Oxidative stress
Encyclopedia
Oxidative stress represents an imbalance between the production and manifestation of reactive oxygen species
and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox
state of tissues can cause toxic effects through the production of peroxide
s and free radicals that damage all components of the cell, including protein
s, lipid
s, and DNA
. Some reactive oxidative species can even act as messengers through a phenomenon called redox signaling
.
In humans, oxidative stress is involved in many diseases. Examples include Sickle Cell Disease, atherosclerosis
, Parkinson's disease
, heart failure, myocardial infarction
, Alzheimer's disease
, Schizophrenia
, Bipolar disorder
, fragile X syndrome
and chronic fatigue syndrome
, but short-term oxidative stress may also be important in prevention of aging by induction of a process named mitohormesis
. Reactive oxygen species can be beneficial, as they are used by the immune system
as a way to attack and kill pathogen
s.
. The effects of oxidative stress depend upon the size of these changes, with a cell being able to overcome small perturbations and regain its original state. However, more severe oxidative stress can cause cell death and even moderate oxidation can trigger apoptosis
, while more intense stresses may cause necrosis
.
A particularly destructive aspect of oxidative* stress is the production of reactive oxygen species
, which include free radicals and peroxide
s. Some of the less reactive of these species (such as superoxide
) can be converted by oxidoreduction reactions
with transition metal
s or other redox cycling compounds (including quinone
s) into more aggressive radical species that can cause extensive cellular damage. The major portion of long term effects is inflicted by damage on DNA. Most of these oxygen-derived species are produced at a low level by normal aerobic metabolism
and the damage they cause to cells is constantly repaired. However, under the severe levels of oxidative stress that cause necrosis, the damage causes ATP
depletion, preventing controlled apoptotic death and causing the cell to simply fall apart.
Table adapted from.
. However, E. coli mutants that lack an active electron transport chain produced as much hydrogen peroxide as wild-type cells, indicating that other enzymes contribute the bulk of oxidants in these organisms. One possibility is that multiple redox-active flavoprotein
s all contribute a small portion to the overall production of oxidants under normal conditions.
Other enzymes capable of producing superoxide are xanthine oxidase
, NADPH oxidases and cytochromes P450
. Hydrogen peroxide is produced by a wide variety of enzymes including several oxidases. Reactive oxygen species play important roles in cell signalling, a process termed redox signaling
. Thus, to maintain proper cellular homeostasis
, a balance must be struck between reactive oxygen production and consumption.
The best studied cellular antioxidants are the enzymes superoxide dismutase
(SOD), catalase
, and glutathione peroxidase
. Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered sulfiredoxin
. Other enzymes that have antioxidant properties (though this is not their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases.
Oxidative stress contributes to tissue injury following irradiation and hyperoxia
. It is suspected (though not proven) to be important in neurodegenerative diseases including Lou Gehrig's disease (aka MND or ALS), Parkinson's disease
, Alzheimer's disease
, and Huntington's disease
. Oxidative stress is thought to be linked to certain cardiovascular disease
, since oxidation of LDL in the vascular endothelium
is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade
due to oxygen reperfusion injury
following hypoxia
. This cascade includes both strokes and heart attacks. Oxidative stress has also been implicated in chronic fatigue syndrome
.
increased the rate of lung cancer. In less high-risk groups, the use of vitamin E appears to reduce the risk of heart disease
. In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is mixed. Since dietary sources contain a wider range of carotenoids and vitamin E tocopherols and tocotrienols from whole foods, ex post facto epidemiological studies can have differing conclusions than artificial experiments using isolated compounds. However, AstraZeneca
's radical scavenging nitrone
drug NXY-059
shows some efficacy in the treatment of stroke.
