Download Block 1: Pathology Dr. Rosenzweig Test 1: Free Radicals Oxidative

Block 1: Pathology
Dr. Rosenzweig
Test 1: Free Radicals
Oxidative Stress
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injury by free radicals, particularly ROS, is important mechanism of cell damage in many pathological conditions
o eg: chemical/radiation injury, ischemia-reperfusion injury, cellular aging, and microbial killing by phagocytes
Free radicals: chemical spp have single Unpaired electron in outer orbit
o highly reactive
o attack organic/inorganic chemicals—proteins, lipids, carbs, nucleic acids—many of which are components of cell
membranes and nuclei
o some reactions= autocatalytic- propogating chain of damage
ROS: type of oxygen-derived free radical whose role in cell injury is well-est.
o produced normally during respiration, but typically removed by cellular defense systems
o FRs may be present at small concentrations, but don’t cause damage
o oxidative stress—excess of FRs
o produced in large amts by leukocytes (neutros and macros) during inflammation; aimed at killing microbes
o implicated in cell injury, cancer, aging, and some degenerative diseases such as Alzheimer’s
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Block 1: Pathology
Dr. Rosenzweig
Test 1: Free Radicals
Generation of FRs
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red-ox reactions that occur during normal metabolic processes
molecular O2 reduced to water with 4 electrons
small amounts of partially reduced intermediates are produced in which diff numbers of electrons have been transferred from
O2
o superoxide anion (one electron)
o hydrogen peroxide (two electrons)
o hydroxyl ions (three electrons
absorption of radient energy
o ionizing radiation (UV, X-rays) can hydrolyze water to hydroxyl rad. and H FRs
rapid bursts of ROS produced in activated leukocytes during inflammation
o controlled reaction carried out by plasma membrane multiprotein complex
o uses NADPH oxidase for redox rxn
o some intracellular oxidases generate superoxide anion
transition metals
o Fenton reaction: (H2O2 + Fe2+ Fe-3++ .OH + OH-)
o Fe/Cu donate/accept free electrons during intracellular reactions
o most intracellular free iron = ferric (Fe3+); must be reduced to ferrous state to participate in Fenton
Removal of FRs
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generally decay spontaneously
superoxide anion O2 and H2O2 in presence of water
conversion of H2O2 by SOD
decomposition to H2O by glutathione peroxidase, catalase
antioxidants: block FR formation/inactivate FRs
o eg: lipid-soluble vitamins E and A; ascorbic acid and glutathione in cytosol
Free Fe and Cu catalyze formation of ROS
o normal circumstances: binds to storage and transport proteins (eg: transferring, ferritin, lactoferrin, and
ceruloplasmin) prevents from participating in ROS generation
Enzymes act as FR-scavengin systems breaks down H2O2 and superoxide anion
o catalase: peroxisomes, decomposes H2O2 to O2 and H2O
o Superoxidase dismutases (SODs): found in many cell types and convert superoxide to H2O2
o Glutathione peroxidase: protects against injury by catalyzing free radical breakdown
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H2O2 + 2GSH → GSSG [glutathione homodimer] + 2H2O, or 2˙OH + 2GSH → GSSG + 2H2O
Pathologic Effects of FRs
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Lipid peroxidation in membranes
o in presence of O2, FRs may cause peroxidation of lipids within plasma and organellar membranes
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Block 1: Pathology
Dr. Rosenzweig
Test 1: Free Radicals
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Oxidative modification of proteins
o FRs promote oxidation of AA side chains, formation of covalent protein-protein cross-links (disulfide bonds) and
oxidation of protein backbone
o oxidative modification of proteins may damage the active sites of enzymes, disrupt the conformation of
structural proteins, and enhance proteasomal degradation of unfolded or misfolded proteins
Lesions in DNA
o can cause single- and double- strand breaks in DNA, cross-linking of DNA strands, and formation of adducts
o implicated in cell aging and malignant transformation of cell
Traditional thinking about FRs: cause necrosis (and they do) BUT can also trigger apoptosis
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