Interactions Between Heavy Metals–Induced Cell Responses and Oxidative Stress

Part of the Nanomedicine and Nanotoxicology book series (NANOMED)


Reactive oxygen species (ROS) are important regulators of physiological and pathophysiological processes and not only simply detrimental due to their chemical nature or by causing oxidative stress. In all the physiologically relevant ROS, the hydroxyl radical possesses the highest one-electron reduction potential and is reactive with almost all types of biomolecules, including lipids, proteins, and nucleic acids. As a result of their reactivity and ability to damage biological targets, hydroxyl radicals can serve as an ideal representative ROS for investigation. Thereby, recent advances in genomics and proteomics have led to the identification of a “redoxome” consisting of hundreds of proteins involved in redox systems. It comprises enzymes generating RONS such as NADPH oxidases and nitric oxide synthases, redox relays such as peroxiredoxins, thioredoxins, and glutaredoxins, enzymes degrading ROS such as superoxide dismutase or catalase, as well as numerous proteins dependent on redox modifications, which are involved in the defense against oxidant, inflammatory and/or proteotoxic stress. Exposure to heavy metals is a common phenomenon due to their environmental pervasiveness. Several of metal ions in trace amounts are required for metabolism, growth, and development. Metal intoxication, particularly, neurotoxicity, genotoxicity, or carcinogenicity is widely known. Toxic xenobiotic metals (Hg, Pb, Cd, As, Sn) have no known biological function. Metal ions interact with oxygen-containing ligands through the formation of free radicals forming stable bonds with S- and N- in the form of SH or imidazole groups in proteins. Following exposure to heavy metals, their metabolism and subsequent excretion from the body depends on the presence of antioxidants (glutathione, α-tocopherol, ascorbate, etc.) associated with the quenching of free radicals by suspending the activity of enzymes (catalase, peroxidase, and superoxide dismutase).


Xenobiotic heavy metals Reactive oxygen species (ROS) Toxicity Oxidative stress Oxidative DNA damage 


  1. Alleman MA, Koster JF, Wilson JHP, Edixhoven-Bosdijk A, Slee RG, Kross MJ, Eijk HGV (1985) The involvement of iron and lipid peroxidation in the pathogenesis of HCB-induced porphyria. Biochem Pharmacol 34(2):161–166CrossRefGoogle Scholar
  2. Aravind P, Prasad MNV (2003) Zinc alleviates cadmium induced toxicity in Ceratophyllum demersum, a fresh water macrophyte. Plant Physiol Biochem 41:391–397CrossRefGoogle Scholar
  3. Aravind P, Prasad MNV (2005) Cadmium-zinc interactions in a hydroponic system using Ceratophyllum demersum L.: adaptive ecophysiology, biochemistry and molecular toxicology. Braz J Plant Physiol 17:3–20CrossRefGoogle Scholar
  4. Aust SD (1989) Metal ions, oxygen radicals and tissue damage. Bibl Nutr Dieta 43:266–277Google Scholar
  5. Babior BM (1999) NADPH oxidase: an update. Blood 93:1464–1476CrossRefGoogle Scholar
  6. Balen B, Tkalec M, Šikić S, Tolić S, Cvjetko P et al (2011) Biochemical responses of Lemna minor experimentally exposed to cadmium and zinc. Ecotoxicology 20:815–826CrossRefGoogle Scholar
  7. Broadley MR, White PJ, Hammond JP, Zelko I, Lux A (2007) Zinc in plants. New Phytol 173:677–702CrossRefGoogle Scholar
