Pro-oxidant
Encyclopedia
Pro-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. For example, an overdose of the analgesic
paracetamol
(acetaminophen) can cause fatal damage to the liver
, partly through its production of reactive oxygen species.
Some substances can act as either antioxidants or pro-oxidants, depending on the specific set of conditions. Some of the conditions that are important include the concentration of the chemical and whether oxygen
or transition metal
s are present. While thermodynamically very favored, reduction of molecular oxygen or peroxide to superoxide
or hydroxyl radical
is spin-forbidden
. This greatly reduces the rates of these reactions, thus allowing aerobic life to exist. As a result, the reduction of oxygen typically involves either the initial formation of singlet oxygen
or spin-orbit coupling through a reduction of a transition-series metal such as manganese, iron, or copper. This reduced metal then transfers the single electron to molecular oxygen or peroxide.
is a classic "pro-oxidant" disease. Another disease associated with the chronic presence of a pro-oxidant transition-series metal is hemochromatosis, associated with elevated iron levels. Likewise, Wilson's disease
is associated with elevated tissue levels of copper. Such syndromes tend to be associated with a common symptomology. This typically includes various combinations of psychosis
, dyskinesia
(including Parkinsonian-like symptomology), pigmentary abnormalities, fibrosis
, deafness, diabetes, and arthritis
. Thus, all are occasional symptoms of (e.g.) hemochromatosis, another name for which is "bronze diabetes". The pro-oxidant herbicide paraquat
, Wilson's disease, and striatal iron have, likewise, been linked to human Parkinsonism
. Paraquat also produces parkinsonian-like symptoms in rodents.
or scar formation is another pro-oxidant-related symptom. For example, interocular copper or vitreous chalcosis is associated with severe vitreous fibrosis
, as is interocular iron. Liver cirrhosis
is also a major symptom of Wilson's disease. The pulmonary fibrosis
produced by paraquat
and the antitumor agent bleomycin
is also thought to be induced by the pro-oxidant properties of these agents. It may be that oxidative stress produced by such agents mimics a normal physiological signal
for fibroblast
conversion to myofibroblast
s.
s that are reducing agents can be pro-oxidants. Vitamin C
has antioxidant activity when it reduces
oxidizing substances such as hydrogen peroxide
, however, it can also reduce metal ions which leads to the generation of free radicals through the fenton reaction
.
The metal ion in this reaction can be reduced, oxidized, and then re-reduced, in a process called redox cycling that can generate reactive oxygen species.
The relative importance of the antioxidant and pro-oxidant activities of antioxidant vitamins is an area of current research, but vitamin C, for example, appears to have a mostly-antioxidant action in the body. However, less data is available for other dietary antioxidants, such as polyphenol antioxidant
s, zinc
, and vitamin E
.
accounts for roughly half the antioxidant ability of plasma. In fact, uric acid may have substituted for ascorbate in human evolution.
However, like ascorbate, uric acid can also mediate the production of active oxygen species and, thus, act as a pro-oxidant. This was first proposed to play a role in the etiology of the Lesch-Nyhan Syndrome
(associated with choreoathetoid dyskinesia) and in hyperuricemic syndrome in dalmatian dogs. The latter responds to treatment with the antioxidant drug orgotein, a pharmaceutical form of superoxide dismutase
. Such animals are also typically "bronzed".
High uric acid levels are also encountered in atherosclerosis
, in metabolic syndrome
, and in stroke
. The issue is whether hyperuricemia is a protective response to oxidative stress in such diseases or whether it is a primary cause. Thus, some researchers think urate-induced oxidative stress is causative in stroke, while others suggest the exact opposite, that urate is neuroprotective by means of its antioxidant properties. Similarly, evidence relates metabolic syndrome to the pro-oxidant properties of urate secondary to fructose-induced hyperuricemia.
levels in hyperhomocysteinemia
are associated with an increased incidence of atherosclerosis and may play a role in Alzheimers. Homocysteine is a powerful reducing agent and, like most such agents, can induce oxidative stress through reducing molecular oxygen to its radical forms. The spin-forbidden nature of this reaction normally requires this be mediated through reduction of some heavy atom, which then transfers the electron to oxygen. Repeated working of this process is known as redox cycling. This has been proposed to play a role in the etiology of such diseases.
s, bleomycin
, and cisplatin
. These agents may show specific toxicity toward cancer cells because of the low level of antioxidant defenses found in tumors. Recent research demonstrates that redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through reactive oxygen species represents a specific vulnerability of malignant cells that can be selectively targeted by pro-oxidant non-genotoxic redox chemotherapeutics.
Oxidative stress
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...