Oxidative stress (as formulated in Harman
's free radical theory of aging
) is also thought to contribute to the aging process. While there is good evidence to support this idea in model organisms such as Drosophila melanogaster
and Caenorhabditis elegans
, recent evidence from Michael Ristow
's laboratory suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species. This process was previously named mitohormesis
or mitochondrial hormesis
on a purely hypothetical basis. The situation in mammals is even less clear. Recent epidemiological findings support the process of mitohormesis, and even suggest that antioxidants may increase disease prevalence
in humans (although the results were influenced by studies on smokers).
, copper
, chromium
, vanadium
and cobalt
are capable of redox
cycling in which a single electron
may be accepted or donated by the metal. This action catalyzes
reactions that produce reactive radical
s and can produce reactive oxygen species
. The most important reactions are probably Fenton's reaction and the Haber-Weiss reaction, in which hydroxyl radical
is produced from reduced iron and hydrogen peroxide. The hydroxyl radical then can lead to modifications of amino acids (e.g. meta-tyrosine
and ortho-tyrosine
formation from phenylalanine
), carbohydrates, initiate lipid peroxidation, and oxidize nucleobases. Most enzymes that produce reactive oxygen species contain one of these metals. The presence of such metals in biological systems in an uncomplexed form (not in a protein or other protective metal complex) can significantly increase the level of oxidative stress. In humans, hemochromatosis is associated with increased tissue iron levels, Wilson's disease
with increased tissue levels of copper, and chronic manganism
with exposure to manganese ores.
The reaction of transition metals with proteins oxidated by Reactive Oxygen Species
or Reactive Nitrogen Species
can yield reactive products that accumulate with time and contribute to aging and disease. For example, in Alzheimer's
patients, peroxidized lipids and proteins accumulate in lysosomes of the patient's brain cells.
s. Quinones can redox cycle with their conjugate semiquinone
s and hydroquinone
s, in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide. Oxidative stress generated by the reducing agent uric acid
may be involved in the Lesch-Nyhan syndrome, stroke
, and metabolic syndrome
. Likewise, production of reactive oxygen species in the presence of homocysteine
may figure in homocystinuria
, as well as atherosclerosis
, stroke
, and Alzheimers.
s producing both ROS and reactive nitrogen species. These include superoxide (•O2-), nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-). Although the use of these highly reactive compounds in the cytotoxic response of phagocytes causes damage to host tissues, the non-specificity of these oxidants is an advantage since they will damage almost every part of their target cell. This prevents a pathogen from escaping this part of immune response by mutation of a single molecular target.
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage. Disturbances in the normal redox
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
state of tissues can cause toxic effects through the production of peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...
s and free radicals that damage all components of the cell, including protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
s, and DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
. Some reactive oxidative species can even act as messengers through a phenomenon called redox signaling
Redox signaling
Redox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
.
In humans, oxidative stress is involved in many diseases. Examples include Sickle Cell Disease, atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, heart failure, myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, Schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
, Bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
, fragile X syndrome
Fragile X syndrome
Fragile X syndrome , Martin–Bell syndrome, or Escalante's syndrome , is a genetic syndrome that is the most commonly known single-gene cause of autism and the most common inherited cause of intellectual disability...
and chronic fatigue syndrome
Chronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
, but short-term oxidative stress may also be important in prevention of aging by induction of a process named mitohormesis
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
. Reactive oxygen species can be beneficial, as they are used by the immune system
Immune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
as a way to attack and kill pathogen
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
s.
Chemical and biological effects
Chemically, oxidative stress is associated with increased production of oxidizing species or a significant decrease in the capability of antioxidant defenses, such as glutathioneGlutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
. The effects of oxidative stress depend upon the size of these changes, with a cell being able to overcome small perturbations and regain its original state. However, more severe oxidative stress can cause cell death and even moderate oxidation can trigger apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
, while more intense stresses may cause necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
.
A particularly destructive aspect of oxidative* stress is the production of reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
, which include free radicals and peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...
s. Some of the less reactive of these species (such as superoxide
Superoxide
A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature...
