GetWiki

{{short description|Free radical toxicity}}File:Free Radical Toxicity.svg|thumb|upright=1.8|right| Oxidative stress mechanisms in tissue injury. Free radical toxicity induced by xenobioticsxenobioticsOxidative stress reflects an imbalance between the systemic manifestation of reactive oxygen species and a biological system's ability to readily detoxify the reactive intermediates or to repair the resulting damage.BOOK, Handbook of Disease Burdens and Quality of Life Measures, Oxidative Stress, Springer New York, New York, NY, 2010, 10.1007/978-0-387-78665-0_6275, 4278–4278, 978-0-387-78664-3, Definition: Imbalance between oxidants and antioxidants in favor of the oxidants., Disturbances in the normal redox state of cells can cause toxic effects through the production of peroxides and free radicals that damage all components of the cell, including proteins, lipids, and DNA. Oxidative stress from oxidative metabolism causes base damage, as well as strand breaks in DNA. Base damage is mostly indirect and caused by the reactive oxygen species generated, e.g., O2− (superoxide radical), OH (hydroxyl radical) and H2O2 (hydrogen peroxide).JOURNAL, Birnboim HC, DNA strand breaks in human leukocytes induced by superoxide anion, hydrogen peroxide and tumor promoters are repaired slowly compared to breaks induced by ionizing radiation, Carcinogenesis, 7, 9, 1511–1517, September 1986, 3017600, 10.1093/carcin/7.9.1511, Further, some reactive oxidative species act as cellular messengers in redox signaling. Thus, oxidative stress can cause disruptions in normal mechanisms of cellular signaling.In humans, oxidative stress is thought to be involved in the development of attention deficit hyperactivity disorder,JOURNAL, Joseph N, Zhang-James Y, Perl A, Faraone SV, Oxidative Stress and ADHD: A Meta-Analysis, Journal of Attention Disorders, 19, 11, 915–924, November 2015, 24232168, 5293138, 10.1177/1087054713510354, cancer, Parkinson's disease,JOURNAL, Hwang O, Role of oxidative stress in Parkinson's disease, Experimental Neurobiology, 22, 1, 11–17, March 2013, 23585717, 3620453, 10.5607/en.2013.22.1.11, Lafora disease,JOURNAL, Romá-Mateo C, Aguado C, García-Giménez JL, Ibáñez-Cabellos JS, Seco-Cervera M, Pallardó FV, Knecht E, Sanz P, 6, Increased oxidative stress and impaired antioxidant response in Lafora disease, Molecular Neurobiology, 51, 3, 932–946, 2015, 24838580, 10.1007/s12035-014-8747-0, free, 13096853, 10261/123869, Alzheimer's disease,JOURNAL, Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J, Free radicals and antioxidants in normal physiological functions and human disease, The International Journal of Biochemistry & Cell Biology, 39, 1, 44–84, 2007, 16978905, 10.1016/j.biocel.2006.07.001, atherosclerosis,JOURNAL, Bonomini F, Tengattini S, Fabiano A, Bianchi R, Rezzani R, Atherosclerosis and oxidative stress, Histology and Histopathology, 23, 3, 381–390, March 2008, 18072094, 10.14670/HH-23.381, heart failure,JOURNAL, Singh N, Dhalla AK, Seneviratne C, Singal PK, Oxidative stress and heart failure, Molecular and Cellular Biochemistry, 147, 1–2, 77–81, 1995, 7494558, 10.1007/BF00944786, 21662824, myocardial infarction,JOURNAL, Ramond A, Godin-Ribuot D, Ribuot C, Totoson P, Koritchneva I, Cachot S, Levy P, Joyeux-Faure M, 6, Oxidative stress mediates cardiac infarction aggravation induced by intermittent hypoxia, Fundamental & Clinical Pharmacology, 27, 3, 252–261, June 2013, 22145601, 10.1111/j.1472-8206.2011.01015.x, 40420948, JOURNAL, Dean OM, van den Buuse M, Berk M, Copolov DL, Mavros C, Bush AI, N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: relevance to schizophrenia and bipolar disorder, Neuroscience Letters, 499, 3, 149–153, July 2011, 21621586, 10.1016/j.neulet.2011.05.027, 32986064, fragile X syndrome,JOURNAL, de Diego-Otero Y, Romero-Zerbo Y, el Bekay R, Decara J, Sanchez L, Rodriguez-de Fonseca F, del Arco-Herrera I, Alpha-tocopherol protects against oxidative stress in the fragile X knockout mouse: an experimental therapeutic approach for the Fmr1 deficiency, Neuropsychopharmacology, 34, 4, 1011–1026, March 2009, 18843266, 10.1038/npp.2008.152, free, sickle-cell disease,JOURNAL, Amer J, Ghoti H, Rachmilewitz E, Koren A, Levin C, Fibach E, Red blood cells, platelets and polymorphonuclear neutrophils of patients with sickle cell disease exhibit oxidative stress that can be ameliorated by antioxidants, British Journal of Haematology, 132, 1, 108–113, January 2006, 16371026, 10.1111/j.1365-2141.2005.05834.x, free, lichen planus,JOURNAL, Aly DG, Shahin RS, Oxidative stress in lichen planus, Acta Dermatovenerologica Alpina, Pannonica, et Adriatica, 19, 1, 3–11, 2010, 20372767, vitiligo,JOURNAL, Arican O, Kurutas EB, Oxidative stress in the blood of patients with active localized vitiligo, Acta Dermatovenerologica Alpina, Pannonica, et Adriatica, 17, 1, 12–16, March 2008, 18454264, autism,JOURNAL, James SJ, Cutler P, Melnyk S, Jernigan S, Janak L, Gaylor DW, Neubrander JA, Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism, The American Journal of Clinical Nutrition, 80, 6, 1611–1617, December 2004, 15585776, 10.1093/ajcn/80.6.1611, free, infection, chronic fatigue syndrome,JOURNAL, Kennedy G, Spence VA, McLaren M, Hill A, Underwood C, Belch JJ, Oxidative stress levels are raised in chronic fatigue syndrome and are associated with clinical symptoms, Free Radical Biology & Medicine, 39, 5, 584–589, September 2005, 16085177, 10.1016/j.freeradbiomed.2005.04.020, and depression;JOURNAL, Jiménez-Fernández S, Gurpegui M, Díaz-Atienza F, Pérez-Costillas L, Gerstenberg M, Correll CU, Oxidative stress and antioxidant parameters in patients with major depressive disorder compared to healthy controls before and after antidepressant treatment: results from a meta-analysis, The Journal of Clinical Psychiatry, 76, 12, 1658–1667, December 2015, 26579881, 10.4088/JCP.14r09179, 10630/29937, free, however, reactive oxygen species can be beneficial, as they are used by the immune system as a way to attack and kill pathogens.JOURNAL, Segal AW, How neutrophils kill microbes, Annual Review of Immunology, 23, 197–223, 2005, 15771570, 2092448, 10.1146/annurev.immunol.23.021704.115653, Short-term oxidative stress may also be important in prevention of aging by induction of a process named mitohormesis,JOURNAL, Gems D, Partridge L, Stress-response hormesis and aging: "that which does not kill us makes us stronger", Cell Metabolism, 7, 3, 200–203, March 2008, 18316025, 10.1016/j.cmet.2008.01.001, free, and is required to initiate stress response processes in plants.JOURNAL, Waszczak C, Carmody M, Kangasjärvi J, Reactive Oxygen Species in Plant Signaling, Annual Review of Plant Biology, 69, 1, 209–236, April 2018, 29489394, 10.1146/annurev-arplant-042817-040322, free,