  8. Cadenas E, Davies KJ (2000) Mitochondrial free radical generation, oxidative stress and aging. Free Radic Biol Med 29:222–230CrossRefGoogle Scholar
  9. Cakmak I (2000) Possible roles of zinc in protecting plant cells from damage by reactive oxygen species. New Phytol 146:185–205CrossRefGoogle Scholar
  10. Castagnetto JM, Hennessy SW, Roberts VA, Getzoff ED, Tainer JA, Pique ME (2002) MDB: the metalloprotein database and browser at the Scripps Research Institute. Nucleic Acids Res 30(1):379–382CrossRefGoogle Scholar
  11. Cervantes C, Campos-Garcia J, Devars S, Gutierrez-Corona F, Loza-Tavera H, Torres-Guzman JC, Moreno-Sanchez R (2001) Interactions of chromium with microorganisms and plants. FEMS Microbiol Rev 25(3):335–347CrossRefGoogle Scholar
  12. Cherif J, Mediouni C, Ben Ammar W, Jemal F (2011) Interactions of zinc and cadmium toxicity in their effects on growth and in antioxidative systems in tomato plants (Solanum lycopersicum). J Environ Sci 23:837–844CrossRefGoogle Scholar
  13. Daiber A (2010) Redox signaling (cross-talk) from and to mitochondria involves mitochondrial pores and reactive oxygen species. Biochim Biophys Acta 1797:897–906CrossRefGoogle Scholar
  14. Damek-Poprawa M, Sawicka-Kapusta K (2004) Histopathological changes in the liver, kidneys, and testes of bank voles environmentally exposed to heavy metal emissions from the steelworks and zinc smelter in Poland. Environ Res 96:72–78CrossRefGoogle Scholar
  15. Das P, Samantaray S, Rout GR (1997) Studies on cadmium toxicity in plants: a review. Environ Pollut 98:29–36CrossRefGoogle Scholar
  16. Dietz KJ, Turkan I, Krieger-Liszkay A (2016) Redox- and reactive oxygen species dependent signaling in and from the photosynthesizing chloroplast. Plant Physiol 171:1541–1550CrossRefGoogle Scholar
  17. Flora SJS, Flora G, Saxena G (2006) Environmental occurrence, health effects and management of lead poisoning. In: Cascas SB, Sordo J (eds) Lead chemistry, analytical aspects, environmental impacts and health effects. Elsevier Publication, Netherlands, pp 158–228CrossRefGoogle Scholar
  18. Flora SJS, Mittal M, Mehta A (2008) Heavy metal induced oxidative stress & its possible reversal by chelation therapy. Indian J Med Res 128:501–523Google Scholar
  19. Flora G, Gupta D, Tiwari A (2012) Toxicity of lead: a review with recent updates. Interdiscip Toxicol 5:47–58CrossRefGoogle Scholar
  20. Gilroy S, Bialasek M, Suzuki N, Gorecka M, Devireddy A, Karpinski S, Mittler R (2016) ROS, calcium and electric signals: key mediators of rapid systemic signaling in plants. Plant Physiol 171:1606–1615CrossRefGoogle Scholar
  21. Gurkan R, Ulusoy HI, Akcay M (2012) Simultaneous determination of dissolved inorganic chromium species in wastewater/natural waters by surfactant sensitized catalytic kinetic spectrophotometry. Arab J Chem 1:S450–S460Google Scholar
  22. Halliwell B (2006) Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiol 141:312–322. Scholar
  23. Halliwell B, Gutteridge JMC (1990) Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol 186:1–85CrossRefGoogle Scholar
  24. Hassan MJ, Zhang G, Wu F, Wie K, Chen Z (2005) Zinc alleviates growth inhibition and oxidative stress caused by cadmium in rice. J Plant Nutr Soil Sci 168:255–261CrossRefGoogle Scholar
