Free Radicals and Other Reactive Species in Disease


Free radicals are generated in a wide variety of chemical and biological systems, including the production of plastics, the ageing of paints, the deterioration of foods, the combustion of fuels and in the human body. In living organisms, the levels of free radicals and other ‘reactive species’ (such as hydrogen peroxide) are controlled by a complex web of antioxidant defences, which minimise (but do not completely prevent) oxidative damage to biomolecules. One reason for this is that reactive species play useful roles, for example, in cell signalling and especially in defence against pathogens. However, over the long human lifespan, oxidative damage may contribute to diseases (e.g. cancer, cardiovascular disease, dementia) and perhaps even to the ageing process itself. Some antioxidants come from the diet, whereas others (such as glutathione and the superoxide dismutase enzymes) are made in vivo.

Key Concepts

  • Oxygen free radicals and other reactive species are made in vivo.
  • Some are made for useful purposes, some ‘accidentally’.
  • Their action is controlled by a balanced and coordinated network of antioxidant defences, whose aim is to modulate their levels so as to allow their useful functions while minimising oxidative damage.
  • Many antioxidant defences are synthesised in vivo but some also come from diet.
  • Reactive species play key roles in the development of human diseases, including Alzheimer disease and cancers caused by chronic inflammation.

Keywords: free radical; antioxidant; superoxide; hydroxyl radical; lipid peroxidation; oxidative stress; mutation; hydrogen peroxide signalling

Figure 1. Structures of reduced (GSH) and oxidised (GSSG) glutathione. GSH is a tripeptide (glutamic acid‐cysteine‐glycine). In GSSG, two GSH molecules join together as the −SH groups of cysteine oxidise to form a disulphide bridge. The enzyme glutathione peroxidase removes H2O2 by the reaction 2 G S H + H 2 O 2 GSSG + 2 H 2 O and GSH is then regenerated by glutathione reductase GSSG + NADPH + H + 2 G S H + NADP + 2 H 2 O 2 2 H 2 O + O 2 Peroxiredoxins (PR) remove H2O2 using the protein thioredoxin; two thiol groups on thioredoxin form a disulphide. Thioredoxin (SH)2 is then regenerated by thioredoxin reductase (TR). Thioredoxin S 2 + NADPH + H + T R NADP + + Thioredoxin S H 2 Reproduced with permission from Halliwell B () © ILSI Europe.
Figure 2. Some of the reasons why tissue injury causes oxidative stress. Reproduced from Halliwell and Gutteridge, © Oxford University Press.
Figure 3. What is the significance of oxidative stress in disease? Reproduced from Halliwell and Gutteridge, © Oxford University Press.


Badaloo AV and Marshall KG (2014) Oxidative stress in childhood severe acute malnutrition. In: Dichi I , Breganó JM , Simão AM and Cecchini R , (eds). Role of Oxidative Stress in Chronic Diseases, Boca Raton, Florida: CRC Press.

Batinić‐Haberle I and Spasojević I (2014) Complex chemistry and biology of redox‐active compounds, commonly known as SOD mimics, affect their therapeutic effects. Antioxidants and Redox Signaling 20 (15): 2323–2325.

Battelli MG , Bolognesi A and Polito L (2014) Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi‐tasking enzyme. Biochimica et Biophysica Acta 1842 (9): 1502–1517.

Brigelius‐Flohé R and Maiorino M (2013) Glutathione peroxidases. Biochimica et Biophysica Acta 1830 (5): 3289–3303.

Butterfield DA , Di Domenico F , Swomley AM , Head E and Perluigi M (2014) Redox proteomics analysis to decipher the neurobiology of Alzheimer‐like neurodegeneration: overlaps in Down's syndrome and Alzheimer's disease brain. Biochemical Journal 463 (2): 177–189.

Cooke MS (2012) Special issue on DNA oxidation: mechanisms, measurement and consequences. Free Radical Research 46 (4): 365–366.

Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nature Reviews Cancer 12 (12): 801–817.

Dalle‐Donne I , Rossi R , Colombo R , Giustarini D and Milzani A (2006) Biomarkers of oxidative damage in human disease. Clinical Chemistry 52 (4): 601.

Dizdaroglu M and Jaruga P (2012) Mechanisms of free radical‐induced damage to DNA. Free Radical Research 46 (4): 382–419.

Feng C (2012) Mechanism of nitric oxide synthase regulation: electron transfer and interdomain interactions. Coordination Chemistry Reviews 256 (3‐4): 393–411.

Floyd RA , Towner RA , He T , Hensley K and Maples KR (2011) Translational research involving oxidative stress and diseases of aging. Free Radical Biology and Medicine 51 (5): 931–941.

Forman JH , Maiorino M and Ursini F (2010) Signalling functions of reactive oxygen species. Biochemistry 49 (5): 835–842.

Halliwell B (2001) Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs and Aging 18 (9): 685–716.

Halliwell B (2015) Antioxidant and anti‐inflammatory components of foods. ILSI Europe Concise Monograph Series 2015.

Halliwell B and Gutteridge JMC (2015) Free Radicals in Biology and Medicine, 5th edn. Oxford, UK: Oxford University Press.

Hedge ML , Hedge PM , Rao KS and Mitra S (2011) Oxidative genome damage and its repair in neurodegenerative diseases: function of transition metals as a double‐edged sword. Journal of Alzheimers Disease 24 (suppl. 2): 183–198.