Chemical and biological effects

Chemically, oxidative stress is associated with increased production of oxidizing species or a significant decrease in the effectiveness of antioxidant defenses, such as glutathione.JOURNAL, Schafer FQ, Buettner GR, Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple, Free Radical Biology & Medicine, 30, 11, 1191–1212, June 2001, 11368918, 10.1016/S0891-5849(01)00480-4, 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.JOURNAL, Lennon SV, Martin SJ, Cotter TG, Dose-dependent induction of apoptosis in human tumour cell lines by widely diverging stimuli, Cell Proliferation, 24, 2, 203–214, March 1991, 2009322, 10.1111/j.1365-2184.1991.tb01150.x, 37720004, Production of reactive oxygen species is a particularly destructive aspect of oxidative stress. Such species include free radicals and peroxides. Some of the less reactive of these species (such as superoxide) can be converted by oxidoreduction reactions with transition metals or other redox cycling compounds (including quinones) into more aggressive radical species that can cause extensive cellular damage.JOURNAL, Valko M, Morris H, Cronin MT, Metals, toxicity and oxidative stress, Current Medicinal Chemistry, 12, 10, 1161–1208, 2005, 15892631, 10.2174/0929867053764635, 10.1.1.498.2796, Most long-term effects are caused by damage to DNA.JOURNAL, Evans MD, Cooke MS, Factors contributing to the outcome of oxidative damage to nucleic acids, BioEssays, 26, 5, 533–542, May 2004, 15112233, 10.1002/bies.20027, 11714476, DNA damage induced by ionizing radiation is similar to oxidative stress, and these lesions have been implicated in aging and cancer. Biological effects of single-base damage by radiation or oxidation, such as 8-oxoguanine and thymine glycol, have been extensively studied. Recently the focus has shifted to some of the more complex lesions. Tandem DNA lesions are formed at substantial frequency by ionizing radiation and metal-catalyzed H2O2 reactions. Under anoxic conditions, the predominant double-base lesion is a species in which C8 of guanine is linked to the 5-methyl group of an adjacent 3'-thymine (G[8,5- Me]T).JOURNAL, Colis LC, Raychaudhury P, Basu AK, Mutational specificity of gamma-radiation-induced guanine-thymine and thymine-guanine intrastrand cross-links in mammalian cells and translesion synthesis past the guanine-thymine lesion by human DNA polymerase eta, Biochemistry, 47, 31, 8070–8079, August 2008, 18616294, 2646719, 10.1021/bi800529f, Most of these oxygen-derived species are produced by normal aerobic metabolism. Normal cellular defense mechanisms destroy most of these. Repair of oxidative damages to DNA is frequent and ongoing, largely keeping up with newly induced damages. In rat urine, about 74,000 oxidative DNA adducts per cell are excreted daily.JOURNAL, Helbock HJ, Beckman KB, Shigenaga MK, Walter PB, Woodall AA, Yeo HC, Ames BN, DNA oxidation matters: the HPLC-electrochemical detection assay of 8-oxo-deoxyguanosine and 8-oxo-guanine, Proceedings of the National Academy of Sciences of the United States of America, 95, 1, 288–293, January 1998, 9419368, 18204, 10.1073/pnas.95.1.288, free, 1998PNAS...95..288H, There is also a steady state level of oxidative damages in the DNA of a cell. There are about 24,000 oxidative DNA adducts per cell in young rats and 66,000 adducts per cell in old rats. Likewise, any damage 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.JOURNAL, Lelli JL, Becks LL, Dabrowska MI, Hinshaw DB, ATP converts necrosis to apoptosis in oxidant-injured endothelial cells, Free Radical Biology & Medicine, 25, 6, 694–702, October 1998, 9801070, 10.1016/S0891-5849(98)00107-5, JOURNAL, Lee YJ, Shacter E, Oxidative stress inhibits apoptosis in human lymphoma cells, The Journal of Biological Chemistry, 274, 28, 19792–19798, July 1999, 10391922, 10.1074/jbc.274.28.19792, free, Polyunsaturated fatty acids, particularly arachidonic acid and linoleic acid, are primary targets for free radical and singlet oxygen oxidations. For example, in tissues and cells, the free radical oxidation of linoleic acid produces racemic mixtures of 