Origin, Function, and Fate of Metallothionein in Human Blood

  • Mohammad Tariqur RahmanEmail author
  • Nazmul Haque
  • Noor Hayaty Abu Kasim
  • Marc De Ley
Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 173)


Toxic heavy metals, toxic organic compounds, reactive oxygen species (ROS), infections, and temperature are well-known metallothionein (MT) inducers in human blood. The current review aims to summarize synthesis, function, and fate of human blood MT in response to the known MT inducers. Part of the MTs that are synthesized in different organs such as the liver, kidney, and spleen is transported and stored in different blood cells and in plasma. Cells of the circulatory system also synthesize MT. From the circulation, MT returns to the kidney where the metal-bound MTs are degraded to release the metal ion that in turn induces MT expression therein. The blood MTs play important roles in metal detoxification, transportation, and storage. By neutralizing ROS, MTs protect blood cells from oxidative stress-induced cytotoxicity and genotoxicity. Arguably, MTs are also involved in immune suppression. Given the permeating distribution of blood MT throughout the body as well as its diverse role in the protection against harmful environmental factors and in metal homeostasis, MT could be better recognized as a major public health protein.


Arsenic Cadmium Cytotoxicity Metal response elements Reactive oxygen species Renal toxicity Zinc 



This work was supported by High Impact Research MOHE Grant UM.C/625/1/HIR/MOHE/DENT/01 and from the Ministry of Higher Education Malaysia and the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (G.0410.98), Belgium.


  1. Abdel-Mageed AB, Zhao F, Rider BJ, Agrawal KC (2003) Erythropoietin-induced metallothionein gene expression: role in proliferation of K562 cells. Exp Biol Med (Maywood) 228:1033–1039Google Scholar
  2. Bagheri PM, Rahman MT, Van Soest S, De Ley M (2009) Differential quantitative zinc-induced expression of human metallothionein isogenes in haematopoietic precursor cell lines. J Trace Elem Med Biol 23:124–131CrossRefGoogle Scholar
  3. Bartholome B, Spies CM, Gaber T, Schuchmann S, Berki T, Kunkel D et al (2004) Membrane glucocorticoid receptors (MGCR) are expressed in normal human peripheral blood mononuclear cells and up-regulated after in vitro stimulation and in patients with rheumatoid arthritis. FASEB J 18:70–80PubMedCrossRefGoogle Scholar
  4. Barua RS, Ambrose JA, Srivastava S, DeVoe MC, Eales-Reynolds LJ (2003) Reactive oxygen species are involved in smoking-induced dysfunction of nitric oxide biosynthesis and upregulation of endothelial nitric oxide synthase: an in vitro demonstration in human coronary artery endothelial cells. Circulation 107:2342–2347PubMedCrossRefGoogle Scholar
  5. Boonprasert K, Ruengweerayut R, Aunpad R, Satarug S, Na-Bangchang K (2012) Expression of metallothionein isoforms in peripheral blood leukocytes from Thai population residing in cadmium-contaminated areas. Environ Toxicol Pharmacol 34:935–940PubMedCrossRefGoogle Scholar
  6. Bremner I, Beattie JH (1990) Metallothionein and the trace minerals. Annu Rev Nutr 10:63–83PubMedCrossRefGoogle Scholar
  7. Bremner I, Mehra RK, Morrison JN, Wood AM (1986) Effects of dietary copper supplementation of rats on the occurrence of metallothionein-I in liver and its secretion into blood, bile and urine. Biochem J 235:735–739PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bulua AC, Simon A, Maddipati R, Pelletier M, Park H, Kim K-Y et al (2011) Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med 208:519–533PubMedPubMedCentralCrossRefGoogle Scholar
  9. Butt TR, Ecker DJ (1987) Yeast metallothionein and applications in biotechnology. Microbiol Rev 51:351–364PubMedPubMedCentralGoogle Scholar
  10. Cao J, Cousins RJ (2000) Metallothionein mRNA in monocytes and peripheral blood mononuclear cells and in cells from dried blood spots increases after zinc supplementation of men. J Nutr 130:2180–2187PubMedGoogle Scholar