, through either creating 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 inhibiting antioxidant
Antioxidant
An 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...
systems. The oxidative stress produced by these chemicals can damage cells and tissues. For example, an overdose of the analgesic
Analgesic
An analgesic is any member of the group of drugs used to relieve pain . The word analgesic derives from Greek an- and algos ....
paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...
(acetaminophen) can cause fatal damage to the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, partly through its production of reactive oxygen species.
Some substances can act as either antioxidants or pro-oxidants, depending on the specific set of conditions. Some of the conditions that are important include the concentration of the chemical and whether oxygen
Oxygen
Oxygen is the element with atomic number 8 and represented by the symbol O. Its name derives from the Greek roots ὀξύς and -γενής , because at the time of naming, it was mistakenly thought that all acids required oxygen in their composition...
or 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 are present. While thermodynamically very favored, reduction of molecular oxygen or peroxide to 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...
or 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 spin-forbidden
Selection rule
In physics and chemistry a selection rule, or transition rule, formally constrains the possible transitions of a system from one state to another. Selection rules have been derived for electronic, vibrational, and rotational transitions...
. This greatly reduces the rates of these reactions, thus allowing aerobic life to exist. As a result, the reduction of oxygen typically involves either the initial formation of singlet oxygen
Singlet oxygen
Singlet oxygen is the common name used for the diamagnetic form of molecular oxygen , which is less stable than the normal triplet oxygen. Because of its unusual properties, singlet oxygen can persist for over an hour at room temperature, depending on the environment...
or spin-orbit coupling through a reduction of a transition-series metal such as manganese, iron, or copper. This reduced metal then transfers the single electron to molecular oxygen or peroxide.
Metals
Transition metals can act as pro-oxidants. For example, chronic manganismManganism
Manganism or manganese poisoning is a toxic condition resulting from chronic exposure to manganese and first identified in 1837 by James Couper.- Presentation :...
is a classic "pro-oxidant" disease. Another disease associated with the chronic presence of a pro-oxidant transition-series metal is hemochromatosis, associated with elevated iron levels. Likewise, 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...
is associated with elevated tissue levels of copper. Such syndromes tend to be associated with a common symptomology. This typically includes various combinations of psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
, dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
(including Parkinsonian-like symptomology), pigmentary abnormalities, fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
, deafness, diabetes, and arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....
. Thus, all are occasional symptoms of (e.g.) hemochromatosis, another name for which is "bronze diabetes". The pro-oxidant herbicide paraquat
Paraquat
Paraquat is the trade name for N,N′-dimethyl-4,4′-bipyridinium dichloride, one of the most widely used herbicides in the world. Paraquat, a viologen, is quick-acting and non-selective, killing green plant tissue on contact. It is also toxic to human beings and animals...
, Wilson's disease, and striatal iron have, likewise, been linked to human Parkinsonism
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
. Paraquat also produces parkinsonian-like symptoms in rodents.
Fibrosis
FibrosisFibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
or scar formation is another pro-oxidant-related symptom. For example, interocular copper or vitreous chalcosis is associated with severe vitreous fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
, as is interocular iron. Liver cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
is also a major symptom of Wilson's disease. The pulmonary fibrosis
Pulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...
produced by paraquat
Paraquat
Paraquat is the trade name for N,N′-dimethyl-4,4′-bipyridinium dichloride, one of the most widely used herbicides in the world. Paraquat, a viologen, is quick-acting and non-selective, killing green plant tissue on contact. It is also toxic to human beings and animals...
and the antitumor agent bleomycin
Bleomycin
Bleomycin is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Bleomycin refers to a family of structurally related compounds. When used as an anticancer agent, the chemotherapeutical forms are primarily bleomycin A2 and B2. It works by causing breaks in DNA...
is also thought to be induced by the pro-oxidant properties of these agents. It may be that oxidative stress produced by such agents mimics a normal physiological signal
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...
for fibroblast
Fibroblast
A fibroblast is a type of cell that synthesizes the extracellular matrix and collagen, the structural framework for animal tissues, and plays a critical role in wound healing...
conversion to myofibroblast
Myofibroblast
A Myofibroblast is a cell that is in between a fibroblast and a smooth muscle cell in differentiation.-Developmental origin:There are many possible ways of myofibroblast development:#Partial smooth muscle differentiation of a fibroblastic cell...
s.
Pro-oxidant vitamins
VitaminVitamin
A vitamin is an organic compound required as a nutrient in tiny amounts by an organism. In other words, an organic chemical compound is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on...
s that are reducing agents can be pro-oxidants. Vitamin C
Vitamin C
Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress...
has antioxidant activity when it reduces
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....
oxidizing substances such as 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...
