Oxidative Stress

Question 1

oxidation

Answer 1

loss of electrons

Question 2

reduction

Answer 2

gain of electrons

Question 3

reactive oxygen species (ROS)

Answer 3

produced as byproducts of normal aerobic metabolism

Question 4

oxygen is a powerful

Answer 4

oxidizing agent (acceptor of electrons)

Question 5

radical

Answer 5

any molecule containing one or more unpaired electrons

Question 6

the two-electron reduction product of oxygen to hydrogen peroxide

Answer 6

does NOT qualify as a radical because it contains no unpaired electrons

Question 7

hydrogen peroxide

Answer 7

is relatively unreactive damage caused is believed to result from the production of highly-reactive hydroxyl radical can react with reduced forms of certain metal ions like iron(II) or copper(I) to produce hydroxyl radical and hydroxyl anion

Question 8

hydroxyl radical is

Answer 8

extremely reactive and can react with almost every molecule found in a living cell - because of this it often doesn’t diffuse very far

Question 9

Intracellular sources of partially reduced oxygen species under normal physiological conditions - 6 kinds

Answer 9

1. auto-oxidation of small molecules 2. soluble enzymes and proteins 3. mitochondrial electron transport 4. endoplasmic reticulum and nuclear membrane electron transport systems 5. peroxisomes 6. plasma membrane

Question 10

auto-oxidation of small molecule

Answer 10

include reduced forms of thiols (-SH), hydroquinones, catecholamines, flavins, tetrahydropterins and heme proteins. Superoxide anion radical is the primary radical formed

Question 11

superoxide anion radical

Answer 11

a good reductant and fair oxidant, it can produce hydrogen peroxide by spontaneous or enzymatic dismutation reaction

Question 12

dismutation

Answer 12

a process of simultaneous oxidation and reduction

Question 13

soluble enzymes and proteins

Answer 13

produce O2- directly these enzyme include xanthine oxidase and aldehyde oxidase

Question 14

mitochondrial electron transport

Answer 14

mitochondrion is a major subcellular site for generation of ROSs the electron transport chain consists of 4 complexes of enzymes, these complexes transport 4 electrons from NADH and FADH2 to reduce oxygen to water - the last complex cytochrome oxidase keeps all the partially-reduced oxygen intermediates tightly bound to its active state (this is the site of the O2- production

Question 15

about what percent of the total electron flux through the chain leaks off to molecular oxygen prematurely to generate…

Answer 15

about 1% of the total electron flux through the chain leaks off to molecular oxygen prematurely to generate superoxide the rate of electron leakage in mitochondria rises with O2 concentration, generation of superoxide anion radical by mitochondria is increased when respiratory chain carriers located on the inner membrane are highly reduced

Question 16

endoplasmic reticulum and nucelar membrane electron transport systems

Answer 16

major mechanism that generates superoxide anion radical is mediated by the cytochrome P450 catayze hydroxylation of xenobiotics and reduce dioxygen

Question 17

peroxisomes

Answer 17

potent sources of cellular H2O2 because of high concentrations of oxidases enzymes including D-amino acid oxidase, urate oxidase, L-alpha hydroxyacid oxidase, and fatty acyl-CoA oxidase also contain catalase to detoxify H2O2

Question 18

Plasma Membrane

Answer 18

critical site for the generation of ROS due to the presence of NAPDH oxidase

Question 19

NADPH oxidase

Answer 19

is a complex enzyme consisting of 2 membrane-bound components and 3 components in the cytosol, plus Rac1 or Rac2. activation involves the phosphorylation of one of the cytosolic components - NADPH oxidase generates superoxide by transferring electrons from NADPH inside the cell across the membrane to extracellular oxygen to generate superoxide anion radical

Question 20

extracellular sources of ROSs

Answer 20

superoxide anion radical, hydrogen peroxide and hypochlorous acid are generated from NADPH oxidase-mediated respiratory burst of phagocytic cells such as neutrophils, monocytes and macrophages phagocyte-derived free radical can damage both the source cell and cells in close apposition to the stimulated phagocytes

Question 21

generation of ROS by environmental agents and under pathogenic conditions - 3 kinds

Answer 21

1. radiation 2. hyperoxia 3. xenobiotics and anticancer agents

Question 22

radiation

Answer 22

includes UV, visible light, heat, gamma, x-ray creates ions, free radicals and excited molecules results in cell mutation and death from ionizing radiation - due to radical reactions with DNA

Question 23

hyperoxia

Answer 23

prolonged exposure to a high concentration of oxygen causes lung injury increased lung production of superoxide and hydrogen peroxide during hyperoxia

Question 24

Xenobiotics and anticancer agents - 2 kinds

Answer 24

1. redox cycling 2. cooxidation

Question 25

redox cycling

Answer 25

quinones the redox cycling starts with one-electron reduction step, resulting semiquinone then passes the electron received onto molecular O each cycle of reduction and oxidation of quinones can generate one superoxide anion radical the reduction of quinones is catalyzed by the NADPH-dependent cytochrome P450 reductase