  25. Huang S, Van Aken O, Schwarzländer M, Belt K, Millar A (2016) The roles of mitochondrial reactive oxygen species in cellular signaling and stress responses in plants. Plant Physiol 171:1551–1559CrossRefGoogle Scholar
  26. Irfan M, Hayat S, Ahmad A, Alyemeni MN (2013) Soil cadmium enrichment: Allocation and plant physiological manifestations. Saudi J Biol Sci 20(1):1–10CrossRefGoogle Scholar
  27. Jankovic A, Korac A, Buzadzic B, Otasevic V, Stancic A, Daiber A, Korac B (2015) Redox implications in adipose tissue (dys)function—a new look at old acquaintances. Redox Biol 6:19–32CrossRefGoogle Scholar
  28. Jones P, Kortenkamp A, O’Brien P, Wang G, Yang G (1991) Evidence for the generation of hydroxyl radicals from a chromium(V) intermediate isolated from the reaction of chromate with glutathione. Arch Biochem Biophys 286:652–655CrossRefGoogle Scholar
  29. Karin M, Delhase M (1998) JNK or IKK, AP-1 or NF-kappaB, which are the targets for MEK kinase 1 action? Proc Natl Acad Sci USA 95:9067–9069CrossRefGoogle Scholar
  30. Kehrer JP (2000) The Haber-Weiss reaction and mechanisms of toxicity. Toxicology 149:43–50CrossRefGoogle Scholar
  31. Kerchev PI, Waszczak C, Lewandowska A et al (2016) Lack of GLYCOLATE OXIDASE 1, but not GLYCOLATE OXIDASE 2, attenuates the photorespiratory phenotype of CATALASE2-deficient Arabidopsis. Plant Physiol 171:1704–1719CrossRefGoogle Scholar
  32. Lanphear BP, Dietrich K, Auinger P, Cox C (2000) Cognitive deficits associated with blood lead concentrations <10 μg/dl in US children and adolescents. Public Health Rep 115:521–529CrossRefGoogle Scholar
  33. Le C, Brumbarova T, Ivanov R, Stoof C, Weber E, Mohrbacher J, Fink-Straube C, Bauer P (2016) Zinc finger of Arabidopsis thaliana12 (ZAT12) interacts with FER-like iron deficiency-induced transcription factor (FIT) linking iron deficiency and oxidative stress responses. Plant Physiol 170:540–557CrossRefGoogle Scholar
  34. Leonard SS, Harris GK, Shi X (2004) Metal-induced oxidative stress and signal transduction. Free Radic Biol Med 37:1921–1942CrossRefGoogle Scholar
  35. Matsumoto ST, Mantovani MS, Malaguttii MIA, Dias AL, Fonseca IC, Marin- Morales MA (2006) Genotoxicity and mutagenicity of water contaminated with tannery effluents, as evaluated by the micronucleus test and comet assay using the fish Oreochromis niloticus and chromosome aberrations in onion root-tips. Genet Mol Biol 29(1):148–158CrossRefGoogle Scholar
  36. Minotti G, Aust SD (1987) The role of iron in the initiation of lipid peroxidation. Chem Phys Lipid 44(2–4):191–208CrossRefGoogle Scholar
  37. Mohanty M, Kumar Patra H (2013) Effect of ionic and chelate assisted hexavalent chromium on mung bean seedlings (Vigna Radiata l. Wilczek. Var k-851) during seedling growth. J Stress Physiol Biochem 9(2):232–241Google Scholar
  38. Monterio HP, Bechara EJH, Abdalla DSP (1991) Free radicals’ involvement in neurological porphyrias and lead poisoning. Mol Cell Biochem 103:73–83Google Scholar
  39. Moraghan JT (1993) Accumulation of cadmium and selected elements in flax seed grown on a calcareous soil. Plant Soil 150:61–68CrossRefGoogle Scholar
  40. Namgung UK, Xia Z (2001) Arsenic induces apoptosis in rat cerebellar neurons via activation of JNK3 and p38 MAP kinases. Toxicol Appl Pharmacol 174:130–138CrossRefGoogle Scholar