13-hydroxy-9Z,11E-octadecadienoic acid, 13-hydroxy-9E,11E-octadecadienoic acid, 9-hydroxy-10E,12-E-octadecadienoic acid (9-EE-HODE), and 11-hydroxy-9Z,12-Z-octadecadienoic acid as well as 4-Hydroxynonenal while singlet oxygen attacks linoleic acid to produce (presumed but not yet proven to be racemic mixtures of) 13-hydroxy-9Z,11E-octadecadienoic acid, 9-hydroxy-10E,12-Z-octadecadienoic acid, 10-hydroxy-8E,12Z-octadecadienoic acid, and 12-hydroxy-9Z-13-E-octadecadienoic (see 13-Hydroxyoctadecadienoic acid and 9-Hydroxyoctadecadienoic acid).JOURNAL, Akazawa-Ogawa Y, Shichiri M, Nishio K, Yoshida Y, Niki E, Hagihara Y, Singlet-oxygen-derived products from linoleate activate Nrf2 signaling in skin cells, Free Radical Biology & Medicine, 79, 164–175, February 2015, 25499849, 10.1016/j.freeradbiomed.2014.12.004, JOURNAL, Yoshida Y, Umeno A, Akazawa Y, Shichiri M, Murotomi K, Horie M, Chemistry of lipid peroxidation products and their use as biomarkers in early detection of diseases, Journal of Oleo Science, 64, 4, 347–356, 2015, 25766928, 10.5650/jos.ess14281, free, Similar attacks on arachidonic acid produce a far larger set of products including various isoprostanes, hydroperoxy- and hydroxy- eicosatetraenoates, and 4-hydroxyalkenals.JOURNAL, Vigor C, Bertrand-Michel J, Pinot E, Oger C, Vercauteren J, Le Faouder P, Galano JM, Lee JC, Durand T, 6, Non-enzymatic lipid oxidation products in biological systems: assessment of the metabolites from polyunsaturated fatty acids, Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences, 964, 65–78, August 2014, 24856297, 10.1016/j.jchromb.2014.04.042,weblink While many of these products are used as markers of oxidative stress, the products derived from linoleic acid appear far more predominant than arachidonic acid products and therefore easier to identify and quantify in, for example, atheromatous plaques.JOURNAL, Waddington EI, Croft KD, Sienuarine K, Latham B, Puddey IB, Fatty acid oxidation products in human atherosclerotic plaque: an analysis of clinical and histopathological correlates, Atherosclerosis, 167, 1, 111–120, March 2003, 12618275, 10.1016/S0021-9150(02)00391-X, Certain linoleic acid products have also been proposed to be markers for specific types of oxidative stress. For example, the presence of racemic 9-HODE and 9-EE-HODE mixtures reflects free radical oxidation of linoleic acid whereas the presence of racemic 10-hydroxy-8E,12Z-octadecadienoic acid and 12-hydroxy-9Z-13-E-octadecadienoic acid reflects singlet oxygen attack on linoleic acid. In addition to serving as markers, the linoleic and arachidonic acid products can contribute to tissue and/or DNA damage but also act as signals to stimulate pathways which function to combat oxidative stress.JOURNAL, Riahi Y, Cohen G, Shamni O, Sasson S, Signaling and cytotoxic functions of 4-hydroxyalkenals, American Journal of Physiology. Endocrinology and Metabolism, 299, 6, E879–E886, December 2010, 20858748, 10.1152/ajpendo.00508.2010, 6062445, JOURNAL, Cho KJ, Seo JM, Kim JH, Bioactive lipoxygenase metabolites stimulation of NADPH oxidases and reactive oxygen species, Molecules and Cells, 32, 1, 1–5, July 2011, 21424583, 3887656, 10.1007/s10059-011-1021-7, JOURNAL, Galano JM, Mas E, Barden A, Mori TA, Signorini C, De Felice C, Barrett A, Opere C, Pinot E, Schwedhelm E, Benndorf R, Roy J, Le Guennec JY, Oger C, Durand T, 6, Isoprostanes and neuroprostanes: total synthesis, biological activity and biomarkers of oxidative stress in humans, Prostaglandins & Other Lipid Mediators, 107, 95–102, December 2013, 23644158, 10.1016/j.prostaglandins.2013.04.003, 33638363,weblink JOURNAL, Cohen G, Riahi Y, Sunda V, Deplano S, Chatgilialoglu C, Ferreri C, Kaiser N, Sasson S, 6, Signaling properties of 4-hydroxyalkenals formed by lipid peroxidation in diabetes, Free Radical Biology & Medicine, 65, 978–987, December 2013, 23973638, 10.1016/j.freeradbiomed.2013.08.163, JOURNAL, Speed N, Blair IA, Cyclooxygenase- and lipoxygenase-mediated DNA damage, Cancer and Metastasis Reviews, 30, 3–4, 437–447, December 2011, 22009064, 3237763, 10.1007/s10555-011-9298-8, {| class="wikitable"! Oxidant !! Description

