Free Radicals and Antioxidants: A new Paradigm has emerged
Main Article Content
Abstract
Despite the tremendous progress Redox Biology has made since the turn of the century, several misconceptions about free radicals with Reactive Oxygen Species most prominently among them and about their neutralization by antioxidants still seem to permeate the literature and common thinking as well: First, all Reactive Oxygen Species are toxic byproducts of mitochondrial respiration and as such cause oxidative damage to biological macromolecules. Second, fundamental differences in terms of reactivity and stability between Reactive Oxygen Species are generally neglected and they are widely still being treated as one chemical entity. Third, mitochondria are the major source of toxic Reactive Oxygen Species and fourth, low-molecular weight natural or synthetic antioxidants scavenge free radicals and thereby diminish oxidative damage. This review will debunk these four faulty assumptions, critically address the failure of large-scale clinical trials involving low-molecular weight antioxidants and subsequently propose a new mechanism of action underlying the undisputable health benefits of nutritional antioxidants in fruits and vegetables.
In summary, it will be shown that data published during the last two decades by leading investigators in the field of Redox Biology provide the ground for a paradigm change regarding free radicals and antioxidants in human health and disease.
Article Details
How to Cite
WEISSIG, Volkmar.
Free Radicals and Antioxidants: A new Paradigm has emerged.
Medical Research Archives, [S.l.], v. 12, n. 7, july 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5456>. Date accessed: 15 nov. 2024.
doi: https://doi.org/10.18103/mra.v12i7.5456.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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3. Sharifi-Rad M, Kumar NVA, Zucca P, et al. Lifestyle, Oxidative Stress, and Antioxidants: Back and Forth in the Pathophysiology of Chronic Diseases. Frontiers in Physiology. 2020;11.
4. McPhee SJ, Ganong, W. F. Pathophyiology of Disease: An Introduction to Clinical Medicine. 5th Edition ed. New York, Chicago, San Francisco, Lisbon, London, Madrid, Mexico City, Milan, New Dehli, San Juan, Seoul, Singapore, Sydney, Toronto: McGraw-Hill, Medical Publishing Division; 2006.
5. Kumar V, Abbas, A. K., Aster, J. C. Robbins Basic Pathology. Philadelphia: Elsevier; 2018.
6. Denisov ET, Afanasef, I. B. Oxidation and Antioxidants in Organic Chemistry and Biology. Boca Raton, FL: CRC Press; 2005.
7. Graham Solomons TW, Fryhle, C. B., Snyder, S. A. Organic Chemistry. 12th ed: Wiley; 2016.
8. Weissig V, Guzman-Villanueva D. Nanocarrier-based antioxidant therapy: promise or delusion? Expert Opin Drug Deliv. 2015;12(11):1783-1790.
9. Steinhubl SR. Why have antioxidants failed in clinical trials? American Journal of Cardiology. 2008;101(10a):14d-19d.
10. Linnane AW, Kios M, Vitetta L. Healthy aging: regulation of the metabolome by cellular redox modulation and prooxidant signaling systems: The essential roles of superoxide anion and hydrogen peroxide. Biogerontology. 2007;8(5):44 5-467.
11. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155.
12. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347(9004):781-786.
13. Sayin VI, Ibrahim MX, Larsson E, Nilsson JA, Lindahl P, Bergo MO. Antioxidants accelerate lung cancer progression in mice. Sci Transl Med. 2014;6 (221):221ra215.
14. Le Gal K, Ibrahim MX, Wiel C, et al. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med. 2015;7(308):308re308.
15. Halliwell B. The antioxidant paradox. Lancet. 2000;355(9210):1179-1180.
16. Halliwell B. The antioxidant paradox: less paradoxical now? British Journal of Clinical Pharmacology. 2013;75(3):637-644.
17. Bonner MY, Arbiser JL. The antioxidant paradox: what are antioxidants and how should they be used in a therapeutic context for cancer. Future Medicinal Chemistry. 2014;6(12):1413-1422.
18. Finley JW, Kong AN, Hintze KJ, Jeffery EH, Ji LL, Lei XG. Antioxidants in Foods: State of the Science Important to the Food Industry. Journal of Agricultural and Food Chemistry. 2011;59(13):683 7-6846.
19. Medicine UNLo. Clinical Trials Database. In. https://clinicaltrials.gov/ct2/home2023.
20. Weissig V, Pettinger TK, Murdock N. Nanopharmaceuticals (part 1): products on the market. Int J Nanomedicine. 2014;9:4357-4373.