  41. Nan Z, Li J, Zhang J, Cheng G (2002) Cadmium and zinc interactions and their transfer in soil-crop system under actual field conditions. Sci Total Environ 285:187–195CrossRefGoogle Scholar
  42. Nehru B, Dua R (1997) The effect of dietary selenium on lead neurotoxicity. J Environ Pathol Toxicol Oncol 16:47–50Google Scholar
  43. Noctor G, Foyer CH (2016) Intracellular redox compartmentation and ROS-related communication in regulation and signaling. Plant Physiol 171:1581–1592CrossRefGoogle Scholar
  44. Pandey N, Gupta B, Pathak GC (2012) Antioxidant responses of pea genotypes to zinc deficiency. Russ J Plant Physiol 59:198–205CrossRefGoogle Scholar
  45. Parlak UK, Yilmaz DD (2012) Response of antioxidant defences to Zn stress in three duckweed species. Ecotoxicol Environ Saf 85:52–58CrossRefGoogle Scholar
  46. Pastor N, Weinstein H, Jamison E, Brenowitz M (2000) A detailed interpretation of OH radical footprints in a TBP–DNA complex reveals the role of dynamics in the mechanism of sequence specific binding. J Mol Biol 304:55–68CrossRefGoogle Scholar
  47. Patrick L (2003) Toxic metals and antioxidants: part II. The role of antioxidants in arsenic and cadmium toxicity. Altern Med Rev 8(2):106–128Google Scholar
  48. Pi J, Horiguchi S, Sun Y, Nikaido M, Shimojo N, Hayashi T (2003a) A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits. Free Radic Biol Med 35:102–113CrossRefGoogle Scholar
  49. Pi J, Horiguchi S, Sun Y, Nikaido M, Shimojo N, Hayashi T et al (2003b) A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits. Free Radical Biol Med 35:102–113CrossRefGoogle Scholar
  50. Pi Jingbo, Wei Qu, Reece Jeffrey M, Kumagai Yoshito, Waalkes Michael P (2003c) Transcription factor Nrf2 activation by inorganic arsenic in cultured keratinocytes: involvement of hydrogen peroxide. Exp Cell Res 290:234–245CrossRefGoogle Scholar
  51. Piotrowska M, Dudka S, Chilopecka A (1994) Effect of elevated concentrations of Cd and Zn in soil on spring wheat yield and metal contents of plants. Water Air Soil Pollut 76:333–341CrossRefGoogle Scholar
  52. Pulido MD, Parrish AR (2003) Metal-induced apoptosis: mechanisms. Mutat Res 533:227–241CrossRefGoogle Scholar
  53. Reid TM, Feig DI, Loeb LA (1994) Mutagenesis by metal-induced oxygen radicals. Environ Health Perspect 102(suppl 3):57–61CrossRefGoogle Scholar
  54. Rentel MC, Lecourieux D, Ouaked F, Usher SL, Petersen L, Okamoto H, Knight H, Peck SC, Grierson CS, Hirt H et al (2004) OXI1 kinase is necessary for oxidative burst-mediated signaling in Arabidopsis. Nature 427:858–861CrossRefGoogle Scholar
  55. Rin K, Kawaguchi K, Yamanaka K, Tezuka M, Oku N, Okada S (1995) DNAstrand breaks induced by dimethylarsinic acid, a metabolite of inorganic arsenics, are strongly enhanced by superoxide anion radicals. Biol Pharm Bull 18:45–58CrossRefGoogle Scholar
  56. Rodriguez MC, Barsanti L, Passarelli V, Evangelista V, Conforti V, Gualtieri P (2007) Effects of chromium on photosynthetic and photoreceptive apparatus of the alga Chlamydomonas reinhardtii. Environ Res 105(2):234–239CrossRefGoogle Scholar
  57. Rodrıguez-Serrano M, Romero-Puertas MC, Sanz-Fern_andez M, Hu J, Sandalio LM (2016) Peroxisomes extend peroxules in a fast response to stress via a reactive oxygen species-mediated induction of the peroxin PEX11a. Plant Physiol 171:1665–1674Google Scholar