, however, it can also reduce metal ions which leads to the generation of free radicals through the 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 ....
.
-
- 2 Fe2+ + 2 H2O2 → 2 Fe3+ + 2 OH· + 2 OH−
- 2 Fe3+ + Ascorbate → 2 Fe2+ + Dehydroascorbate
The metal ion in this reaction can be reduced, oxidized, and then re-reduced, in a process called redox cycling that can generate reactive oxygen species.
The relative importance of the antioxidant and pro-oxidant activities of antioxidant vitamins is an area of current research, but vitamin C, for example, appears to have a mostly-antioxidant action in the body. However, less data is available for other dietary antioxidants, such as polyphenol antioxidant
Polyphenol antioxidant
A polyphenol antioxidant is a type of antioxidant containing a polyphenolic substructure. Numbering over 4,000 distinct species, many of these compounds have antioxidant activity in vitro but are unlikely to have antioxidant roles in vivo...
s, zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
, and vitamin E
Vitamin E
Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...
.
Uric acid
The pro-oxidant properties of reductants can also have clinical consequences. For example, in humans, uric acidUric 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...
accounts for roughly half the antioxidant ability of plasma. In fact, uric acid may have substituted for ascorbate in human evolution.
However, like ascorbate, uric acid can also mediate the production of active oxygen species and, thus, act as a pro-oxidant. This was first proposed to play a role in the etiology of the Lesch-Nyhan Syndrome
Lesch-Nyhan syndrome
Lesch–Nyhan syndrome , also known as Nyhan's syndrome, Kelley-Seegmiller syndrome and Juvenile gout, is a rare inherited disorder caused by a deficiency of the enzyme hypoxanthine-guanine phosphoribosyltransferase , produced by mutations in the HPRT gene located on X chromosome. LNS affects about...
(associated with choreoathetoid dyskinesia) and in hyperuricemic syndrome in dalmatian dogs. The latter responds to treatment with the antioxidant drug orgotein, a pharmaceutical form of 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...
. Such animals are also typically "bronzed".
High uric acid levels are also encountered in atherosclerosis
Atherosclerosis
Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...
, in 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...
, and in 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...
. The issue is whether hyperuricemia is a protective response to oxidative stress in such diseases or whether it is a primary cause. Thus, some researchers think urate-induced oxidative stress is causative in stroke, while others suggest the exact opposite, that urate is neuroprotective by means of its antioxidant properties. Similarly, evidence relates metabolic syndrome to the pro-oxidant properties of urate secondary to fructose-induced hyperuricemia.
Hyperhomocysteinemia
In humans, elevated homocysteineHomocysteine
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...
levels in hyperhomocysteinemia
Hyperhomocysteinemia
Hyperhomocysteinemia or hyperhomocysteinaemia is a medical condition characterized by an abnormally large level of homocysteine in the blood....
are associated with an increased incidence of atherosclerosis and may play a role in Alzheimers. Homocysteine is a powerful reducing agent and, like most such agents, can induce oxidative stress through reducing molecular oxygen to its radical forms. The spin-forbidden nature of this reaction normally requires this be mediated through reduction of some heavy atom, which then transfers the electron to oxygen. Repeated working of this process is known as redox cycling. This has been proposed to play a role in the etiology of such diseases.
Anticancer Drugs
Several important anticancer agents both bind to DNA and generate reactive oxygen species. These include adriamycin and other anthracyclineAnthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy derived from Streptomyces bacterium Streptomyces peucetius var...
s, bleomycin
Bleomycin
Bleomycin is a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Bleomycin refers to a family of structurally related compounds. When used as an anticancer agent, the chemotherapeutical forms are primarily bleomycin A2 and B2. It works by causing breaks in DNA...
, and cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
. These agents may show specific toxicity toward cancer cells because of the low level of antioxidant defenses found in tumors. Recent research demonstrates that redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through reactive oxygen species represents a specific vulnerability of malignant cells that can be selectively targeted by pro-oxidant non-genotoxic redox chemotherapeutics.
See also
- 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...
- Oxidizing agentOxidizing agentAn oxidizing agent can be defined as a substance that removes electrons from another reactant in a redox chemical reaction...
- Reducing agentReducing agentA reducing agent is the element or compound in a reduction-oxidation reaction that donates an electron to another species; however, since the reducer loses an electron we say it is "oxidized"...
- Methylene blueMethylene blueMethylene blue is a heterocyclic aromatic chemical compound with the molecular formula C16H18N3SCl. It has many uses in a range of different fields, such as biology and chemistry. At room temperature it appears as a solid, odorless, dark green powder, that yields a blue solution when dissolved in...
- DCPIP