorphonuclear leukocytes during inflammation

  • Nitric oxide –

    • NO is produced by endothelial cells, macrophages, neurons and other cell types

    • NO can act as free radical and can also be converted into highly reactive peroxynitrite anion (ONOO^–), NO₂ and NO₃^–

  • Enzymatic metabolism of exogenous chemicals and drugs generate free radicals e.g. – CCl3 from CCl4

  • Reperfusion injury

  • Transition metals such as iron and copper donate or accept free electrons during intracellular reactions and catalyze free radical formation (Fenton reaction)

• Cells have defense system to prevent free radical injury

  • Normally free radicals are neutralized by anti – oxidant enzymes and substances like

    • Superoxide dismutase – present in cytoplasm and produced by mitochondria

    • Catalase – produced by peroxisomes

    • Glutathione peroxidase – produced by mitochondria and present in cytoplasm

    • Vitamin C in cytoplasm

    • Ferritin and Ceruloplasmin present in cytoplasm – Levels of active forms of iron and copper are minimized by binding of ions to storage and transport proteins like transferrin, ferritin, ceruloplasmin there by minimizing the formation of hydroxyl ion

    • Vitamins E, A and β Carotene in the plasma membrane and cell membrane of organelles

  • An imbalance between free radical generating & radical scavenging systems results in “oxidative stress”

• Fenton reaction

  • Oxygen is converted into superoxide (O₂^–) by oxidative enzymes in the endoplasmic reticulum, mitochondria, plasma membrane, peroxisomes and cytosol

  • Superoxide (O₂^–) is converted into Hydrogen peroxide by dismutation. Hydrogen peroxide is also derived from oxidases in peroxisomes

  • Hydrogen peroxide is converted into Hydroxyl by the Cu²⁺/ Fe²⁺ catalyzed Fenton reaction. This reaction is reversible and hydroxyl can be converted into hydrogen peroxide in the presence of Glutathione peroxidase

  • Intracellular free iron is in the Ferric state (Fe³⁺) and must be reduced to Ferrous form to participate in reaction

 

• Effects of Free radicals are-

  • • Lipid peroxidation of membrane

    • Oxidative modification of proteins

    • Lesions in DNA

  • Lipid peroxidation of membrane –

    • Double bonds in unsaturated fatty acids of membrane lipids are attacked by oxygen derived free radicals, particularly by OH

    • This produces peroxides which initiates the autocatalytic reaction

  • Oxidative modification of proteins

    • Free radicals promote oxidation of amino acid residue side chains, formation of protein-protein cross linkages (e.g. disulfide bonds ) & oxidation of protein back bone       protein fragmentation

    • Oxidative modification of proteins damage the active sites of enzymes, disrupt the conformation of structural proteins and enhance proteosomal degradation of unfolded and misfolded proteins

  • Lesions in DNA

    • Free radicals cause single and double stranded breaks in DNA, cross – linking of DNA strands and formation of adducts

    • Oxidative DNA damage has been implicated in cell ageing & in malignant transformation

Reference

• Kumar, Abbas and Fausto. Robbins and Cotrans Pathologic Basis of Disease. 8th edition