  58. Romero-Puertas MC, Palma JM, Gómez M, del Rio LA, Sandalio LM (2002) Cadmium causes the oxidative modifications of proteins in pea plants. Plant, Cell Environ 25:677–686CrossRefGoogle Scholar
  59. Salonen JT, Seppanen K, Nyyssonen K et al (1995) Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in eastern finnish men. Circulation 91:645–655CrossRefGoogle Scholar
  60. Sanita Di Toopi L, Gabrielli R (1999) Response to cadmium in higher plants. Environ Exp Bot 41:105–130CrossRefGoogle Scholar
  61. Schiller CM, Fowler BA, Woods JS (1977) Effects of arsenic on pyruvate dehydrogenase activation. Environ Health Perspect 19:205–207CrossRefGoogle Scholar
  62. Schulz E, Wenzel P, Munzel T, Daiber A (2014) Mitochondrial redox signaling: interaction of mitochondrial reactive oxygen species with other sources of oxidative stress. Antioxid Redox Signal 20:308–324CrossRefGoogle Scholar
  63. Schutzendubel A, Polle A (2002) Plant responses to abiotic stresses: heavy metal-induced oxidative stress and protection by mycorrhization. J Exp Bot 53:1351–1365Google Scholar
  64. Shah K, Kumar RG, Verma S, Dubey RS (2001) Effect of cadmium on lipid peroxidation, superoxide anion generation and activities of antioxidant enzymes in growing rice seedlings. Plant Sci 161:1135–1144CrossRefGoogle Scholar
  65. Shenker BJ, Guo TL, Shapiro IM (1998) Low-level methylmercury exposure causes human T-cells to undergo apoptosis: evidence of mitochondrial dysfunction. Environ Res 77:149–159CrossRefGoogle Scholar
  66. Shi X, Dalai NS (1993) Vanadate-mediated hydroxyl radical generation from superoxide radical in the presence of NADH: Haber–Weiss versus Fenton mechanism. Arch Biochem Biophys 3M:336–341CrossRefGoogle Scholar
  67. Shi H, Shi X, Liu KJ (2004) Oxidative mechanism of arsenic toxicity and carcinogenesis. Mol Cell Biochem 255:67–78CrossRefGoogle Scholar
  68. Son MH, Kang KW, Lee CH, Kim SG (2001) Potentiation of arsenic-induced cytotoxicity by sulfur amino acid deprivation (SAAD) through activation of ERK1/2, p38 kinase and JNK1: the distinct role of JNK1 in SAAD-potentiated mercury toxicity. Toxicol Lett 121:45–55CrossRefGoogle Scholar
  69. Štefanić PP, Šikić S, Cvjetko P, Balen B (2012) Cadmium and zinc induced similar changes in protein and glycoprotein patterns in tobacco (Nicotiana tabacum L.) seedlings and plants. Arh Hig Rada Toksikol 63:321–335Google Scholar
  70. Stohs SJ, Bagchi D (1995) Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med 18(2):321–336CrossRefGoogle Scholar
  71. Szabo C, Ischiropoulus H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Dicov 6:662–680CrossRefGoogle Scholar
  72. Takagi D, Takumi S, Hashiguchi M, Sejima T, Miyake C (2016) Superoxide and singlet oxygen produced within the thylakoid membranes both cause photosystem I photoinhibition. Plant Physiol 171:1626–1634CrossRefGoogle Scholar
  73. Thannickal VJ, Fanburg BL (2000) Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279:L1005–L1028CrossRefGoogle Scholar
  74. Tian S, Wang X, Li P, Wang H, Ji H, Xie J, Qiu Q, Shen D, Dong H (2016) Plant aquaporin AtPIP1; 4 links apoplastic H2O2 induction to disease immunity pathways. Plant Physiol 171:1635–1650CrossRefGoogle Scholar
