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 Luděk Bláha, PřF MU, RECETOX
www.recetox.cz
BIOMARKERS AND TOXICITY MECHANISMS
06 – Mechanisms
Oxidative stress
OPVK_MU_stred_2

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Importance of redox (oxido-reduction) homeostasis
http://www.mdpi.com/cancers/cancers-03-01285/article_deploy/html/images/cancers-03-01285f1-1024.png
Traditional view – “too much oxidants” is bad
Prooxidants (Oxidative stress) à damage to macromolecules à death

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Importance of redox (oxido-reduction) homeostasis
The potential beneficial and harmful roles of antioxidants in tumorigenesis.
http://www.nature.com/nrm/journal/v15/n6/full/nrm3801.html
Modified view (2014) – “too much of anything is bad”

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Importance of redox (oxido-reduction) homeostasis
•Redox homeostasis
–natural homeostatic levels of prooxidants and antioxidants
–keeping cell metabolism and signalling balanced
–
•Disruptions of homeostasis
–à depletion of oxygen
•Change in metabolism, acidosis in tissues, signalling  (e.g. TUMORS)
•Less studied – new field – REDOX SIGNALLING
à overproduction of prooxidants  = oxidative stress
•GENERAL MECHANISM OF TOXICITY AND AGING
•
http://www.neurogenol.co.uk/images/oxidativestress.gif

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•Oxygen (O2)
–principal molecule in living organisms
•terminal acceptor of electones
–highly reactive molecule
•formation of reactive derivatives à ROS à toxicity
•
•Other reactive molecules and ROS sources
–(details follow)
•production in mitochondria (byproducts of metabolism)
•redox-cycling (quinones of xenobiotics)
•Fenton-reaction (metals)
•oxidations mediated via MFOs (CYPs)
•depletion of antioxidants (reactive molecules)
Pro oxidants

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Key Reactive Oxygen Species (ROS)
SOD = Superoxide dismutase

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Fenton reaction
(from organic chemistry classes)
Fe3+/2+
But also OTHER METALS (!)
TERMS, NAMES, REACTIONS

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Reactivity of ROS (short rate à instability = reactivity)


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Sources or ROS


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http://www.qub.ac.uk/schools/SchoolofBiologicalSciences/People/DrAGalkin/Research/Image1,172487,en.
jpg
Mitochondria
Superoxide production in oxidative respiration

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Redox cycling compounds and ROS production
C:\Documents and Settings\Ludek Blaha\Plocha\E3.GIF
http://www.plantstress.com/articles/Oxidative%20Stress_files/IMG00031.gif
http://www.cse.emory.edu/sciencenet/undergrad/SURE/Posters/images/dave_fig1.gif
Natural cycling
quinone ßà semiquinone
Toxicity =
Interference with
“xeno”quinones
and similar compounds
Example 1 – BaP quinone
Example 2 – Paraquate pesticide

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Metals and impacts on redox homeostasis
(* direct ROS production / * binding to proteins)
http://www.cell.com/cms/attachment/600379/4726988/gr1.jpg
, Cr
+ H2O2
(Fenton reaction)

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CYP450 as ROS source
(example CYP2E1, MEOS – microsomal ethanol oxidising system)
http://themedicalbiochemistrypage.org/images/cyp2e1-activities.jpg

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Irradiation as a source of ROS and oxidative damage
(reminder – check lectures on toxicity towards DNA)
http://image.slidesharecdn.com/radioactivity-120828105904-phpapp02/95/radioactivity-12-728.jpg?cb=1
346151619
ROS

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Protection against ROS-induced damage


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Antioxidant responses 1 - enzymatic
Highlighted enzymes
discussed further
within the „biomarker“ part

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Antioxidant responses 2 – small molecules: GSH
http://www.nature.com/nrd/journal/v12/n12/images/nrd4002-f1.jpg
http://ajpgi.physiology.org/content/ajpgi/291/1/G1/F1.large.jpg
Highlighted enzymes
discussed further
within the „biomarker“ part

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Antioxidant responses 2 – small molecules: dietary antioxidants
http://www.nature.com/nrd/journal/v12/n12/images/nrd4002-f1.jpg
Ascorbate
Carotenoids
Flavonoids
http://en.citizendium.org/images/5/54/Carotenoids2.png
http://eng.ege.edu.tr/%7Eotles/antioxidants/pages/antioxidants_that_are_naturally_found_in_foods_do
syalar/image040.jpg
Flavonoids

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EFFECTS Enzymes & DNA
àOther lectures
�
Lipid peroxidation
à Following slide

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http://physrev.physiology.org/content/physrev/88/4/1243/F1.large.jpg
Lipid peroxidation = radical reaction à fast propagation
MDA as a biomarker

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Biomarkers of oxidative damage
(will be discussed later)

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Health effects of oxidative stress … multiple
e.g. acute coronary syndrome (ACS) à myocardial infarction
http://www.geneactivatornrf2.org/wp-content/uploads/2013/03/oxidative_stress_diseases-600.gif