•O	-}}, superoxide anion	O	electron transport chain. Rather unreactive but can release {{chem>Fe	ferritin. Undergoes dismutation to form {{chem>H	O|2}} spontaneously or by enzymatic catalysis and is a precursor for metal-catalyzed •OH formation.

H	O|2}}, hydrogen peroxide	•O	-}} or by direct reduction of {{chem	2}}. Lipid-soluble and thus able to diffuse across membranes.

|•OH, hydroxyl radical

Fenton's reagent>Fenton reaction and decomposition of peroxynitrite. Extremely reactive, will attack most cellular components

Hydroperoxide>organic hydroperoxide|Formed by radical reactions with cellular components such as lipids and nucleobases.

|RO•, alkoxy and ROO•, peroxy radicals|Oxygen centred organic radicals. Lipid forms participate in lipid peroxidation reactions. Produced in the presence of oxygen by radical addition to double bonds or hydrogen abstraction.|HOCl, hypochlorous acid

H	O|2}} by myeloperoxidase. Lipid-soluble and highly reactive. Will readily oxidize protein constituents, including thiol groups, amino groups and methionine.

|ONOO-, peroxynitrite

•O	-}} 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.

Table adapted from.BOOK, Sies H, Oxidative stress: introductory remarks, Oxidative Stress, Sies H, Academic Press, 1985, 1–7, London, BOOK, Docampo R, Antioxidant mechanisms, Biochemistry and Molecular Biology of Parasites, Marr J, Müller M, Academic Press, London, 1995, 147–160, JOURNAL, Rice-Evans CA, Gopinathan V, Oxygen toxicity, free radicals and antioxidants in human disease: biochemical implications in atherosclerosis and the problems of premature neonates, Essays in Biochemistry, 29, 39–63, 1995, 9189713,

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 phosphorylation. E. coli mutants that lack an active electron transport chain produce as much hydrogen peroxide as wild-type cells, indicating that other enzymes contribute the bulk of oxidants in these organisms.JOURNAL, Seaver LC, Imlay JA, Are respiratory enzymes the primary sources of intracellular hydrogen peroxide?, The Journal of Biological Chemistry, 279, 47, 48742–48750, November 2004, 15361522, 10.1074/jbc.M408754200, free, One possibility is that multiple redox-active flavoproteins all contribute a small portion to the overall production of oxidants under normal conditions.JOURNAL, Messner KR, Imlay JA, Mechanism of superoxide and hydrogen peroxide formation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase, The Journal of Biological Chemistry, 277, 45, 42563–42571, November 2002, 12200425, 10.1074/jbc.M204958200, free, JOURNAL, Imlay JA, Pathways of oxidative damage, Annual Review of Microbiology, 57, 1, 395–418, 2003, 14527285, 10.1146/annurev.micro.57.030502.090938, 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.The amino acid methionine is prone to oxidation, but oxidized methionine can be reversible. Oxidation of methionine is shown to inhibit the phosphorylation of adjacent Ser/Thr/Tyr sites in proteins.JOURNAL, Hardin SC, Larue CT, Oh MH, Jain V, Huber SC, Coupling oxidative signals to protein phosphorylation via methionine oxidation in Arabidopsis, The Biochemical Journal, 422, 2, 305–312, August 2009, 19527223, 2782308, 10.1042/BJ20090764, This gives a plausible mechanism for cells to couple oxidative stress signals with cellular mainstream signaling such as phosphorylation.

