Free radicals
Free radicals are molecules characterized by one or more unpaired electrons, which often makes them highly reactive. The most common free radicals in biological systems are reactive oxygen species (ROS), primarily generated during mitochondrial respiration. Among these, superoxide and hydrogen peroxide play critical roles, with hydrogen peroxide potentially converting to the more harmful hydroxyl radical under certain conditions. Free radicals can arise from both internal metabolic processes and external sources, such as tobacco smoke, sunlight, and pollution. Their ability to damage DNA, proteins, and lipids can lead to significant health issues, including various cancers, particularly through mechanisms like oxidative stress and mutations in key genes. Populations at higher risk for free radical-related damage include those with low antioxidant intake, genetic deficiencies, or chronic inflammatory conditions. The historical understanding of free radicals in aging and disease has evolved, highlighting their complex role in both physiological functions and pathological conditions. Understanding free radicals is crucial for recognizing their impact on health and the importance of antioxidants in mitigating oxidative stress.
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Subject Terms
Free radicals
ALSO KNOWN AS: Radicals, reactive species
RELATED CANCERS: Cancers of the skin, airways, gastrointestinal tract, liver, bladder, prostate, and kidney, as well as leukemia and other cancers
DEFINITION: Free radicals are molecules with one or more unpaired electrons. Although there are stable radical species, the most common of which is oxygen, unpaired electrons most frequently confer high reactivity and oxidizing potential to free radicals. The most abundant free radicals in biological systems are molecules with the unpaired electron belonging to an oxygen atom. They are known as reactive oxygen species and are mainly, but not exclusively, derived from the incomplete reduction of oxygen during mitochondrial respiration, which generates the superoxide anion radical (O2-). Superoxide is converted to hydrogen peroxide (H2O2) in a reaction driven by the enzyme superoxide dismutase. Hydrogen peroxide is converted to water and detoxified by glutathione peroxidase and catalase. Hydrogen peroxide is not a free radical; however, when produced in excess (for example, in leukocytes during the respiratory burst that takes place in inflammatory processes) or when its enzymatic detoxifying mechanisms are deficient, hydrogen peroxide can be converted to hydroxyl radical (OH) in the presence of transition metals such as iron or copper. The hydroxyl radical is the most harmful reactive oxygen species because it can hydroxylate or abstract an electron from most macromolecules, including enzymes, membrane lipids, and DNA, sometimes resulting in mutagenesis.
In addition to reactive oxygen species, another significant free radical in the cell is nitric oxide (NO), which is synthesized from arginine by nitric oxide synthase. Nitric oxide fills essential physiological functions but it can also act as an oxidant. Living organisms have developed enzymatic and nonenzymatic mechanisms to neutralize free radicals. When the generation of free radicals overpowers the capacity of the natural antioxidant defense systems, oxidative stress occurs. Signs of oxidative stress have been found in many forms of human cancer.
Exposure routes: The pathologically related free radicals originate within the body as a product of normal aerobic metabolic processes and inflammatory reactions, but some environmental agents, such as radiation and pollutants, with diverse routes of exposure, can increase the production of free radicals.
Where found: Free-radical-generating agents are diverse, as are their sources. The most common are tobacco smoke, sunlight, X-rays, and automobile exhausts. Others include the carcinogens benzene, inorganic arsenic compounds, cadmium compounds, aflatoxins, and asbestos.
At risk: Populations at highest risk are those with a low dietary intake of antioxidants or genetic deficiencies in antioxidant enzymes (for example, glutathione peroxidase) or deoxyribonucleic acid (DNA) repair mechanisms, along with tobacco smokers, people who spend a long time in areas of heavy traffic or who are directly exposed to sunlight, and those with chronic inflammatory conditions.
Etiology and symptoms of associated cancers: The carcinogenic potential of free radicals arises from their ability to damage DNA, modify proteins by oxidation, and induce lipid peroxidation. The most frequently found form of oxidative DNA damage is the hydroxylation of purine and pyrimidine bases. Other consequences of free radical actions for DNA are the generation of strand breaks, deamination, and formation of etheno adducts. Oxidative modifications of proteins include nitration, nitrosylation, and acetylation, among others. In addition, one of the most damaging effects of free radicals is lipid peroxidation because of its self-propagating nature, which greatly affects the properties and functioning of cell membranes. Furthermore, lipid peroxidation products, such as the reactive aldehydes malondialdehyde and 4-hydroxynonenal, can damage DNA and proteins in the same way as free radicals.
DNA oxidative damage can cause mutations in cancer-related genes, such as tumor-suppressor genes or oncogenes, and lead to the initiation and progression of cancer. Likewise, carcinogenesis can be induced by post-translational oxidative modification of proteins involved in the regulation of cell growth, signal transduction pathways, DNA repair, or other mechanisms of cellular homeostasis. For instance, free radicals are known to induce the transcription of the proto-oncogenes FOS (also known as c-fos), JUN (c-jun), and MYC (c-myc), which stimulate cell growth. Also, posttranslational oxidative modifications of TP53 (p53), a tumor-suppressor protein, can inhibit its antiproliferative activity. Lastly, free radicals can promote not only tumor growth but also tumor migration and metastasis by activating matrix metalloproteinases and stimulating the release of vascular endothelial growth factor. A current view of free radical actions supports the notion that these species do not act in a purely stochastic manner but are second messengers in redox-sensitive mechanisms of regulation of gene expression and enzyme activity. Aberrant and sustained redox signaling in oxidative stress situations leads to pathological changes, including cancer.
History: The relevance of free radicals in biological systems was first proposed by Denham Harman in 1956 in his classic article “Aging: A Theory Based on Free Radical and Radiation Chemistry.” Harman viewed age-related diseases as the result of an accumulation of oxidative damage. In the same year, in vitro studies showing the ability of oxygen reactive species to induce chromosome fragmentation in the presence of iron suggested for the first time the hypothesis of free-radical-induced carcinogenesis. Since then, the concept has been extended and free radicals have been found to be involved in most pathological conditions.
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