Pro-oxidant

Pro-oxidants are chemicals that induce oxidative stress, usually through either creating reactive oxygen species or inhibiting antioxidant systems.^[1] Oxidative stress produced by such 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.^[2][3]

Some substances can act as either antioxidants or pro-oxidants, depending on the specific set of conditions.^[4][5] Important variables include the concentration of the chemical and whether oxygen or transition metals 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.

Metals

Transition metals can act as pro-oxidants. For example, chronic manganism is a classic "pro-oxidant" disease.^[6] Another disease associated with the chronic presence of a pro-oxidant transition-series metal iron is hemochromatosis. 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.^[7] 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.

Fibrosis

Fibrosis 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 myofibroblasts.

Pro-oxidant vitamins

Vitamins that are reducing agents can be pro-oxidants. Vitamin C has antioxidant activity when it reduces oxidizing substances such as hydrogen peroxide,^[8] however, it can also reduce metal ions which leads to the generation of free radicals through the fenton reaction.^[9][10]

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.^[9][11] However, less data is available for other dietary antioxidants, such as polyphenol antioxidants,^[12] zinc,^[13] and vitamin E.^[14]

Uric acid

The pro-oxidant properties of reductants can also have clinical consequences. For example, in humans, uric acid accounts for roughly half the antioxidant ability of plasma. In fact, uric acid may have substituted for ascorbate in human evolution.^[15]

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^[16][17][18] (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 ^[19]. 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.^[7] Thus, some researchers think urate-induced oxidative stress is causative in stroke,^[20] while others suggest the exact opposite, that urate is neuroprotective by means of its antioxidant properties.^[21] Similarly, evidence relates metabolic syndrome to the pro-oxidant properties of urate secondary to fructose-induced hyperuricemia.^[22]

Hyperhomocysteinemia

In humans, elevated homocysteine 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.^{[7][23][24][25]}

Anticancer Drugs

Several important anticancer agents both bind to DNA and generate reactive oxygen species. These include adriamycin and other anthracyclines, 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.^[26]

See also

• Antioxidant
• Oxidizing agent
• Reducing agent
• Methylene blue
• DCPIP

References

[[]sr:Prooksidans]