Diseases

Oxidative stress is suspected to be important in neurodegenerative diseases including Lou Gehrig's disease (aka MND or ALS), Parkinson's disease, Alzheimer's disease, Huntington's disease, depression, and multiple sclerosis.JOURNAL, Haider L, Fischer MT, Frischer JM, Bauer J, Höftberger R, Botond G, Esterbauer H, Binder CJ, Witztum JL, Lassmann H, 6, Oxidative damage in multiple sclerosis lesions, Brain, 134, Pt 7, 1914–1924, July 2011, 21653539, 3122372, 10.1093/brain/awr128, JOURNAL, Patel VP, Chu CT, Nuclear transport, oxidative stress, and neurodegeneration, International Journal of Clinical and Experimental Pathology, 4, 3, 215–229, March 2011, 21487518, 3071655, It is also indicated in Neurodevelopmental conditions such as Autism Spectrum Disorder.JOURNAL, Hollis F, Kanellopoulos AK, Bagni C, Mitochondrial dysfunction in Autism Spectrum Disorder: clinical features and perspectives, Current Opinion in Neurobiology, 45, 178–187, August 2017, 28628841, 10.1016/j.conb.2017.05.018, 3617876, Indirect evidence via monitoring biomarkers such as reactive oxygen species, and reactive nitrogen species production indicates oxidative damage may be involved in the pathogenesis of these diseases,JOURNAL, Nunomura A, Castellani RJ, Zhu X, Moreira PI, Perry G, Smith MA, Involvement of oxidative stress in Alzheimer disease, Journal of Neuropathology and Experimental Neurology, 65, 7, 631–641, July 2006, 16825950, 10.1097/01.jnen.0000228136.58062.bf, free, JOURNAL, Bošković M, Vovk T, Kores Plesničar B, Grabnar I, Oxidative stress in schizophrenia, Current Neuropharmacology, 9, 2, 301–312, June 2011, 22131939, 3131721, 10.2174/157015911795596595, while cumulative oxidative stress with disrupted mitochondrial respiration and mitochondrial damage are related to Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases.JOURNAL, Ramalingam M, Kim SJ, Reactive oxygen/nitrogen species and their functional correlations in neurodegenerative diseases, Journal of Neural Transmission, 119, 8, 891–910, August 2012, 22212484, 10.1007/s00702-011-0758-7, 2615132, 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 (ME/CFS).JOURNAL, Nijs J, Meeus M, De Meirleir K, Chronic musculoskeletal pain in chronic fatigue syndrome: recent developments and therapeutic implications, Manual Therapy, 11, 3, 187–191, August 2006, 16781183, 10.1016/j.math.2006.03.008, Oxidative stress also contributes to tissue injury following irradiation and hyperoxia, as well as in diabetes. In hematological cancers, such as leukemia, the impact of oxidative stress can be bilateral. Reactive oxygen species can disrupt the function of immune cells, promoting immune evasion of leukemic cells. On the other hand, high levels of oxidative stress can also be selectively toxic to cancer cells.JOURNAL, Domka K, Goral A, Firczuk M, cROSsing the Line: Between Beneficial and Harmful Effects of Reactive Oxygen Species in B-Cell Malignancies, Frontiers in Immunology, 11, 1538, 2020, 32793211, 7385186, 10.3389/fimmu.2020.01538, free, JOURNAL, Udensi UK, Tchounwou PB, Dual effect of oxidative stress on leukemia cancer induction and treatment, Journal of Experimental & Clinical Cancer Research, 33, 106, December 2014, 25519934, 4320640, 10.1186/s13046-014-0106-5, free, Oxidative stress is likely to be involved in age-related development of cancer. The reactive species produced in oxidative stress can cause direct damage to the DNA and are therefore mutagenic, and it may also suppress apoptosis and promote proliferation, invasiveness and metastasis.JOURNAL, Halliwell B, Oxidative stress and cancer: have we moved forward?, The Biochemical Journal, 401, 1, 1–11, January 2007, 17150040, 10.1042/BJ20061131, Infection by Helicobacter pylori which increases the production of reactive oxygen and nitrogen species in human stomach is also thought to be important in the development of gastric cancer.JOURNAL, Handa O, Naito Y, Yoshikawa T, Redox biology and gastric carcinogenesis: the role of Helicobacter pylori, Redox Report, 16, 1, 1–7, 2011, 21605492, 6837368, 10.1179/174329211X12968219310756, free, Oxidative stress can cause DNA damage in neurons. In neuronal progenitor cells, DNA damage is associated with increased secretion of amyloid beta proteins Aβ40 and Aβ42.Welty S, Thathiah A, Levine AS. DNA Damage Increases Secreted Aβ40 and Aβ42 in Neuronal Progenitor Cells: Relevance to Alzheimer's Disease. J Alzheimers Dis. 2022;88(1):177–190. doi: 10.3233/JAD-220030. PMID: 35570488; PMCID: PMC9277680 This association supports the existence of a causal relationship between oxidative DNA damage and Aβ accumulation and suggests that oxidative DNA damage may contribute to Alzheimer's disease (AD) pathology. AD is associated with an accumulation of DNA damage (double-strand breaks) in vulnerable neuronal and glial cell populations from early stages onward,Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, Rissman RA, Masliah E, Mucke L. Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease. Acta Neuropathol Commun. 2019 May 17;7(1):77. doi: 10.1186/s40478-019-0723-5. PMID: 31101070; PMCID: PMC6524256 and DNA double-strand breaks are increased in the hippocampus of AD brains compared to non-AD control brains.Thadathil N, Delotterie DF, Xiao J, Hori R, McDonald MP, Khan MM. DNA Double-Strand Break Accumulation in Alzheimer's Disease: Evidence from Experimental Models and Postmortem Human Brains. Mol Neurobiol. 2021 Jan;58(1):118–131. doi: 10.1007/s12035-020-02109-8. Epub 2020 Sep 8. PMID: 32895786

