ANTIOXIDANT / OXIDANT BALANCE:
Antioxidant /
Oxidant Balance:
Mr ROS Hyde - Uncontrolled ROS play a role in disease and degenerative conditions
Mr ROS Hyde
Uncontrolled ROS play a role in disease and degenerative
conditions
ROS Radical Attack!
UNCONTROLLED ROS can inflict damage leading to
health problems
Health Problems Resulting from Radical Damage
ROS
Radical Attack!Each cell in the body is hit by approximately 10,000 radicals
every day!
In trying to gain stability, by "stealing"
(or donating) an
electron,
ROS radicals
quickly react with most nearby molecules, including proteins, lipids, carbohydrates
and DNA. When the "attacked" molecule loses (or gains)
an electron , it becomes a
radical itself, beginning a chain reaction which
can result in the disruption of a living cell.
Most radicals
can pull an electron from (i.e. oxidize)
most biochemical compounds. The amount of
damage incurred is dependent upon both
the number of radical hits, and the amount of protection by the
antioxidant "damage
control" system.
ROS can inflict damage ("Oxidative Stress")
leading to health problemsIts all about balance. While
oxygen and its ROS
offspring are an essential part of many, normal body processes,
aerobic cells may experience
oxidative stress
damage if their antioxidant protection mechanisms are overwhelmed by excessivve amounts of
ROS .
E.g. The process of neutralizing
ROS
contained in unsaturated oils use up the body's
antioxidant supplies.
Examples of where
ROS are OVER-produced and can result in significant
damage to cells:
WBCs.
Neutrophils specialize in ROS production,
using them to kill invading pathogens.Cells
exposed to abnormal environments. E.g. hypoxia, hyperoxia
Many drugs. Have oxidizing effects on cells and lead to
ROS production
Ionizing radiation. Well known to generate
ROS within biological systems. Damage is higher in
well oxygenated tissues than in oxygen-deficient tissues.
Body components damaged by
ROS. Uncontrolled (excess)
ROS can cause damage to
the most oxidatively-sensitive cellular components:
Unsaturated membrane lipids
Proteins and nucleic acids (i.e.
DNA, RNA).
This can cause local injury, cellular malfunction, and eventual organ malfunction
leading to a variety of diseases, or even death.
Damage to unsaturated Lipids in Cell membranes
and Lipoproteins. Polyunsaturated
fatty acids (PUFAs) in cell membranes
and lipoproteins are the key to bringing robust oxidation back to a
low-energy producing or fermenting cell. However,
unsaturated fatty acids will readily give up an electron when attacked by
ROS (
Hydroxyl Radical
,in a self-perpetuating
process called lipid peroxidation. The breakdown of the resultant lipid hydroperoxides
often involves transition metal ion catalysis .
Cellular membranes and lipoproteins (vehicles in which lipids travel in
the bloodstream) are prominent targets of ROS attack,
undergoing numerous structurally and functionally disruptive effects:
Increased
membrane rigidity Decreased
activity of membrane-bound enzymes. e.g. Sodium/Potassium
pumpsAltered
activity of membrane receptors and altered electrolyte transport.
Especially to sodium and calcium ions. Increased intracellular sodium
ion causes water to follow them causing cellular swelling. Increased calcium ions
damage mitochondria and cause "cellular hardening", seen in arterial
plaque.Less permeability/fluidity.
This rigidity is a common feature of aging.
Superoxide
O2 •
-
hydroxyl
OH• radicals
initiate peroxidation in the cellular,
mitochondrial, nuclear, and endoplasmic reticulum membranes.
This increases the cellular permeability for Ca2+ ions whose
increased cellular concentrations damage the mitochondria.
ROS also oxidize
and degrade amino acids, and their oxidation of nuclear and mitochondrial
DNA, results in strand breaks and other types of DNA damage.
Protein damage.
Proteins
and nucleic acids have less reaction sites than
PU FAs for ROS
reactions to propagate chain reactions.
Damage occurs only if radicals accumulate (which is not likely in normal cells),
or if the damage is focussed on a particular site of the protein, such as if a protein
binds a transition metal ion.
Marx G, Chevion M; 1986
Stadtman ER, Oliver CN;
1991.
Protein
hydroperoxide. Macquarie University, discovered a new form of free
radical damage to the body's proteins, called "protein hydroperoxide". They have
since gone on to show this same type of damage also occurs on the body's cholesterol
carrying particles (lipoproteins).
DNA damage.
Oxidi z ing radicals
readily attack DNA if they are formed in its vicinity as seen
in radiation. As with proteins there seems little possibility that the damage may
spread into a chain reaction. Again for damage to occur it must either be site specific
(leading to strand breaks) or it must elude the repair systems before replication
occurs leading to mutations .
Cheesman and Slater, 1993
The extreme reactivity and multiple intermediates of
oxygen make it difficult to detect and
trace its course. Consequently, we look for the "footprints" of
oxygen reactions to determine
cause-effect relationships in stress responses
radical damageROS -induced oxidative
damages may be precursors to aging and diseases .
E.g.
cancer , heart
disease, diabetes
mellitus , atherosclerosis, rheumatoid arthritis, hypertension, sleep apnea,
brain damage and dementia-related diseases such as Alzheimer's disease and Parkinson's
disease.
ROS (or their metabolites) are highly chemically reactive and able to damage
cells (occurring even in healthy cells):
Attack cell membranes -
causing cell membrane dysfunction, altered receptor function;
Attack red blood
cells;
Modify proteins:
Deactivate enzymes, damage protein receptors;
Cause damage in DNA / RNA strands.
Can trigger mutations in tissue and organs leading to cancer:
"Vegetable oils which are rich
in linoleic acid (eg. Corn and sunflower oils) are potent promoters of
tumor growth ."
Prof. R. Kearney, Sydney University, 1987;
High lung cancer rates among women in
China are associated with lipid peroxidized oils in fumes -from cooking with polyunsaturated
vegetable oils in a wok.
Cause damage
in arteries / atherosclerosis / heart disease. Resulting in plaque buildup. Endothelial cells, smooth muscle cell and macrophages
can release radicals, which cause lipid peroxidation. A continued high level of
unopposed oxidized lipids causes endothelial cell damage in blood vessel walls and
can lead to generation of foam cells and plaque, particularly by oxidizing LDL,
which can directly damage endothelial cells;
Cause damage
in the skin. Causing wrinkles and premature
aging;
Cause brain
damage. Can lead to dementia;