  11. Carlin DJ, Naujokas MF, Bradham KD, Cowden J, Heacock M, Henry HF et al (2016) Arsenic and environmental health: state of the science and future research opportunities. Environ Health Perspect 124:890–899PubMedGoogle Scholar
  12. Carpene E, Andreani G, Isani G (2007) Metallothionein functions and structural characteristics. J Trace Elem Med Biol 21(Suppl 1):35–39PubMedCrossRefGoogle Scholar
  13. Chang XL, Jin TY, Zhou YF (2006) Metallothionein 1 isoform gene expression induced by cadmium in human peripheral blood lymphocytes. Biomed Environ Sci 19:104–109PubMedGoogle Scholar
  14. Chang X, Jin T, Chen L, Nordberg M, Lei L (2009) Metallothionein I isoform mRNA expression in peripheral lymphocytes as a biomarker for occupational cadmium exposure. Exp Biol Med 234:666–672CrossRefGoogle Scholar
  15. Collingwood TN, Urnov FD, Wolffe AP (1999) Nuclear receptors: coactivators, corepressors and chromatin remodeling in the control of transcription. J Mol Endocrinol 23:255–275PubMedCrossRefGoogle Scholar
  16. Coyle P, Philcox JC, Carey LC, Rofe AM (2002) Metallothionein: the multipurpose protein. Cell Mol Life Sci 59:627–647PubMedCrossRefGoogle Scholar
  17. Dalton T, Palmiter RD, Andrews GK (1994) Transcriptional induction of the mouse metallothionein-I gene in hydrogen peroxide-treated Hepa cells involves a composite major late transcription factor/antioxidant response element and metal response promoter elements. Nucleic Acids Res 22:5016–5023PubMedPubMedCentralCrossRefGoogle Scholar
  18. Das K, De Groof A, Jauniaux T, Bouquegneau JM (2006) Zn, Cu, Cd and Hg binding to metallothioneins in harbour porpoises Phocoena phocoena from the Southern North Sea. BMC Ecol 6:2PubMedPubMedCentralCrossRefGoogle Scholar
  19. Davis SR, Cousins RJ (2000) Metallothionein expression in animals: a physiological perspective on function. J Nutr 130:1085–1088PubMedGoogle Scholar
  20. Di Croce L, Okret S, Kersten S, Gustafsson JA, Parker M, Wahli W, Beato M (1999) Steroid and nuclear receptors. EMBO J 18:6201–6210PubMedPubMedCentralCrossRefGoogle Scholar
  21. Domènech J, Mir G, Huguet G, Capdevila M, Molinas M, Atrian S (2006) Plant metallothionein domains: functional insight into physiological metal binding and protein folding. Biochimie 88:583–593PubMedCrossRefGoogle Scholar
  22. Dorian C, Gattone VH II, Klaassen CD (1992) Accumulation and degradation of the protein moiety of cadmium-metallothionein (CdMT) in the mouse kidney. Toxicol Appl Pharmacol 117:242–248PubMedCrossRefGoogle Scholar
  23. Droge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMedCrossRefGoogle Scholar
  24. Edwards SE, Maxson P, Miranda ML, Fry RC (2015) Cadmium levels in a North Carolina Cohort: identifying risk factors for elevated levels during pregnancy. J Expo Sci Environ Epidemiol 25:427–432PubMedCrossRefGoogle Scholar
  25. El-Refaiy AI, Eissa F (2012) Protective effects of ascorbic acid and zinc against cadmium-induced histopathological, histochemical and cytogenetic changes in rats. Comun Sci 3:162–180Google Scholar
  26. Falnoga I, Zelenik Pevec A, Slejkovec Z, Znidaric MT, Zajc I, Mlakar SJ et al (2012) Arsenic trioxide (ATO) influences the gene expression of metallothioneins in human glioblastoma cells. Biol Trace Elem Res 149:331–339PubMedCrossRefGoogle Scholar
  27. Formigari A, Irato P, Santon A (2007) Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects. Comp Biochem Physiol C Toxicol Pharmacol 146:443–459PubMedCrossRefGoogle Scholar
  28. Garla R, Ganger R, Mohanty BP, Verma S, Bansal MP, Garg ML (2016) Metallothionein does not sequester arsenic(III) ions in condition of acute arsenic toxicity. Toxicology 366–367:68–73. doi: 10.1016/j.tox.2016.08.008 PubMedCrossRefGoogle Scholar
  29. Garrett SH, Sens MA, Todd JH, Somji S, Sens DA (1999) Expression of MT-3 protein in the human kidney. Toxicol Lett 105:207–214PubMedCrossRefGoogle Scholar
