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.

Uncontrolled ROS can inflict damage ("Oxidative Stress") leading to health problems

Its 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 antioxidantprotection 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 particular),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 pumps
• Altered 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.

Protein damage.    Proteins and nucleic acids have less reaction sites than PUFAs 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.   Oxidizing 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

Health problems resulting from radical damage

ROS-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;