  75. Tkalec M, Prebeg T, Roje V, Pevalek-Kozlina B, Ljubesˇic´ N (2008) Cadmium induced responses in duckweed Lemna minor L. Acta Physiol Plant 30:881–890CrossRefGoogle Scholar
  76. Tran TA, Vassileva V, Petrov P, Popova LP (2013) Cadmium-induced structural disturbances in Pisum sativum leaves are alleviated by nitric oxide. Turk J Bot 37:698–707CrossRefGoogle Scholar
  77. Tripathi RM, Raghunath R, Mahapatra S (2001) Blood lead and its effect on Cd, Cu, Zn, Fe and hemoglobin levels of children. Sci Total Environ 277:161–168CrossRefGoogle Scholar
  78. Ullrich SM, Ramsey MH, Helios-Rybicka E (1999) Total and exchangeable concentrations of heavy metal in soils near Bytom, an area of Pb/Zn mining and smelting in upper Silesia, Poland. Appl Geochem 14:187–196CrossRefGoogle Scholar
  79. Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Physiol Rev 73:79–118CrossRefGoogle Scholar
  80. Waalkes MP, Liu J, Ward JM, Diwan LA (2004) Mechanisms underlying arsenic carcinogenesis: hypersensitivity of mice exposed to inorganic arsenic during gestation. Toxicology 198:31–38CrossRefGoogle Scholar
  81. Wang C, Zhang SH, Wang PF, Qian J, Hou J et al (2009) Excess Zn alters the nutrient uptake and induces the antioxidative responses in submerged plant Hydrilla verticillata (L.f.) Royle. Chemosphere 76:938–945CrossRefGoogle Scholar
  82. Wiggers GA, Pecanha FM, Briones AM et al (2008) Low mercury concentrations cause oxidative stress and endothelial dysfunction in conductance and resistance arteries. Am J Physiol Heart Circ Physiol 295:H1033–H1043CrossRefGoogle Scholar
  83. Wilde KL, Stauber JL, Markich SJ, Franklin NM, Brown PL (2006) The effect of pH on the uptake and toxicity of copper and zinc in a tropical freshwater alga (Chlorella sp.). Arch Environ Contam Toxicol 51:174–185CrossRefGoogle Scholar
  84. Wolińska A, Stępniewska Z, Włosek R (2013) The influence of old leather tannery district on chromium contamination of soils, water and plants. Nat Sci 5(2A):253–258Google Scholar
  85. Wu F, Zhang G (2002) Alleviation of cadmium-toxicity by application of zinc and ascorbic acid in barley. J Plant Nutr 25:2745–2761CrossRefGoogle Scholar
  86. Yamanaka K, Takabayashi F, Mizoi M, An Y, Hasegawa A, Okada S (2001) Oral exposure of dimethylarsinic acid, a main metabolite of inorganic arsenics, in mice leads to an increase in 8-Oxo-2’-deoxyguanosine level, specifically in the target organs for arsenic carcinogenesis. Biochem Biophys Res Commun 287:66–70CrossRefGoogle Scholar
  87. Younes M, Strubelt O (1991) Vanadate-induced toxicity towards isolated perfused rat livers: the role of lipid peroxidation. Toxicology 66:63–74CrossRefGoogle Scholar
  88. Yourtee DM, Elkins LL, Nalvarte EL, Smith RE (1992) Amplification of doxorubicin mutagenicity by cupric ion. Toxicol Appl Pharmacol 116:57–65CrossRefGoogle Scholar
  89. Zhang S, Chen S, Li W, Guo X, Zhao P, Xu J, Chen Y, Pan Q, Liu X, Zychlinski D, Lu H, Tortorella M, Schambach A, Wang Y, Pei D, Esteban M (2011) Rescue of ATP7B function in hepatocyte-like cells from Wilson’s disease-induced pluripotent stem cells using gene therapy or the chaperone drug curcumin. Hum Mol Genet 20:3176–3187CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Physical Chemistry and Nanoscience, Department of Chemistry, Faculty of ScienceAl Baha UniversityBaljurashiSaudi Arabia

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