  30. Ghaffari S (2008) Oxidative stress in the regulation of normal and neoplastic hematopoiesis. Antioxid Redox Signal 10:1923–1940PubMedPubMedCentralCrossRefGoogle Scholar
  31. Gracy RW, Talent JM, Kong Y, Conrad CC (1999) Reactive oxygen species: the unavoidable environmental insult? Mutat Res 428:17–22PubMedCrossRefGoogle Scholar
  32. Grider A, Bailey LB, Cousins RJ (1990) Erythrocyte metallothionein as an index of zinc status in humans. Proc Natl Acad Sci U S A 87:1259–1262PubMedPubMedCentralCrossRefGoogle Scholar
  33. Griese M, Kusenbach G, Lusebring K, Koster W, Roth B, Reinhardt D (1988) Glucocorticoid receptors in mononuclear blood cells and their correlation to endogenous and exogenous corticoids in healthy and asthmatic children. Eur J Pediatr 147:490–495PubMedCrossRefGoogle Scholar
  34. Groten JP, Luten JB, Bruggeman IM, Temmink JH, van Bladeren PJ (1992) Comparative toxicity and accumulation of cadmium chloride and cadmium-metallothionein in primary cells and cell lines of rat intestine, liver and kidney. Toxicol In Vitro 6:509–517PubMedCrossRefGoogle Scholar
  35. Groten JP, Koeman JH, van Nesselrooij JH, Luten JB, van Vlissingen JMF, Stenhuis WS et al (1994) Comparison of renal toxicity after long-term oral administration of cadmium chloride and cadmium-metallothionein in rats. Fundam Appl Toxicol 23:544–552PubMedCrossRefGoogle Scholar
  36. Hamer DH (1986) Metallothionein. Annu Rev Biochem 55:913–951PubMedCrossRefGoogle Scholar
  37. Haq F, Mahoney M, Koropatnick J (2003) Signaling events for metallothionein induction. Mutat Res 533:211–226PubMedCrossRefGoogle Scholar
  38. Hattangadi SM, Lodish HF (2007) Regulation of erythrocyte lifespan: do reactive oxygen species set the clock? J Clin Invest 117:2075–2077PubMedPubMedCentralCrossRefGoogle Scholar
  39. Hennigar SR, Kelley AM, McClung JP (2016) Metallothionein and zinc transporter expression in circulating human blood cells as biomarkers of zinc status: a systematic review. Adv Nutr 7(4):735–746. doi: 10.3945/an.116.012518 PubMedPubMedCentralCrossRefGoogle Scholar
  40. Hidalgo J, Giralt M, Garvey JS, Armario A (1988) Physiological role of glucocorticoids on rat serum and liver metallothionein in basal and stress conditions. Am J Physiol 254:E71–E78PubMedGoogle Scholar
  41. Holmstrom KM, Finkel T (2014) Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol 15:411–421PubMedCrossRefGoogle Scholar
  42. Huber KL, Cousins RJ (1993a) Zinc metabolism and metallothionein expression in bone marrow during erythropoiesis. Am J Phys Endocrinol Metab 264:E770–E775Google Scholar
  43. Huber KL, Cousins RJ (1993b) Metallothionein expression in rat bone marrow is dependent on dietary zinc but not dependent on interleukin-1 or interleukin-6. J Nutr 123:642–648PubMedGoogle Scholar
  44. Ignatowicz E, Wozniak A, Kulza M, Senczuk-Przybylowska M, Cimino F, Piekoszewski W et al (2013) Exposure to alcohol and tobacco smoke causes oxidative stress in rats. Pharmacol Rep 65:906–913PubMedCrossRefGoogle Scholar
  45. Irato P, Santovito G, Piccinni E, Albergoni V (2001) Oxidative burst and metallothionein as a scavenger in macrophages. Immunol Cell Biol 79:251–254PubMedCrossRefGoogle Scholar
  46. Irvine GW, Summers KL, Stillman MJ (2013) Cysteine accessibility during As3+ metalation of the α- and β-domains of recombinant human MT1A. Biochem Biophys Res Commun 433:477–483PubMedCrossRefGoogle Scholar
  47. Järup L, Åkesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238:201–208PubMedCrossRefGoogle Scholar
  48. Jiang L-J, Maret W, Vallee BL (1998) The glutathione redox couple modulates zinc transfer from metallothionein to zinc-depleted sorbitol dehydrogenase. Proc Natl Acad Sci U S A 95:3483–3488PubMedPubMedCentralCrossRefGoogle Scholar
  49. Jonai H, Yamada H, Suzuki K, Otsuka F, Koizumi S (1992) Estimation of metallothionein synthesis in cadmium-exposed human lymphocytes by gel electrophoresis and silver staining. Ind Health 30:129–137PubMedCrossRefGoogle Scholar