21. Weissig V, Guzman-Villanueva D. Nanopharmaceuticals (part 2): products in the pipeline. Int J Nanomedicine. 2015;10:1245-1257.
22. Stone WL, Smith M. Therapeutic uses of antioxidant liposomes. Mol Biotechnol. 2004;27(3): 217-230.
23. Du L, Li J, Chen C, Liu Y. Nanocarrier: a potential tool for future antioxidant therapy. Free Radic Res. 2014;48(9):1061-1069.
24. Corvo ML, Marinho HS, Marcelino P, et al. Superoxide dismutase enzymosomes: carrier capacity optimization, in vivo behaviour and therapeutic activity. Pharm Res. 2015;32(1):91-102.
25. Vaiserman A, Koliada A, Zayachkivska A, Lushchak O. Nanodelivery of Natural Antioxidants: An Anti-aging Perspective. Front Bioeng Biotechnol. 2019;7:447.
26. Gomberg M. An instance of trivalent carbon: triphenylmethyl. Journal of the American Chemical Society. 1900;22(11):757-771.
27. Gomberg M. On trivalent carbon. Journal of the American Chemical Society. 1902;24(7):597-628.
28. Smith O. Nobel Prize for NO research. Nat Med. 1998;4(11):1215.
29. (NIH) NCI. Free radical https://wwwcancergov/publications/dictionaries/cancer-terms/def/free-radical. 2023.
30. Forman HJ, Zhang H. Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat Rev Drug Discov. 2021;20 (9):689-709.
31. Murphy MP, Bayir H, Belousov V, et al. Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo. Nat Metab. 2022;4(6):651-662.
32. Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21(7):363-383.
33. Phaniendra A, Jestadi DB, Periyasamy L. Free radicals: properties, sources, targets, and their implication in various diseases. Indian J Clin Biochem. 2015;30(1):11-26.
34. Sies H, Chance B. The steady state level of catalase compound I in isolated hemoglobin-free perfused rat liver. FEBS Lett. 1970;11(3):172-176.
35. Jones DP, Radi R. Redox pioneer: professor Helmut Sies. Antioxid Redox Signal. 2014;21(18): 2459-2468.
36. Krengel U, Tornroth-Horsefield S. Biochemistry. Coping with oxidative stress. Science. 2015;347(6218):125-126.
37. Lambeth JD. NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol. 2004;4(3):181-189.
38. Gerschman R, Gilbert DL, Nye SW, Dwyer P, Fenn WO. Oxygen poisoning and x-irradiation: a mechanism in common. Science. 1954;119 (3097):623-626.
39. Pomatto LCD, Davies KJA. Adaptive homeostasis and the free radical theory of ageing. Free Radic Biol Med. 2018;124:420-430.
40. Harman D. Aging: a theory based on free radical and radiation chemistry. J Gerontol. 1956; 11(3):298-300.
41. Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972;20(4):145-147.
42. Sanz A, Stefanatos RK. The mitochondrial free radical theory of aging: a critical view. Curr Aging Sci. 2008;1(1):10-21.
43. Grivennikova VG, Vinogradov AD. Generation of superoxide by the mitochondrial Complex I. Biochim Biophys Acta. 2006;1757(5-6):553-561.
44. Winterbourn CC. Biological Chemistry of superoxide radicals. ChemTexts. 2020;6:1-13.
45. Babior BM, Kipnes RS, Curnutte JT. Biological defense mechanisms. The production by leukocytes of superoxide, a potential bactericidal agent. J Clin Invest. 1973;52(3):741-744.
46. McCord JM, Fridovich I. Superoxide dismutases: you've come a long way, baby. Antioxid Redox Signal. 2014;20(10):1548-1549.
47. Hampton LMT, Jeffries MKS, Venables BJ. A practical guide for assessing respiratory burst and phagocytic cell activity in the fathead minnow, an emerging model for immunotoxicity. MethodsX. 2020;7:100992.
48. Suh YA, Arnold RS, Lassegue B, et al. Cell transformation by the superoxide-generating oxidase Mox1. Nature. 1999;401(6748):79-82.
49. Cheng G, Cao Z, Xu X, van Meir EG, Lambeth JD. Homologs of gp91phox: cloning and tissue expression of Nox3, Nox4, and Nox5. Gene. 2001;269(1-2):131-140.
50. Geiszt M, Kopp JB, Varnai P, Leto TL. Identification of renox, an NAD(P)H oxidase in kidney. Proc Natl Acad Sci U S A. 2000;97(14): 8010-8014.