) can be converted by oxidoreduction reactions
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
with transition metal
Transition metal
The term transition metal has two possible meanings:*The IUPAC definition states that a transition metal is "an element whose atom has an incomplete d sub-shell, or which can give rise to cations with an incomplete d sub-shell." Group 12 elements are not transition metals in this definition.*Some...
s or other redox cycling compounds (including quinone
Quinone
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...
s) into more aggressive radical species that can cause extensive cellular damage. The major portion of long term effects is inflicted by damage on DNA. Most of these oxygen-derived species are produced at a low level by normal aerobic metabolism
Cellular respiration
Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate , and then release waste products. The reactions involved in respiration are catabolic reactions that involve...
and the damage they cause to cells is constantly repaired. However, under the severe levels of oxidative stress that cause necrosis, the damage causes ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
depletion, preventing controlled apoptotic death and causing the cell to simply fall apart.
| Oxidant | Description |
|---|---|
| •O2-, superoxide Superoxide A superoxide, also known by the obsolete name hyperoxide, is a compound that possesses the superoxide anion with the chemical formula O2−. The systematic name of the anion is dioxide. It is important as the product of the one-electron reduction of dioxygen O2, which occurs widely in nature... anion |
One-electron reduction state of O2, formed in many autoxidation reactions and by the electron transport chain Electron transport chain An electron transport chain couples electron transfer between an electron donor and an electron acceptor with the transfer of H+ ions across a membrane. The resulting electrochemical proton gradient is used to generate chemical energy in the form of adenosine triphosphate... . Rather unreactive but can release Fe2+ from iron-sulfur proteins and ferritin Ferritin Ferritin is a ubiquitous intracellular protein that stores iron and releases it in a controlled fashion. The amount of ferritin stored reflects the amount of iron stored. The protein is produced by almost all living organisms, including bacteria, algae and higher plants, and animals... . Undergoes dismutation to form H2O2 spontaneously or by enzymatic catalysis and is a precursor for metal-catalyzed •OH formation. |
| H2O2, hydrogen peroxide Hydrogen peroxide Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent... |
Two-electron reduction state, formed by dismutation of •O2- or by direct reduction of O2. Lipid soluble and thus able to diffuse across membranes. |
| •OH, hydroxyl radical Hydroxyl radical The hydroxyl radical, •OH, is the neutral form of the hydroxide ion . Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are produced from the decomposition of hydroperoxides or, in... |
Three-electron reduction state, formed by Fenton reaction Fenton's reagent Fenton's reagent is a solution of hydrogen peroxide and an iron catalyst that is used to oxidize contaminants or waste waters. Fenton's reagent can be used to destroy organic compounds such as trichloroethylene and tetrachloroethylene .... and decomposition of peroxynitrite Peroxynitrite Peroxynitrite is the anion with the formula ONOO−. It is an unstable structural isomer of nitrate, NO3−, which has the same formula but a different structure. Although peroxynitrous acid is highly reactive, its conjugate base peroxynitrite is stable in basic solution... . Extremely reactive, will attack most cellular components |
| ROOH, organic hydroperoxide Peroxide A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide... |
Formed by radical reactions with cellular components such as lipid Lipid Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others... s and nucleobase Nucleobase Nucleobases are a group of nitrogen-based molecules that are required to form nucleotides, the basic building blocks of DNA and RNA. Nucleobases provide the molecular structure necessary for the hydrogen bonding of complementary DNA and RNA strands, and are key components in the formation of stable... s. |
| RO•, alkoxy and ROO•, peroxy radicals | Oxygen centred organic radicals. Lipid forms participate in lipid peroxidation Lipid peroxidation Lipid peroxidation refers to the oxidative degradation of lipids. It is the process in which free radicals "steal" electrons from the lipids in cell membranes, resulting in cell damage. This process proceeds by a free radical chain reaction mechanism... reactions. Produced in the presence of oxygen by radical addition to double bonds or hydrogen abstraction. |
