FREE RADICALS

MECHANISM OF CELL INJURY BY

FREE RADICALS
 Free radicals are chemical species that have
a single unpaired electron in outer orbit.
 Highly reactive
 Some reactions are autocatalytic-propagating
the chain of damage
REACTIVE OXYGEN
SPECIES(ROS)

 Accumulation of oxygen derived free radicals

–OXIDATIVE STRESS
 Increased production and decrease in
scavenging of ROS –excess of free radicals.
 Pathologic process like
 cell injury,
 cancer ,
 cellular aging
 degenrative diseases-Alzheimers disease
 Chemical and radiation injury
 Microbial killing by phagocytes
GENERATION OF FREE RADICALS
 1.Reduction-oxidation reaction
 o₂+H₂ 2H₂o
 Partially reduced intermediates like
superoxide anion,hydrogen peroxide,hydroxyl
ion
 2.Absorption of radiant energy, e.g:uv light,x
rays
 H₂o o∙H + H
 3.During inflammation,ROS produced in
activated leukocytes
 Plasma membrane uses NADPH OXIDASE for
redox reaction,generate superoxide anion(
 o₂ o₂∙‾ H₂o₂

NADPH NADP
 4.Free radicals from exogenous chemical or
drug,having similar effects of ROS
E.g: ccl₄ ∙ccl₃
5.Transition metals like iron ,copper-catalyze
free radical formation
H₂o₂+Fe2+ Fe3+ + o∙H +oH‾
Fenton reaction
 Nitric oxide(NO),generated by endothelial
cells,macrophages and neurons.
 NITRIC OXIDE SYNTHASE
 Arginine NO
NO
 Can act as free radical
 NO + o₂ ONOO‾
REMOVAL OF FREE RADICAL
 Spontaneous decay
 Free radical scavening system

Non Enzymatic mechanism

Antioxidants
vitamin E,A,& Ascorbic acid,
glutathione in cytosol.
Reactivity of metals minimized by their
binding to storage and transport proteins
e.g: transferrin,ceruloplasmin,ferritin
 Enzymatic mechanisms
 Catalse enzyme- peroxisomes

2H₂o₂ o₂ +2H₂o
Superoxide dismutase-MnSOD:Mitochondria
copper-zn SOD :cytosol
o₂∙‾+2H H₂o₂+ o₂

Glutathione peroxidase

H₂o₂+2GSH GSSG+H₂o OR

2*OH+2GSH GSSG+H₂o
 Intracellular ratio of oxidised glutathione to
reduced glutathione is an important indicator
of cells ability to detoxify ROS
 Refflection of oxidative state of cell
PATHOLOGIC EFECTS OF FREE
RADICALS
 LIPID PEROXIDATION IN MEMBRANES
 Oxidative damage occur when double bonds
in USFA of membranes lipids attacked by free
radicals,*OH.
 Yields peroxides
 OXIDATIVE MODIFICATION OF PROTEINS
 Free radicals promote -Oxidation of aminoacid
sidechains
Formation of covalent protein-protein cross
lines
Oxidation of protein backbone
 Results in –damage active sites of enzymes
disrupt conformation of structural proteins
Enhance proteosomal degradation of
unfolded proteins
 LESIONS IN DNA
 free radicals cause single or double strand
breaks on DNA
 Crosslinking of DNA strands & formation of
adducts
 OXIDATIVE DNA damage-seen in cell aging,
malignant transformation of cells.
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