Oxidative Stress
A living organism is constantly subjected to molecular attacks, damaging cells and biological macromolecules.
Reactive Oxygen Species (ROS)
ROS are molecules derived from the oxidation-reduction process. During reduction, a substance gains electrons from a reducing agent, named an "anti-oxidant". A molecule that loses its electron (and thus gains in oxygen) is called a "pro-oxidant," and this is what ROS are. They are generally unstable and thus highly reactive.
There are several ROS, but what these molecules have in common is that they contain oxygen and are highly reactive. Examples of free radicals are:
- hydroxyl (OH-),
- superoxide (O2-)
- nitric oxide (NO)
while others are not:
- peroxynitrite (ONOO),
- hydrogen peroxide (H2O2)
- lipid peroxides (LOOH).
Sources of ROS
The energy fuel of the cell is oxygen, a very powerful oxidizing agent. The electron chain located in the mitochondrial membrane is the major ROS production site. Most enzymes involved in the generating of ROS are:
Both complexes of electron transport chains
generate ROS
- NADH dehydrogenase complex
- complex III (cytochrome bc1)
- monoamine oxidases
- succinate dehydrogenase
- aconitase
- a-ketoglutarate dehydrogenase.
Nitric oxide is produced by nitric oxide synthase (NOS). In addition, phagocytic cells use ROS as a first defense line in innate immunity ("oxidative burst"). ROS are produced by NADPH oxidase family members, and are involved in apoptosis activation, cytokines production, inflammatory and anti-microbial reaction. Finally, ROS may come from other sources, such as food or other elements (smoking, pollution, ...)
Antioxidants
The body defends itself against these ROS, because large quantities are harmful. Many antioxidant molecules are found in mitochondria:
- vitamin E and coenzyme Q10: trapping ROS
- cytochrome C molecules: removing produced superoxide
- glutathione (GSH): maintaining balance of intracellular redox thiol groups.
There are several enzymatic processes to turn superoxide into a single water molecule, for instance through superoxide dismutase and catalase. The glutathione system is maintained by glutathione reductase and peroxidase. Also, various redoxines reduce peroxide molecules. Vitamins C and E, polyphenols (red wine), carotenes (fruits and vegetables), flavones (soybeans) are other anti-oxidant molecules, either circulating or cellular.
Oxidative Stress
Oxidative stress is defined as an imbalance between anti-oxidant and oxidant molecules. This may come from an increased production of ROS. It may be caused, for example, during an infection or illness, when oxidases are excessively stimulated. Furthermore, it is also possible that this may be caused by a decline or dysfunction in the antioxidant defenses.
Effects of ROS
ROS are highly reactive, and can create chemical changes in macromolecules. Cell membranes are prone to peroxidation. DNA and RNA are subject to mutations. Many protein modifications such as nitration or carbonylation can damage proteins causing dysfunction or damage. Some aldheidic products (4-hydroxy-2-nonenal, HNE) get attached to proteins. Too many modifications can cause cell apoptosis.
In Hepatic Encephalopathy
It is believed that oxidative stress plays an important role in the pathogenesis of hepatic encephalopathy. Studies investigating the role of ammonia in association with oxidative stress are underway (Bosoi et al, 2009).
Ammonia
Animal models