| HOCl, hypochlorous acid Hypochlorous acid Hypochlorous acid is a weak acid with the chemical formula HClO. It forms when chlorine dissolves in water. It cannot be isolated in pure form due to rapid equilibration with its precursor... |
Formed from H2O2 by myeloperoxidase Myeloperoxidase Myeloperoxidase is a peroxidase enzyme that in humans is encoded by the MPO gene. Myeloperoxidase is most abundantly expressed in neutrophil granulocytes . It is a lysosomal protein stored in azurophilic granules of the neutrophil... . Lipid soluble and highly reactive. Will readily oxidize protein constituents, including thiol groups, amino groups and methionine Methionine Methionine is an α-amino acid with the chemical formula HO2CCHCH2CH2SCH3. This essential amino acid is classified as nonpolar. This amino-acid is coded by the codon AUG, also known as the initiation codon, since it indicates mRNA's coding region where translation into protein... . |
| ONOO-, peroxynitrite Peroxynitrite Peroxynitrite is the anion with the formula ONOO−. It is an unstable structural isomer of nitrate, NO3−, which has the same formula but a different structure. Although peroxynitrous acid is highly reactive, its conjugate base peroxynitrite is stable in basic solution... |
Formed in a rapid reaction between •O2- and NO•. Lipid soluble and similar in reactivity to hypochlorous acid. Protonation forms peroxynitrous acid, which can undergo homolytic cleavage to form hydroxyl radical and nitrogen dioxide Nitrogen dioxide Nitrogen dioxide is the chemical compound with the formula it is one of several nitrogen oxides. is an intermediate in the industrial synthesis of nitric acid, millions of tons of which are produced each year. This reddish-brown toxic gas has a characteristic sharp, biting odor and is a prominent... . |
Table adapted from.
Production and consumption of oxidants
One source of reactive oxygen under normal conditions in humans is the leakage of activated oxygen from mitochondria during oxidative phosphorylationOxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
. However, E. coli mutants that lack an active electron transport chain produced as much hydrogen peroxide as wild-type cells, indicating that other enzymes contribute the bulk of oxidants in these organisms. One possibility is that multiple redox-active flavoprotein
Flavoprotein
Flavoproteins are proteins that contain a nucleic acid derivative of riboflavin: the flavin adenine dinucleotide or flavin mononucleotide ....
s all contribute a small portion to the overall production of oxidants under normal conditions.
Other enzymes capable of producing superoxide are xanthine oxidase
Xanthine oxidase
Xanthine oxidase Xanthine oxidase Xanthine oxidase (XO (sometimes 'XAO'), a form of xanthine oxidoreductase that generates reactive oxygen species. Is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and can further catalyze the oxidation of xanthine to uric acid...
, NADPH oxidases and cytochromes P450
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...
. Hydrogen peroxide is produced by a wide variety of enzymes including several oxidases. Reactive oxygen species play important roles in cell signalling, a process termed redox signaling
Redox signaling
Redox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
. Thus, to maintain proper cellular homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
, a balance must be struck between reactive oxygen production and consumption.
The best studied cellular antioxidants are the enzymes superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
(SOD), catalase
Catalase
Catalase is a common enzyme found in nearly all living organisms that are exposed to oxygen, where it catalyzes the decomposition of hydrogen peroxide to water and oxygen...
, and glutathione peroxidase
Glutathione peroxidase
Glutathione peroxidase is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage...
. Less well studied (but probably just as important) enzymatic antioxidants are the peroxiredoxins and the recently discovered sulfiredoxin
Sulfiredoxin
In enzymology, a sulfiredoxin is an enzyme that catalyzes the chemical reactionThe 3 substrates of this enzyme are peroxiredoxin-, ATP, and a thiol, whereas its 4 products are peroxiredoxin-, ADP, phosphate, and a disulfide.This enzyme is involved in antioxidant metabolism by re-activating...
. Other enzymes that have antioxidant properties (though this is not their primary role) include paraoxonase, glutathione-S transferases, and aldehyde dehydrogenases.