Antioxidants as supplements

{{Further|Antioxidant}}The use of antioxidants to prevent some diseases is controversial.JOURNAL, Meyers DG, Maloley PA, Weeks D, Safety of antioxidant vitamins, Archives of Internal Medicine, 156, 9, 925–935, May 1996, 8624173, 10.1001/archinte.156.9.925, In a high-risk group like smokers, high doses of beta carotene increased the rate of lung cancer since high doses of beta-carotene in conjunction of high oxygen tension due to smoking results in a pro-oxidant effect and an antioxidant effect when oxygen tension is not high.JOURNAL, Ruano-Ravina A, Figueiras A, Freire-Garabal M, Barros-Dios JM, Antioxidant vitamins and risk of lung cancer, Current Pharmaceutical Design, 12, 5, 599–613, 2006, 16472151, 10.2174/138161206775474396, JOURNAL, Zhang P, Omaye ST, Antioxidant and prooxidant roles for beta-carotene, alpha-tocopherol and ascorbic acid in human lung cells, Toxicology in Vitro, 15, 1, 13–24, February 2001, 11259865, 10.1016/S0887-2333(00)00054-0, In less high-risk groups, the use of vitamin E appears to reduce the risk of heart disease.JOURNAL, Pryor WA, Vitamin E and heart disease: basic science to clinical intervention trials, Free Radical Biology & Medicine, 28, 1, 141–164, January 2000, 10656300, 10.1016/S0891-5849(99)00224-5, However, while consumption of food rich in vitamin E may reduce the risk of coronary heart disease in middle-aged to older men and women, using vitamin E supplements also appear to result in an increase in total mortality, heart failure, and hemorrhagic stroke. The American Heart Association therefore recommends the consumption of food rich in antioxidant vitamins and other nutrients, but does not recommend the use of vitamin E supplements to prevent cardiovascular disease.JOURNAL, Saremi A, Arora R, Vitamin E and cardiovascular disease, American Journal of Therapeutics, 17, 3, e56–e65, 2010, 19451807, 10.1097/MJT.0b013e31819cdc9a, 25631305, In other diseases, such as Alzheimer's, the evidence on vitamin E supplementation is also mixed.JOURNAL, Boothby LA, Doering PL, Vitamin C and vitamin E for Alzheimer's disease, The Annals of Pharmacotherapy, 39, 12, 2073–2080, December 2005, 16227450, 10.1345/aph.1E495, 46645284, JOURNAL, Kontush K, Schekatolina S, Vitamin E in neurodegenerative disorders: Alzheimer's disease, Annals of the New York Academy of Sciences, 1031, 1, 249–262, December 2004, 15753151, 10.1196/annals.1331.025, 33556198, 2004NYASA1031..249K, 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. AstraZeneca's radical scavenging nitrone drug NXY-059 shows some efficacy in the treatment of stroke.JOURNAL, Fong JJ, Rhoney DH, NXY-059: review of neuroprotective potential for acute stroke, The Annals of Pharmacotherapy, 40, 3, 461–471, March 2006, 16507608, 10.1345/aph.1E636, 38016035, 10.1.1.1001.6501, Oxidative stress (as formulated in Denham 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,JOURNAL, Larsen PL, Aging and resistance to oxidative damage in Caenorhabditis elegans, Proceedings of the National Academy of Sciences of the United States of America, 90, 19, 8905–8909, October 1993, 8415630, 47469, 10.1073/pnas.90.19.8905, free, 1993PNAS...90.8905L, JOURNAL, Helfand SL, Rogina B, Genetics of aging in the fruit fly, Drosophila melanogaster, Annual Review of Genetics, 37, 1, 329–348, 2003, 14616064, 10.1146/annurev.genet.37.040103.095211, 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.JOURNAL, Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M, Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress, Cell Metabolism, 6, 4, 280–293, October 2007, 17908557, 10.1016/j.cmet.2007.08.011, free, The situation in mammals is even less clear.JOURNAL, Sohal RS, Mockett RJ, Orr WC, Mechanisms of aging: an appraisal of the oxidative stress hypothesis, Free Radical Biology & Medicine, 33, 5, 575–586, September 2002, 12208343, 10.1016/S0891-5849(02)00886-9, JOURNAL, Sohal RS, Role of oxidative stress and protein oxidation in the aging process, Free Radical Biology & Medicine, 33, 1, 37–44, July 2002, 12086680, 10.1016/S0891-5849(02)00856-0, JOURNAL, Rattan SI, Theories of biological aging: genes, proteins, and free radicals, Free Radical Research, 40, 12, 1230–1238, December 2006, 17090411, 10.1080/10715760600911303, 11125090, 10.1.1.476.9259, Recent epidemiological findings support the process of mitohormesis, but a 2007 meta-analysis finds that in studies with a low risk of bias (randomization, blinding, follow-up), some popular antioxidant supplements (vitamin A, beta carotene, and vitamin E) may increase mortality risk (although studies more prone to bias reported the reverse).JOURNAL, Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C, February 2007, Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis, JAMA, 297, 8, 842–857, 10.1001/jama.297.8.842, 17327526, . See also the letter {{webarchive|url=https://web.archive.org/web/20080724000517weblink|date=2008-07-24}} to JAMA by Philip Taylor and Sanford Dawsey and the reply {{webarchive|url=https://web.archive.org/web/20080624223353weblink|date=2008-06-24}} by the authors of the original paper.The USDA removed the table showing the Oxygen Radical Absorbance Capacity (ORAC) of Selected Foods Release 2 (2010) table due to the lack of evidence that the antioxidant level present in a food translated into a related antioxidant effect in the body.WEB,weblink Oxygen Radical Absorbance Capacity (ORAC) of Selected Foods, Release 2 (2010), USDA,