Jiang X , Yang Z , Chandrakala AN , Pressley D and Parthasarathy S (2011) Oxidised low density lipoproteins – do we know enough about them? Cardiovascular Drugs and Therapy 25 (5): 367–377.

Johri A and Beal MF (2012) Mitochondrial dysfunction in neurodegenerative diseases. Journal of Pharmacology and Experimental Therapeutics. 342 (3): 619–630.

Lambeth JD and Neish AS (2014) Nox enzymes and new thinking on reactive oxygen: a double‐edged sword revisited. Annual Review of Pathology 9: 119–145.

Li J , Liu W , Ding S , et al. (2008) Hyperbaric oxygen preconditioning induces tolerance against brain ischemia‐reperfusion injury by upregulation of antioxidant enzymes in rats. Brain Research 1210: 223.

Libby P , Ridker PM and Hansson GK (2011) Progress and challenges in translating the biology of atherosclerosis. Nature 473 (7347): 317–325.

Michels AJ , Hagen TM and Frei B (2013) Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function. Annual Review of Nutrition 33: 45–70.

Niki E (2014) Role of vitamin E as a lipid‐soluble peroxyl radical scavenger: in vitro and in vivo evidence. Free Radical Biology and Medicine 66: 3–12.

Nowotny K , Jung T , Grune T and Höhn A (2014) Accumulation of modified proteins and aggregate formation in ageing. Experimental Gerontology 57: 122–131.

Orrenius S , Nicotera P and Zhivotovsky B (2011) Cell death mechanisms and their implications in toxicology. Toxicological Sciences 119 (1): 3–19.

Phani S , Loike JD and Przedborski S (2012) Neurodegeneration and inflammation in Parkinson's disease. Parkinsonism & Related Disorders 18 (suppl. 1): S207–S209.

Radi R (2013) Protein tyrosine nitration: biochemical mechanisms and structural basis of functional effects. Accounts of Chemical Research 46 (2): 550–559.

Rayman MP (2012) Selenium and human health. Lancet 379 (9822): 1256–1268.

Rhee SG , Woo HA , Kil IS and Bae SH (2012) Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides. Journal of Biological Chemistry 287 (7): 4403–4410.

Scott G (ed) (1993) Atmospheric Oxygen and Antioxidants, vol. 1–3. Amsterdam, The Netherlands: Elsevier.

Sies H (ed) (1991) Oxidative Stress. Oxidants and Antioxidants. New York: Academic Press.

Sies H (2014) Role of metabolic H2O2 generation: redox signalling and oxidative stress. Journal of Biological Chemistry 289: 8735.

von Sonntag C (ed) (2010) Free‐Radical‐Induced DNA Damage and Its Repair: A Chemical Perspective. Heidelberg, Germany: Springer.

Sultana R and Butterfield DA (2013) Oxidative modification of brain proteins in Alzheimer's disease: perspective on future studies based on results of redox proteomics studies. Journal of Alzheimers Disease 33 (suppl. 1): S243–S251.

Traber MG and Stevens JF (2011) Vitamins C and E: beneficial effects from a mechanistic perspective. Free Radical Biology and Medicine 51 (5): 1000–1013.

Verlarde MC , Flynn JM , Day NU , Melov S and Campisi J (2012) Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin. Aging 4 (1): 3–12.

Further Reading

Dichi I , Breganó JM , Simão AM and Cecchini R (eds) (2014) Role of Oxidative Stress in Chronic Diseases, Boca Raton, Florida: CRC Press.

Finley JW , An K , Hintze KJ , et al. (2011) Antioxidants in foods: state of the science important to the food industry. Journal of Agricultural and Food Chemistry 59 (13): 6837–6846.

Forum issue on SOD mimics. (2014) Batinic‐Haberle I and Ivan Spasojevic I (eds.), Antioxidants & Redox Signaling 20 (5).

Gruber J , Chen CB , Fong S , et al. (2015) Caenorhabditis elegans, what we can and cannot learn from ageing worms? Antioxidants & Redox Signaling, ahead of print. Doi:10.1089/ars.2014.6210.

Jung T and Grune T (2014) The proteasome and the degradation of oxidized proteins: part II – protein oxidation and proteasomal degradation. Redox Biology 2: 99–104.

Kirkwood TB and Melov S (2011) On the programmed/non‐programmed nature of ageing within the life history. Current Biology 21 (18): R701–R707.

Milne GL , Yin H , Hardy KD , Davies SS and Roberts LG II (2011) Isoprostane generation and function. Chemical Reviews 111 (10): 5973–5996.

Reverri EJ , Morrissey BM , Cross CE and Steinberg FM (2014) Inflammation, oxidative stress, and cardiovascular disease risk factors in adults with cystic fibrosis. Free Radical Biology and Medicine 76C: 261–277.

Rifkind JM and Nagababu E (2013) Hemoglobin redox reactions and red blood cell aging. Antioxidants & Redox Signaling 18 (17): 2274–2283.

Zorov DB , Juhaszova M and Sollott SJ (2014) Mitochondrial reactive oxygen species (ROS) and ROS‐induced ROS release. Physiological Reviews 94 (3): 909–950.

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Halliwell, Barry(Mar 2015) Free Radicals and Other Reactive Species in Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0002269.pub3]