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Redox- and non-redox-metal-induced formation of free radicals and their role in human disease.
Arch Toxicol. 2016 Jan; 90(1):1-37.AT

Abstract

Transition metal ions are key elements of various biological processes ranging from oxygen formation to hypoxia sensing, and therefore, their homeostasis is maintained within strict limits through tightly regulated mechanisms of uptake, storage and secretion. The breakdown of metal ion homeostasis can lead to an uncontrolled formation of reactive oxygen species, ROS (via the Fenton reaction, which produces hydroxyl radicals), and reactive nitrogen species, RNS, which may cause oxidative damage to biological macromolecules such as DNA, proteins and lipids. An imbalance between the formation of free radicals and their elimination by antioxidant defense systems is termed oxidative stress. Most vulnerable to free radical attack is the cell membrane which may undergo enhanced lipid peroxidation, finally producing mutagenic and carcinogenic malondialdehyde and 4-hydroxynonenal and other exocyclic DNA adducts. While redox-active iron (Fe) and copper (Cu) undergo redox-cycling reactions, for a second group of redox-inactive metals such as arsenic (As) and cadmium (Cd), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. While arsenic is known to bind directly to critical thiols, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. Redox-inert zinc (Zn) is the most abundant metal in the brain and an essential component of numerous proteins involved in biological defense mechanisms against oxidative stress. The depletion of zinc may enhance DNA damage by impairing DNA repair mechanisms. Intoxication of an organism by arsenic and cadmium may lead to metabolic disturbances of redox-active copper and iron, with the occurrence of oxidative stress induced by the enhanced formation of ROS/RNS. Oxidative stress occurs when excessive formation of ROS overwhelms the antioxidant defense system, as is maintained by antioxidants such as ascorbic acid, alpha-tocopherol, glutathione (GSH), carotenoids, flavonoids and antioxidant enzymes which include SOD, catalase and glutathione peroxidase. This review summarizes current views regarding the role of redox-active/inactive metal-induced formation of ROS, and modifications to biomolecules in human disease such as cancer, cardiovascular disease, metabolic disease, Alzheimer's disease, Parkinson's disease, renal disease, blood disorders and other disease. The involvement of metals in DNA repair mechanisms, tumor suppressor functions and interference with signal transduction pathways are also discussed.

Authors+Show Affiliations

Faculty of Chemical and Food Technology, Slovak University of Technology, 812 37, Bratislava, Slovakia. marian.valko@stuba.sk. The Center for Basic and Applied Research, University Hradec Kralove, Hradec Kralove, Czech Republic. marian.valko@stuba.sk.Department of Chemistry, Faculty of Natural Sciences, Constantine the Philosopher University, 949 74, Nitra, Slovakia.Fresh Lands, P.O. Box 2074, Reading, Berkshire, RG4 5ZQ, UK.The Center for Basic and Applied Research, University Hradec Kralove, Hradec Kralove, Czech Republic. Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic.Biomedical Research Center, University Hospital Hradec Kralove, Hradec Kralove, Czech Republic. Department of Chemistry, Faculty of Science, University Hradec Kralove, Hradec Kralove, Czech Republic.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

26343967

Citation

Valko, Marian, et al. "Redox- and Non-redox-metal-induced Formation of Free Radicals and Their Role in Human Disease." Archives of Toxicology, vol. 90, no. 1, 2016, pp. 1-37.
Valko M, Jomova K, Rhodes CJ, et al. Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Arch Toxicol. 2016;90(1):1-37.
Valko, M., Jomova, K., Rhodes, C. J., Kuča, K., & Musílek, K. (2016). Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. Archives of Toxicology, 90(1), 1-37. https://doi.org/10.1007/s00204-015-1579-5
Valko M, et al. Redox- and Non-redox-metal-induced Formation of Free Radicals and Their Role in Human Disease. Arch Toxicol. 2016;90(1):1-37. PubMed PMID: 26343967.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Redox- and non-redox-metal-induced formation of free radicals and their role in human disease. AU - Valko,Marian, AU - Jomova,Klaudia, AU - Rhodes,Christopher J, AU - Kuča,Kamil, AU - Musílek,Kamil, Y1 - 2015/09/07/ PY - 2015/08/02/received PY - 2015/08/11/accepted PY - 2015/9/8/entrez PY - 2015/9/8/pubmed PY - 2016/10/16/medline KW - Human disease KW - Metals KW - Oxidative stress KW - Reactive oxygen species KW - Toxicity SP - 1 EP - 37 JF - Archives of toxicology JO - Arch. Toxicol. VL - 90 IS - 1 N2 - Transition metal ions are key elements of various biological processes ranging from oxygen formation to hypoxia sensing, and therefore, their homeostasis is maintained within strict limits through tightly regulated mechanisms of uptake, storage and secretion. The breakdown of metal ion homeostasis can lead to an uncontrolled formation of reactive oxygen species, ROS (via the Fenton reaction, which produces hydroxyl radicals), and reactive nitrogen species, RNS, which may cause oxidative damage to biological macromolecules such as DNA, proteins and lipids. An imbalance between the formation of free radicals and their elimination by antioxidant defense systems is termed oxidative stress. Most vulnerable to free radical attack is the cell membrane which may undergo enhanced lipid peroxidation, finally producing mutagenic and carcinogenic malondialdehyde and 4-hydroxynonenal and other exocyclic DNA adducts. While redox-active iron (Fe) and copper (Cu) undergo redox-cycling reactions, for a second group of redox-inactive metals such as arsenic (As) and cadmium (Cd), the primary route for their toxicity is depletion of glutathione and bonding to sulfhydryl groups of proteins. While arsenic is known to bind directly to critical thiols, other mechanisms, involving formation of hydrogen peroxide under physiological conditions, have been proposed. Redox-inert zinc (Zn) is the most abundant metal in the brain and an essential component of numerous proteins involved in biological defense mechanisms against oxidative stress. The depletion of zinc may enhance DNA damage by impairing DNA repair mechanisms. Intoxication of an organism by arsenic and cadmium may lead to metabolic disturbances of redox-active copper and iron, with the occurrence of oxidative stress induced by the enhanced formation of ROS/RNS. Oxidative stress occurs when excessive formation of ROS overwhelms the antioxidant defense system, as is maintained by antioxidants such as ascorbic acid, alpha-tocopherol, glutathione (GSH), carotenoids, flavonoids and antioxidant enzymes which include SOD, catalase and glutathione peroxidase. This review summarizes current views regarding the role of redox-active/inactive metal-induced formation of ROS, and modifications to biomolecules in human disease such as cancer, cardiovascular disease, metabolic disease, Alzheimer's disease, Parkinson's disease, renal disease, blood disorders and other disease. The involvement of metals in DNA repair mechanisms, tumor suppressor functions and interference with signal transduction pathways are also discussed. SN - 1432-0738 UR - https://www.unboundmedicine.com/medline/citation/26343967/Redox__and_non_redox_metal_induced_formation_of_free_radicals_and_their_role_in_human_disease_ L2 - https://dx.doi.org/10.1007/s00204-015-1579-5 DB - PRIME DP - Unbound Medicine ER -