Metal catalysts

Metals such as iron, 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 production of reactive radicals and reactive oxygen species.* BOOK, Pratviel G, Sigel A, Sigel H, Sigel RK, Interplay between Metal Ions and Nucleic Acids, Metal Ions in Life Sciences, 10, 2012, Springer, 10.1007/978-94-007-2172-2_7, 22210340, 201–216, Oxidative DNA Damage Mediated by Transition Metal Ions and Their Complexes, 978-94-007-2171-5, The reaction of transition metals with proteins oxidated by reactive oxygen or nitrogen species can yield reactive products that accumulate and contribute to aging and disease. For example, in Alzheimer's patients, peroxidized lipids and proteins accumulate in lysosomes of the brain cells.JOURNAL, Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD, Free radicals and antioxidants in human health: current status and future prospects, The Journal of the Association of Physicians of India, 52, 794–804, October 2004, 15909857,

Non-metal redox catalysts

Certain organic compounds in addition to metal redox catalysts can also produce reactive oxygen species. One of the most important classes of these is the quinones. Quinones can redox cycle with their conjugate semiquinones and hydroquinones, in some cases catalyzing the production of superoxide from dioxygen or hydrogen peroxide from superoxide.

Immune defense

The immune system uses the lethal effects of oxidants by making the production of oxidizing species a central part of its mechanism of killing pathogens; with activated phagocytes producing both reactive oxygen and nitrogen species. These include superoxide {{chem|(•O|2|-|)}}, nitric oxide (•NO) and their particularly reactive product, peroxynitrite (ONOO-).JOURNAL, Nathan C, Shiloh MU, Reactive oxygen and nitrogen intermediates in the relationship between mammalian hosts and microbial pathogens, Proceedings of the National Academy of Sciences of the United States of America, 97, 16, 8841–8848, August 2000, 10922044, 34021, 10.1073/pnas.97.16.8841, free, 2000PNAS...97.8841N, 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.

Male infertility

Sperm DNA fragmentation appears to be an important factor in the cause of male infertility, since men with high DNA fragmentation levels have significantly lower odds of conceiving.JOURNAL, Wright C, Milne S, Leeson H, Sperm DNA damage caused by oxidative stress: modifiable clinical, lifestyle and nutritional factors in male infertility, Reproductive Biomedicine Online, 28, 6, 684–703, June 2014, 24745838, 10.1016/j.rbmo.2014.02.004, free, Oxidative stress is the major cause of DNA fragmentation in spermatozoa. A high level of the oxidative DNA damage 8-oxo-2'-deoxyguanosine is associated with abnormal spermatozoa and male infertility.JOURNAL, Guz J, Gackowski D, Foksinski M, Rozalski R, Zarakowska E, Siomek A, Szpila A, Kotzbach M, Kotzbach R, Olinski R, 6, Comparison of oxidative stress/DNA damage in semen and blood of fertile and infertile men, PLOS ONE, 8, 7, e68490, 2013, 23874641, 3709910, 10.1371/journal.pone.0068490, free, 2013PLoSO...868490G,

