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Chok Biochem 3rd Shift Reviewer o2 Metab Toxic

Chok Biochem 3rd Shift Reviewer o2 Metab Toxic

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OXYGEN METABOLISM AND TOXICITY
Oxygen
\u2022
Molecular O2 \u2013 two unpaired electrons with parallel spins (antibonding character)
\u2022
To accept e- one electron (either O2 or substrate) must spin invert
\u2022
Spin inversion \u2013 large thermodynamic / kinetic barrier, multistep, \u2191 Ea; protective
\u2022
One e- reductions of O2 are not subject to kinetic barrier
\u2022
Oxidative Stress \u2013 state wherein level of ROS > endogenous antioxidant defenses\ue000
\u2191 FR\ue000 local injury (lipids most prone)\ue000 organ dysfunction
Free Radicals (FR)
\u2022
Chemical species with unpaired e- in valence shell
\u2022
\u2193 chemical specificity = abstracts e- indiscriminately
\u2022
Generation
o
Homolytic covalent bond cleavage: A:B\ue000 A\u00b7 + B\u00b7
o
Single e- loss: X\ue000 e- + X+\u00b7
o
e- addition: Y\ue000 e- + Y-\u00b7
Reactive Oxygen Species Properties
\u2022
major O2 metabolites by 1e- reduction
\u2022
Cytotoxic oxidative chain reaction: indiscriminately extracts e- from molecules forming new FRs
ROS
Formation
Notes
O2-
Superoxide
ETC, leakage @ CoQ, accidental nonspecific CoQH + O2
central role in formation of other reactive intermediates
H2O2
Hydrogen
Peroxide
2-electron reduction of O2
Dismutation Rxn: 2O2- + 2H+\ue000 H2O2 + O2 via SOD
not a FR, but an oxidizing agent, main source of OH\u00b7 in presence of transition metals,
Dismutation: radical\ue000 nonradical
OH\u00b7
Hydroxyl radical
Fenton Rxn: Fe2+ + H2O2\ue000 Fe3+ + OH- + OH\u00b7;
Haber-Weiss Rxn: O2- + H2O2\ue000 O2 + H2O + OH\u00b7
probable initiator of chain reactions, forms lipid peroxides, most reactive against biological
molecules (membrane lipids)
1O2
Singlet Oxygen
Pigment rxn
non radical, strong oxidant, electronically excited, mutagenic form of O2: e- paired in \u03c0 orbital
NO
Nitric oxide
arginine\ue000 citrulline + NO via NOS
endothelium derived relaxing factor, gaseous FR
ONOO-Peroxynitrite
NO + O2-
HOCl
Hypochlorous acidH2O2 + Cl-\ue000 HOCL + OH- via myeloperoxidase
major bactericidal agent in activated polys
Source
Mechanism
Examples
EndogenousAutoxidation
reduction of O2 diradical, abstraction from Fe2+ by O2
catecholamines, hemoglobin, myoglobin, reduced CytC, thiol
Enzymatic oxidation
Oxidation
H2O2 + Cl-\ue000 HOCl
xanthine oxidase (XO) (ischemia-reperfusion), prostaglandin synthase, lipoxygenase;
myeloperoxidase (neutrophils)
Respiratory burst
\u2191 O2 in phagocytes, flavoprotein Cyt-b-245 NADPH oxidase +
immune response\ue000 O2-\ue000 dismutate to H2O2\ue000 OH\u00b7 + HOCl
Chronic granulomatous disease (CGD) \u2013 defective NADPH-oxidase system\ue000 prone to
bacterial infections by catalase producers
Subcellular Organelles
ETC leaks\ue000 \u2191 O2- during \u2191 O2 or ischemia
Mitochondria, microsomes & peroxisomes (H2O2)
Transition metal ions
Fenton reaction
Fe, Cu, and other e- donors
Ischemia reperfusion
injury
Ischemia\ue000 \u2191 xanthine & XO, \u2193 SOD & GSHP