Oxidative stress contributes to tissue injury following irradiation and hyperoxia
Hyperoxia
Hyperoxia is excess oxygen or higher than normal partial pressure of oxygen.In medicine, it refers to excess oxygen in the lungs or other body tissues, which can be caused by breathing air or oxygen at pressures greater than normal atmospheric pressure...
. It is suspected (though not proven) to be important in neurodegenerative diseases including Lou Gehrig's disease (aka MND or ALS), Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
, Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
, and Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
. Oxidative stress is thought to be linked to certain cardiovascular disease
Cardiovascular disease
Heart disease or cardiovascular disease are the class of diseases that involve the heart or blood vessels . While the term technically refers to any disease that affects the cardiovascular system , it is usually used to refer to those related to atherosclerosis...
, since oxidation of LDL in the vascular endothelium
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
is a precursor to plaque formation. Oxidative stress also plays a role in the ischemic cascade
Ischemic cascade
The ischemic cascade is a series of biochemical reactions that are initiated in the brain and other aerobic tissues after seconds to minutes of ischemia . This is typically secondary to stroke, injury, or cardiac arrest due to heart attack. Most ischemic neurons that die do so due to the...
due to oxygen reperfusion injury
Reperfusion injury
Reperfusion injury is the tissue damage caused when blood supply returns to the tissue after a period of ischemia or lack of oxygen. The absence of oxygen and nutrients from blood during the ischemic period creates a condition in which the restoration of circulation results in inflammation and...
following hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
. This cascade includes both strokes and heart attacks. Oxidative stress has also been implicated in chronic fatigue syndrome
Chronic fatigue syndrome
Chronic fatigue syndrome is the most common name used to designate a significantly debilitating medical disorder or group of disorders generally defined by persistent fatigue accompanied by other specific symptoms for a minimum of six months, not due to ongoing exertion, not substantially...
.
Antioxidants as supplements
The use of antioxidants to prevent disease is controversial. In a high-risk group like smokers, high doses of beta caroteneCarotene
The term carotene is used for several related unsaturated hydrocarbon substances having the formula C40Hx, which are synthesized by plants but cannot be made by animals. Carotene is an orange photosynthetic pigment important for photosynthesis. Carotenes are all coloured to the human eye...
increased the rate of lung cancer. In less high-risk groups, the use of vitamin E appears to reduce the risk of heart disease
Heart disease
Heart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
. In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is mixed. Since dietary sources contain a wider range of carotenoids and vitamin E tocopherols and tocotrienols from whole foods, ex post facto epidemiological studies can have differing conclusions than artificial experiments using isolated compounds. However, AstraZeneca
AstraZeneca
AstraZeneca plc is a global pharmaceutical and biologics company headquartered in London, United Kingdom. It is the world's seventh-largest pharmaceutical company measured by revenues and has operations in over 100 countries...
's radical scavenging nitrone
Nitrone
A nitrone is the N-oxide of an imine and a functional group in organic chemistry. The general structure is R1R2C=NR3+O- where R3 is different from H.A nitrone is 1,3-dipole in 1,3-dipolar cycloadditions...
drug NXY-059
NXY-059
Disufenton sodium is the disulfonyl derivative of the neuroprotective spin trap phenylbutynitrone or "PBN". It was under development at the drug company AstraZeneca. A 2005 phase-3 clinical trial called "SAINT-1" reported some efficacy in the acute treatment of ischemia injury due to stroke...
shows some efficacy in the treatment of stroke.
Oxidative stress (as formulated in Harman
Denham Harman
Denham Harman , MD, PhD, FACP, FAAA biogerontologist is Professor emeritus at the University of Nebraska Medical Center. Harman is widely known as the "father of the free radical theory of aging".-Background:...
's free radical theory of aging
Free-radical theory
The free-radical theory of aging states that organisms age because cells accumulate free radical damage over time. A free radical is any atom or molecule that has a single unpaired electron in an outer shell. While a few free radicals such as melanin are not chemically reactive, most...