Question 26

cooxidation

Answer 26

peroxidase-dependent cyclooxygenase component can convert AA to the cyclic endoperoxide-hydroperoxide PGG2. the peroxidase component then reduces PGG2 to PGH2 for each molecule of hydroperoxide reduce 2 molecules of xenobiotic can be oxidized the classes of compounds that undergo one-electron oxidation by peroxidase include aromatic amines, phenols, hydroquinones, and polycyclic hydrocarbons

Question 27

cellular macromolecular targets of ROS are affected by

Answer 27

the halflives, solubility, and diffusion distance hydrogen peroxide can cross the membrane as readily as water

Question 28

the reactivity of reactive oxygen species has a major influence on

Answer 28

diffusion distance

Question 29

free radicals can cause functional alterations in

Answer 29

lipids, proteins and DNA

Question 30

lipids: lipid peroxidation

Answer 30

loss of membrane fluidity - reduced membrane potential (increased permeability to ions such as calcium)

Question 31

proteins: protein denaturation

Answer 31

loss of enzyme activity - increased Ca conc. activation of Ca-dependent proteinases

Question 32

DNA: base modification

Answer 32

production of 8-hydroxyguanine, thymine glycerol, 5-hydroxymethyl uracil, DNA strand breakage - mutations - cell cycle changes

Question 33

cellular damages eventually casue

Answer 33

cell death via necrosis and apoptosis, tissue injury and various diseases

Question 34

cellular targets of ROS: small molecules

Answer 34

amino acids, nucleotides, carbohydrates, unsaturated lipids, cofactors, neurotransmitters, antioxidants

Question 35

cellular targets of ROS: macromolecules

Answer 35

lipids, proteins, DNA

Question 36

Glutathione

Answer 36

widely distributed in biological systems, a tripeptide maintained in the reduced form - major source of reducing power can also interact with superoxide and hydroxyl radicals nonenzymatically

Question 37

Vitamin E

Answer 37

lipid soluble, concentrates in the hydrophobic interior of membranes function in antioxidant defense mainly through its ability to reduce the lipid radicals to form fatty acids and vitamin E radicals - then reduced by interaction with other agent such as vitamin C or glutathione Vitamin E is very effective to prevent the rapid auto-oxidation of unsaturated fatty acids

Question 38

Vitamin C

Answer 38

not only promotes ratdial reactions but also reacts quickly with superoxide it’s a pro-oxidant at low concentrations and an antioxidant at higher concentrations

Question 39

Superoxide dismutase (SOD)

Answer 39

catalyzes dismutation of superoxide radical to form hydrogen peroxide and oxygen Three types: 1. copper/zinc containign SOD 2. manganese containing SOD 3. extracellular SOD (ECSOD)

Question 40

Copper/Zinc containing SOD

Answer 40

located on human chromosome 21, related with down syndrome phenotypes (located on the same chromosome), increased hydrogen peroxide production, lipid peroxidation

Question 41

MAnganese containing SOD

Answer 41

located on human chromosome 6 pivotal role in mitochondrial antioxidant defense

Question 42

extracellular SOD

Answer 42

contains copper and zinc at the active site located on chromosome 4, found primarily in the intravascular and extracellular fluids like plasma, lymph and synovial fluid play a role in protecting the endothelial cells against the superoxide anion radical generated during the local tissue inflammation

Question 43

catalse

Answer 43

heme-containing enzyme, capable of catalyzing the decomposition of hydrogen peroxide to oxygen and water

Question 44

glutathione peroxidase

Answer 44

can reduce hydrogen peroxide or lipid hydroperoxides using glutathione as a reducing agent to form water present in both cytosol and mitochondria

Question 45

Nitric oxide

Answer 45

a reactive free radical which plays an important role as both a signaling molecule in cell-cell communication and cytotoxic role in inflammation NO maintains a basal vasodilator tone, responsible for agonist-induced enodothelium0dependent vasodilation and maintains the endothelium a quiescent state by inhibiting endothelial cell smooth muscle tone, long-term synaptic depression and long-term potential of synaptic transmission

Question 46

NO is formed by

Answer 46

the conversion of L-arginine to L-citrulline by NOsynthase at least 3 forms of NO’s have been found in humans

Question 47

one of the detrimental effects of NO

Answer 47

results from its interaction with superoxide anion radical NO reacts with superoxide anion radical under physiological conditions to yield peroxynitrite anion - this reaction is 3X faster than the rate at which SOD scavenges superoxide anion; it’s normally minimized by high SOD activity and low O2- and NOradical concentrations

Question 48

peroxynitrite can react with

Answer 48

protein, DNA and lipids more stable than OH and O2- and therefore is able to diffuse up to several cell diameters once peroxynitrite is protonated it will decompose to form hydroxyl and nitrogen dioxide radicals

Question 49

oxidative stress

Answer 49

refers to the cytologic consequences of a mismatch between the production of ROS and the ability of the cell to defend against them can occur when the production of ROS is increased or with the capacity of scavenging of ROS or repair of oxidatively modified macromolecules is decreased or both oxidative stress contributes to the pathogenesis of a # of human diseases