51. Banfi B, Molnar G, Maturana A, et al. A Ca(2+)-activated NADPH oxidase in testis, spleen, and lymph nodes. J Biol Chem. 2001;276(40):375 94-37601.
52. Edens WA, Sharling L, Cheng G, et al. Tyrosine cross-linking of extracellular matrix is catalyzed by Duox, a multidomain oxidase/ peroxidase with homology to the phagocyte oxidase subunit gp91phox. J Cell Biol. 2001;154(4) :879-891.
53. De Deken X, Wang D, Many MC, et al. Cloning of two human thyroid cDNAs encoding new members of the NADPH oxidase family. J Biol Chem. 2000;275(30):23227-23233.
54. Butturini E, Butera G, Pacchiana R, Carcereri de Prati A, Mariotto S, Donadelli M. Redox Sensitive Cysteine Residues as Crucial Regulators of Wild-Type and Mutant p53 Isoforms. Cells. 2021;10(11).
55. McCord JM, Fridovich I. Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein). J Biol Chem. 1969;244(22):6049-6055.
56. McCord JM, Fridovich I. The utility of superoxide dismutase in studying free radical reactions. I. Radicals generated by the interaction of sulfite, dimethyl sulfoxide, and oxygen. J Biol Chem. 1969;244(22):6056-6063.
57. Antonyuk SV, Strange RW, Marklund SL, Hasnain SS. The structure of human extracellular copper-zinc superoxide dismutase at 1.7 A resolution: insights into heparin and collagen binding. J Mol Biol. 2009;388(2):310-326.
58. Borgstahl GE, Parge HE, Hickey MJ, et al. Human mitochondrial manganese superoxide dismutase polymorphic variant Ile58Thr reduces activity by destabilizing the tetrameric interface. Biochemistry. 1996;35(14):4287-4297.
59. Cao X, Antonyuk SV, Seetharaman SV, et al. Structures of the G85R variant of SOD1 in familial amyotrophic lateral sclerosis. J Biol Chem. 2008;283(23):16169-16177.
60. Sies H. Hydrogen peroxide as a central redox signaling molecule in physiological oxidative stress: Oxidative eustress. Redox Biol. 2017;11: 613-619.
61. Wong HS, Benoit B, Brand MD. Mitochondrial and cytosolic sources of hydrogen peroxide in resting C2C12 myoblasts. Free Radic Biol Med. 2019;130:140-150.
62. Michaelis L. Free radicals as intermediate steps of oxidation-reductions. Cold Spring Harb Symp Quant Biol. 1939;7:33-49.
63. Moss RW. Free Radical: Albert Szent-Gyorgyi and the Battle over Vitamin C. New York: Paragon House Publishers; 1988.
64. Forman HJ, Davies KJ, Ursini F. How do nutritional antioxidants really work: nucleophilic tone and para-hormesis versus free radical scavenging in vivo. Free Radic Biol Med. 2014;66:24-35.
65. Institute NC. Dictionary. https://wwwcancergov/publications/dictionaries/cancer-terms/def/antioxidant. 2024.
66. Rahaman MM, Hossain R, Herrera-Bravo J, et al. Natural antioxidants from some fruits, seeds, foods, natural products, and associated health benefits: An update. Food Sci Nutr. 2023;11(4): 1657-1670.
67. Meccariello R, D'Angelo S. Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview. Antioxidants (Basel). 2021;10(4).
68. Jhoo JW, Lo CY, Li S, et al. Stability of black tea polyphenol, theaflavin, and identification of theanaphthoquinone as its major radical reaction product. J Agric Food Chem. 2005;53(15):6146-6150.
69. Sang S, Hou Z, Lambert JD, Yang CS. Redox properties of tea polyphenols and related biological activities. Antioxid Redox Signal. 2005;7(11-12):1704-1714.
70. Sang S, Lee MJ, Hou Z, Ho CT, Yang CS. Stability of tea polyphenol (-)-epigallocatechin-3-gallate and formation of dimers and epimers under common experimental conditions. J Agric Food Chem. 2005;53(24):9478-9484.
71. Aoshima H, Hirase T, Tada T, et al. Safety evaluation of a heavy oil-degrading bacterium, Rhodococcus erythropolis C2. J Toxicol Sci. 2007;32(1):69-78.
72. Lambert JD, Kwon SJ, Hong J, Yang CS. Salivary hydrogen peroxide produced by holding or chewing green tea in the oral cavity. Free Radic Res. 2007;41(7):850-853.
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