) is also thought to contribute to the aging process. While there is good evidence to support this idea in model organisms such as Drosophila melanogaster
Drosophila melanogaster
Drosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
and Caenorhabditis elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
, recent evidence from Michael Ristow
Michael Ristow
Michael Ristow is a German medical researcher who has published influential articles on the metabolic basis of human diseases, including type 2 diabetes, obesity and cancer, as well as general aging processes...
's laboratory suggests that oxidative stress may also promote life expectancy of Caenorhabditis elegans by inducing a secondary response to initially increased levels of reactive oxygen species. This process was previously named mitohormesis
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
or mitochondrial hormesis
Hormesis
Hormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
on a purely hypothetical basis. The situation in mammals is even less clear. Recent epidemiological findings support the process of mitohormesis, and even suggest that antioxidants may increase disease prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
in humans (although the results were influenced by studies on smokers).
Metal catalysts
Metals such as ironIron
Iron is a chemical element with the symbol Fe and atomic number 26. It is a metal in the first transition series. It is the most common element forming the planet Earth as a whole, forming much of Earth's outer and inner core. It is the fourth most common element in the Earth's crust...
, copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
, chromium
Chromium
Chromium is a chemical element which has the symbol Cr and atomic number 24. It is the first element in Group 6. It is a steely-gray, lustrous, hard metal that takes a high polish and has a high melting point. It is also odorless, tasteless, and malleable...
, vanadium
Vanadium
Vanadium is a chemical element with the symbol V and atomic number 23. It is a hard, silvery gray, ductile and malleable transition metal. The formation of an oxide layer stabilizes the metal against oxidation. The element is found only in chemically combined form in nature...
and cobalt
Cobalt
Cobalt is a chemical element with symbol Co and atomic number 27. It is found naturally only in chemically combined form. The free element, produced by reductive smelting, is a hard, lustrous, silver-gray metal....
are capable of redox
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
cycling in which a single electron
Electron
The electron is a subatomic particle with a negative elementary electric charge. It has no known components or substructure; in other words, it is generally thought to be an elementary particle. An electron has a mass that is approximately 1/1836 that of the proton...
may be accepted or donated by the metal. This action catalyzes
Catalysis
Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....
reactions that produce reactive radical
Radical (chemistry)
Radicals are atoms, molecules, or ions with unpaired electrons on an open shell configuration. Free radicals may have positive, negative, or zero charge...
s and can produce reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
. The most important reactions are probably Fenton's reaction and the Haber-Weiss reaction, in which hydroxyl radical
Hydroxyl radical
The hydroxyl radical, •OH, is the neutral form of the hydroxide ion . Hydroxyl radicals are highly reactive and consequently short-lived; however, they form an important part of radical chemistry. Most notably hydroxyl radicals are produced from the decomposition of hydroperoxides or, in...
is produced from reduced iron and hydrogen peroxide. The hydroxyl radical then can lead to modifications of amino acids (e.g. meta-tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
and ortho-tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
formation from phenylalanine
Phenylalanine
Phenylalanine is an α-amino acid with the formula C6H5CH2CHCOOH. This essential amino acid is classified as nonpolar because of the hydrophobic nature of the benzyl side chain. L-Phenylalanine is an electrically neutral amino acid, one of the twenty common amino acids used to biochemically form...
), carbohydrates, initiate lipid peroxidation, and oxidize nucleobases. Most enzymes that produce reactive oxygen species contain one of these metals. The presence of such metals in biological systems in an uncomplexed form (not in a protein or other protective metal complex) can significantly increase the level of oxidative stress. In humans, hemochromatosis is associated with increased tissue iron levels, Wilson's disease
Wilson's disease
Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease...
with increased tissue levels of copper, and chronic manganism
Manganism
Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese and first identified in 1837 by James Couper.- Presentation :...
with exposure to manganese ores.