Reperfusion\ue000 \u2191 O2 = e- acceptor & XO cofactor\ue000 O2- and H2O2
Xanthine oxidase
ExogenousDrugs
\u2191 FR during hyperoxia
Antibiotics w/quinoid ormetals (nitrofurantoin),antineoplastics (bleomycin),
anthracycline(andriamycin), pro-oxidants(met hotre xate)
Radiation
Transfers energy to cellular components = 1\u00b0 radicals\ue000 2\u00b0 rxn
Electromagnetic (X-rays, \u03b3-rays) or particulate radiation (e-, photons, neutrons, \u03b1 & \u03b2
particles)
Tobacco smoking
Alveolar damage, FRs in gas phase, semiquinones in tar phase
Lung microhemorrhages\ue000 Fe\ue000 Fenton\ue000\u2191 neutrophils = \u2191 FR
Contains aldehydes, epoxides, peroxides
NO, peroxyl radicals, carbon-centered radical
Inorganic particles
Phagocytosis\ue000 cell rupture\ue000 proteolytic enzymes\ue000 \u2191
neutrophil\ue000 \u2191 FR
Mineral dust, silica, asbestos
Gases
Degradation\ue000 hydroxyl radicals
Photodissociation\ue000 chlorine radicals
O3 Ozone \u2013 not FR, oxidizing agent, 2 unpaired e-
CFCs
Defense Mechanisms
Enzymes
Superoxide Dismutase (SOD)
O2-\ue000 H2O2 + O2, requires Cu, Zn, Mn
1\u00b0 defense, CuZnSOD in plasma and cytosol, MnSOD in mitochondria
Catalase
H2 O2 + H2 O2\ue000 H2 O+ O2
in peroxisomes > cytosol and microsome, Fe @ active site,
\u2191 in liver and RBC, \u2193 in brain heart, and skel muscle
Glutathione peroxidase (GSHP)
H2O2 and lipid peroxides + Glutathione (GSH)\ue000 H2O + GSSG, requires selenium
Metalchelat
ors
Ferritin
Multi-protein shell surrounding FE3+ core, prevents Fenton
Transferrin
Binds Fe3+
Ceruloplasmin
Converts Fe2+ to Fe3+
Albumin
Binds to Cu2+ > Fe
Urate
Chelates Fe and Cu, from purine catabolism
LowMWscaven
gers/Vitami
ns
Vitamin E (\u03b1 tocopherol)
Major membrane bound chain-breaking antioxidant, fat soluble, reacts with peroxyl and other radicals
Terminates FR lipid peroxidation by e- donation\ue000 tocopheryl radical\ue000 stable, nonfunctional, oxidized tocopheryl quinone + VitC\ue000 reduced
Vitamin C
Water soluble, most effective aqueous phase antioxidant
Accepts e- from O2-, H2O2, HOCl, OH\u00b7, OOH radicals
L-ascorbate\ue001 e-, H+\ue000 ascorbyl radical\ue001 -e\ue000 dehydro-L-ascorbic acid
Carotenoids / VitA / \u03b2-carotene
Chain-breakingantio xidant, fat-soluble, from carrots, tomato (lycopene)
Accepts e- from lipid peroxy radicals\ue000 free radical intermediate
Glutathione
Maintains reduced cysteinyl in Hb, prevents methmyoglobin formation
Cellular compartmentation
Separation of species and sites involved in ROS formation, ferritin, peroxisomes
Repair mechanisms
DNA repair, oxidized FA removal from membrane, oxidized protein degradation and resynthesis
Cellular Damage
Causes
Targets
Effects
Lipid
peroxidation
initiated by FR (i.e. OH\u00b7)\ue000 chain reaction
polyunsaturated lipid
(LH)

OH\u00b7 + LH\ue000 LH\u00b7\ue000
propagated by O2\ue000 LOO\u00b7 (lipid peroxy radical) + LOOH (lipid peroxide)\ue000
degraded LOOH + malondialdehyde (blood soluble)

Termination: antioxidant e- donation in 2 steps = stabilized oxidized compound

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