The Role of Free Radicals in Health and Disease
The Role of Free Radicals in Health and Disease
The Role of Free Radicals in Health and Disease
A free radical is an atom or group of atoms that have one or more unpaired electrons. Free
radicals can have positive, negative or neutral charge. They are formed as necessary
intermediates in a variety of normal biochemical reactions, but when generated in excess or not
appropriately controlled, free radicals can wreak havoc on a broad range of macromolecules. A
prominent feature of free radicals is that they have extremely high chemical reactivity, which
explains not only their normal biological activities, but how they inflict damage on cells.
There are many types of free radicals, but those of most concern in biological systems are
derived from oxygen, and known collectively as reactive oxygen species (ROS). Oxygen has two
unpaired electrons in separate orbitals in its outer shell. This electronic structure makes oxygen
especially susceptible to radical formation.
• superoxide anion
• peroxide (hydrogen peroxide)
• hydroxyl radical
Oxygen-derived radicals are generated constantly as part of normal aerobic life. They are formed
in mitochondria as oxygen is reduced along the electron transport chain. Reactive oxygen
species are also formed as necessary intermediates in a variety of enzyme reactions.
Examples of situations in which oxygen radicals are overproduced in cells include:
• White blood cells such as neutrophils specialise in producing oxygen radicals, which
are used in host defense to kill invading pathogens.
• Cells exposed to abnormal environments such as hypoxia or hyperoxia generate
abundant and often damaging reactive oxygen species. A number of drugs have
oxidizing effects on cells and lead to production of oxygen radicals.
• Ionizing radiation is well known to generate oxygen radicals within biological
systems. Interestingly, the damaging effects of radiation are higher in well
oxygenated tissues than in tissues deficient in oxygen.
It is best not to think of oxygen radicals as "bad". They are generated in a number of reactions
essential to life and, as mentioned above, phagocytic cells generate radicals to kill invading
pathogens. There is also a large body evidence indicating that oxygen radicals are involved in
intercellular and intracellular signalling. For example, addition of superoxide or hydrogen
peroxide to a variety of cultured cells leads to an increased rate of DNA replication and cell
proliferation - in other words, these radicals function as mitogens.
Despite their beneficial activities, reactive oxygen species clearly can be toxic to cells. By
definition, radicals possess an unpaired electron, which makes them highly reactive and thereby
able to damage all macromolecules, including lipids, proteins and nucleic acids.
One of the best known toxic effects of oxygen radicals is damage to cellular membranes (plasma,
mitochondrial and endomembrane systems), which is initiated by a process known as lipid
peroxidation. A common target for peroxidation is unsaturated fatty acids present in membrane
phospholipids.
Reactions involving radicals occur in chain reactions. Note in the figure above that a hydrogen
is abstracted from the fatty acid by hydroxyl radical, leaving a carbon-centered radical as part
of the fatty acid. That radical then reacts with oxygen to yield the peroxy radical, which can then
react with other fatty acids or proteins.
In addition to effects on phospholipids, radicals can also directly attack membrane proteins and
induce lipid-lipid, lipid-protein and protein-protein crosslinking, all of which obviously have
effects on membrane function.
Alcohol, oxidative stress, and free radical damage
Alcohol promotes the generation of ROS and/or interferes with the body's normal defense
mechanisms against these compounds through numerous processes, particularly in the
liver. For example, alcohol breakdown in the liver results in the formation of molecules
whose further metabolism in the cell leads to ROS production. Alcohol also stimulates
the activity of enzymes called cytochrome P450s, which contribute to ROS production.
Further, alcohol can alter the levels of certain metals in the body, thereby facilitating
ROS production. Finally, alcohol reduces the levels of agents that can eliminate ROS
(i.e., antioxidants). The resulting state of the cell, known as oxidative stress, can lead to
cell injury. ROS production and oxidative stress in liver cells play a central role in the
development of alcoholic liver disease
Oxidative stress, originating from reactive oxygen species and free radicals provides a constant
challenge to eukaryotic cell survival. While implicated in a number of degenerative diseases,
some associated with aging and with aging itself, the manner and extent to which oxidative stress
contributes to the initiation or implementation of programmed-cell death is problematic. If
oxidative stress is an important modulator of programmed-cell death, any ability intentionally to
augment or inhibit it might ameliorate diseases in which the process is abnormally underactive or
overactive
Oxidative stress is thought to be linked to certain cardiovascular disease, since oxidation of LDL
in the endothelium is a precursor to plaque formation. Oxidative stress also plays a role in the
ischemic cascade due to oxygen deprivation. This includes Stroke and Heart attack
Life on Earth evolved in the presence of oxygen, and necessarily adapted by evolution of a large
battery of antioxidant systems. Some of these antioxidant molecules are present in all lifeforms
examined, from bacteria to mammals, indicating their appearance early in the history of life.
Many antioxidants work by transiently becoming radicals themselves. These molecules are
usually part of a larger network of cooperating antioxidants that end up regenerating the original
antioxidant. For example, vitamin E becomes a radical, but is regenerated through the activity of
the antioxidants vitamin C and glutathione.
Enzymatic Antioxidants
Three groups of enzymes play significant roles in protecting cells from oxidant stress:
Superoxide dismutases (SOD) are enzymes that catalyze the conversion of two
superoxides into hydrogen peroxide and oxygen. The benefit here is that hydrogen
peroxide is substantially less toxic that superoxide. SOD accelerates this detoxifying
reaction roughly 10,000-fold over the non-catalyzed reaction.
Nonenzymatic Antioxidants
Vitamin E is the major lipid-soluble antioxidant, and plays a vital role in protecting
membranes from oxidative damage. Its primary activity is to trap peroxy radicals in
cellular membranes.
Glutathione may well be the most important intracellular defense against damage by
reactive oxygen species. It is a tripeptide (glutamyl-cysteinyl-glycine). The cysteine
provides an exposed free sulphydryl group (SH) that is very reactive, providing an
abundant target for radical attack. Reaction with radicals oxidises glutathione, but the
reduced form is regenerated in a redox cycle involving glutathione reductase and the
electron acceptor NADPH.
In addition to these "big three", there are numerous small molecules that function as antioxidants.
Examples include bilrubin, uric acid, flavonoids and carotenoids.
Researches have found mitochondrial antioxidant therapy to be the most efficacious in reducing
pathological changes and in not producing adverse effects in cases of neurodegenerative
diseases. Thus, mitochondrial antioxidant therapy is promising as a treatment for
neurodegenerative patients. Once in the mitochondria, they rapidly neutralize free radicals and
decrease mitochondrial toxicity. Thus, mitochondrially targeted antioxidants are promising
candidates for treating these patients.
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