The reaction of transition metals with proteins oxidated by Reactive Oxygen Species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
or Reactive Nitrogen Species
Reactive nitrogen species
Reactive nitrogen species are a family of antimicrobial molecules derived from nitric oxide and superoxide produced via the enzymatic activity of inducible nitric oxide synthase 2 and NADPH oxidase respectively...
can yield reactive products that accumulate with time and contribute to aging and disease. For example, in Alzheimer's
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
patients, peroxidized lipids and proteins accumulate in lysosomes of the patient's brain cells.
Non-metal redox catalysts
Certain organic compounds in addition to metal redox catalyts can also produce reactive oxygen species. One of the most important classes of these are the quinoneQuinone
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...
s. Quinones can redox cycle with their conjugate semiquinone
Semiquinone
Semiquinone is a free radical resulting from the removal of one hydrogen atom with its electron during the process of dehydrogenation of a hydroquinone to quinone or alternatively the addition of a single H atom to a quinone....
s and hydroquinone
Hydroquinone
Hydroquinone, also benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol, having the chemical formula C6H42. Its chemical structure, shown in the table at right, has two hydroxyl groups bonded to a benzene ring in a para position. It is a white granular solid...
s, in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide. Oxidative stress generated by the reducing agent uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...
may be involved in the Lesch-Nyhan syndrome, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, and metabolic syndrome
Metabolic syndrome
Metabolic syndrome is a combination of medical disorders that, when occurring together, increase the risk of developing cardiovascular disease and diabetes. It affects one in five people in the United States and prevalence increases with age...
. Likewise, production of reactive oxygen species in the presence of homocysteine
Homocysteine
Homocysteine is a non-protein amino acid with the formula HSCH2CH2CHCO2H. It is a homologue of the amino acid cysteine, differing by an additional methylene group. It is biosynthesized from methionine by the removal of its terminal Cε methyl group...
may figure in homocystinuria
Homocystinuria
Homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase...
, as well as atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
, and Alzheimers.
Immune defense
The immune system uses the lethal effects of oxidants by making production of oxidizing species a central part of its mechanism of killing pathogens; with activated phagocytePhagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...
s producing both ROS and reactive nitrogen species. These include superoxide (•O2-), nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-). Although the use of these highly reactive compounds in the cytotoxic response of phagocytes causes damage to host tissues, the non-specificity of these oxidants is an advantage since they will damage almost every part of their target cell. This prevents a pathogen from escaping this part of immune response by mutation of a single molecular target.
See also
- AcatalasiaAcatalasiaAcatalasia is an autosomal recessive peroxisomal disorder caused by a complete lack of catalase.-Presentation:...
- Nitric oxideNitric oxideNitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
- Denham HarmanDenham HarmanDenham Harman , MD, PhD, FACP, FAAA biogerontologist is Professor emeritus at the University of Nebraska Medical Center. Harman is widely known as the "father of the free radical theory of aging".-Background:...
- Harry DemopoulosHarry DemopoulosHarry B. Demopoulos, MD is an pioneer in the medical aspects of free radicals, especially in the areas of ischaemic injury, the toxicity of anticancer drugs, and in spinal cord injury...
- Pro-oxidantPro-oxidantPro-oxidants are chemicals that induce oxidative stress, through either creating reactive oxygen species or inhibiting antioxidant systems. The oxidative stress produced by these chemicals can damage cells and tissues...
- AntioxidantAntioxidantAn antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...
- Redox signalingRedox signalingRedox signaling is when free radicals, reactive oxygen species , and other electronically activated species such as nitric oxide act as biological messengers. Arguably, hydrogen sulfide and carbon monoxide are also redox signaling molecules...
- MitohormesisHormesisHormesis is the term for generally favorable biological responses to low exposures to toxins and other stressors. A pollutant or toxin showing hormesis thus has the opposite effect in small doses as in large doses...
- MalondialdehydeMalondialdehydeMalondialdehyde is the organic compound with the formula CH22. The structure of this species is more complex than this formula suggests. This reactive species occurs naturally and is a marker for oxidative stress.- Structure and synthesis :...
, an oxidative stress marker