Aging

{{Further|Ageing}}In a rat model of premature aging, oxidative stress induced DNA damage in the neocortex and hippocampus was substantially higher than in normally aging control rats.JOURNAL, Sinha JK, Ghosh S, Swain U, Giridharan NV, Raghunath M, Increased macromolecular damage due to oxidative stress in the neocortex and hippocampus of WNIN/Ob, a novel rat model of premature aging, Neuroscience, 269, 256–264, June 2014, 24709042, 10.1016/j.neuroscience.2014.03.040, 9934178, Numerous studies have shown that the level of 8-oxo-2'-deoxyguanosine, a product of oxidative stress, increases with age in the brain and muscle DNA of the mouse, rat, gerbil and human.BOOK, Bernstein H, Payne CM, Bernstein C, Garewal H, Dvorak K, Cancer and Aging as Consequences of Un-Repaired DNA Damage, New Research on DNA Damages, Kimura H, Suzuki A, Nova Science Publishers, Inc., New York, 2008, 1–47, 978-1-60456-581-2,weblink dead,weblink 2014-10-25, Further information on the association of oxidative DNA damage with aging is presented in the article DNA damage theory of aging. However, it was recently shown that the fluoroquinolone antibiotic Enoxacin can diminish aging signals and promote lifespan extension in nematodes C. elegans by inducing oxidative stress.JOURNAL, Pinto S, Sato VN, De-Souza EA, Ferraz RC, Camara H, Pinca AP, Mazzotti DR, Lovci MT, Tonon G, Lopes-Ramos CM, Parmigiani RB, Wurtele M, Massirer KB, Mori MA, 6, Enoxacin extends lifespan of C. elegans by inhibiting miR-34-5p and promoting mitohormesis, Redox Biology, 18, 84–92, September 2018, 29986212, 6037660, 10.1016/j.redox.2018.06.006,

Origin of eukaryotes

The great oxygenation event began with the biologically induced appearance of oxygen in the Earth's atmosphere about 2.45 billion years ago. The rise of oxygen levels due to cyanobacterial photosynthesis in ancient microenvironments was probably highly toxic to the surrounding biota. Under these conditions, the selective pressure of oxidative stress is thought to have driven the evolutionary transformation of an archaeal lineage into the first eukaryotes.JOURNAL, Gross J, Bhattacharya D, Uniting sex and eukaryote origins in an emerging oxygenic world, Biology Direct, 5, 53, August 2010, 20731852, 2933680, 10.1186/1745-6150-5-53, free, Oxidative stress might have acted in synergy with other environmental stresses (such as ultraviolet radiation and/or desiccation) to drive this selection. Selective pressure for efficient repair of oxidative DNA damages may have promoted the evolution of eukaryotic sex involving such features as cell-cell fusions, cytoskeleton-mediated chromosome movements and emergence of the nuclear membrane. Thus, the evolution of meiotic sex and eukaryogenesis may have been inseparable processes that evolved in large part to facilitate repair of oxidative DNA damages.Bernstein H, Bernstein C. Sexual communication in archaea, the precursor to meiosis. pp. 103–117 in Biocommunication of Archaea (Guenther Witzany, ed.) 2017. Springer International Publishing {{ISBN|978-3-319-65535-2}} DOI 10.1007/978-3-319-65536-9JOURNAL, Hörandl E, Speijer D, How oxygen gave rise to eukaryotic sex, Proceedings. Biological Sciences, 285, 1872, 20172706, February 2018, 29436502, 5829205, 10.1098/rspb.2017.2706,

COVID-19 and cardiovascular injury

It has been proposed that oxidative stress may play a major role in determining cardiac complications in COVID-19.JOURNAL, Majumder N, Deepak V, Hadique S, Aesoph D, Velayutham M, Ye Q, Mazumder MH, Lewis SE, Kodali V, Roohollahi A, Guo NL, Hu G, Khramtsov VV, Johnson RJ, Wen S, Kelley EE, Hussain S, 6, Redox imbalance in COVID-19 pathophysiology, Redox Biology, 56, 102465, October 2022, 36116160, 9464257, 10.1016/j.redox.2022.102465, JOURNAL, Loffredo L, Violi F, COVID-19 and cardiovascular injury: A role for oxidative stress and antioxidant treatment?, International Journal of Cardiology, 312, 136, August 2020, 32505331, 7833193, 10.1016/j.ijcard.2020.04.066, free,

See also

{{col div|colwidth=30em}}

• Antioxidative stress
• Acatalasia
• Bruce Ames
• Malondialdehyde, an oxidative stress marker
• Mitochondrial free radical theory of aging
• Mitohormesis
• Nitric oxide
• Pro-oxidant
• Reductive stress

{{colend}}

References

{{reflist|30em}}{{Authority control}}