  50. Kagi JH (1991) Overview of metallothionein. Methods Enzymol 205:613–626PubMedCrossRefGoogle Scholar
  51. Kang YJ (1999) The antioxidant function of metallothionein in the heart. Proc Soc Exp Biol Med 222:263–273PubMedCrossRefGoogle Scholar
  52. Karin M, Herschman HR (1980) Glucocorticoid hormone receptor mediated induction of metallothionein synthesis in HeLa cells. J Cell Physiol 103:35–40PubMedCrossRefGoogle Scholar
  53. Karin M, Imbra RJ, Heguy A, Wong G (1985) Interleukin 1 regulates human metallothionein gene expression. Mol Cell Biol 5:2866–2869PubMedPubMedCentralCrossRefGoogle Scholar
  54. Kavushansky A, Ben-Shachar D, Richter-Levin G, Klein E (2009) Physical stress differs from psychosocial stress in the pattern and time-course of behavioral responses, serum corticosterone and expression of plasticity-related genes in the rat. Stress 12:412–425PubMedCrossRefGoogle Scholar
  55. Kelly EJ, Sandgren EP, Brinster RL, Palmiter RD (1997) A pair of adjacent glucocorticoid response elements regulate expression of two mouse metallothionein genes. Proc Natl Acad Sci U S A 94:10045–10050PubMedPubMedCentralCrossRefGoogle Scholar
  56. Klaassen CD, Liu J, Diwan BA (2009) Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 238:215–220PubMedPubMedCentralCrossRefGoogle Scholar
  57. Koh M, Kim H-J (2001) The effects of metallothionein on the activity of enzymes involved in removal of reactive oxygen species. Bull Kor Chem Soc 22:362–366Google Scholar
  58. Krężel A, Hao Q, Maret W (2007) The zinc/thiolate redox biochemistry of metallothionein and the control of zinc ion fluctuations in cell signaling. Arch Biochem Biophys 463:188–200PubMedCrossRefGoogle Scholar
  59. Leszczyszyn OI, Imam HT, Blindauer CA (2013) Diversity and distribution of plant metallothioneins: a review of structure, properties and functions. Metallomics 5:1146–1169PubMedCrossRefGoogle Scholar
  60. Liu J, Cheng M-L, Yang Q, Shan K-R, Shen J, Zhou Y et al (2007) Blood metallothionein transcript as a biomarker for metal sensitivity: low blood metallothionein transcripts in arsenicosis patients from Guizhou, China. Environ Health Perspect 115:1101–1106PubMedPubMedCentralCrossRefGoogle Scholar
  61. Lu J, Jin T, Nordberg G, Nordberg M (2001) Metallothionein gene expression in peripheral lymphocytes from cadmium-exposed workers. Cell Stress Chaperones 6:97–104PubMedPubMedCentralCrossRefGoogle Scholar
  62. Lu J, Jin T, Nordberg G, Nordberg M (2005) Metallothionein gene expression in peripheral lymphocytes and renal dysfunction in a population environmentally exposed to cadmium. Toxicol Appl Pharmacol 206:150–156PubMedCrossRefGoogle Scholar
  63. Lynes MA, Garvey JS, Lawrence DA (1990) Extracellular metallothionein effects on lymphocyte activities. Mol Immunol 27:211–219PubMedCrossRefGoogle Scholar
  64. Lynes MA, Borghesi LA, Youn J, Olson EA (1993) Immunomodulatory activities of extracellular metallothionein. I. Metallothionein effects on antibody production. Toxicology 85:161–177PubMedCrossRefGoogle Scholar
  65. Mahbub ES, Haque N, Salma U, Ahmed A (2011) Immune modulation in response to stress and relaxation. Pak J Biol Sci 14:363–374CrossRefGoogle Scholar
  66. Mao J, Yu H, Wang C, Sun L, Jiang W, Zhang P et al (2012) Metallothionein MT1M is a tumor suppressor of human hepatocellular carcinomas. Carcinogenesis 33:2568–2577PubMedCrossRefGoogle Scholar
  67. Maret W (1994) Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. Proc Natl Acad Sci U S A 91:237–241PubMedPubMedCentralCrossRefGoogle Scholar
  68. Margoshes M, Vallee BL (1957) A cadmium protein from equine kidney cortex. J Am Chem Soc 79:4813–4814CrossRefGoogle Scholar
  69. Michel V, Peinnequin A, Alonso A, Buguet A, Cespuglio R, Canini F (2007) Effect of glucocorticoid depletion on heat-induced Hsp70, IL-1β and TNF-α gene expression. Brain Res 1164:63–71PubMedCrossRefGoogle Scholar
  70. Min KS, Ohyanagi N, Ohta M, Onosaka S, Tanaka K (1995) Effect of erythropoiesis on splenic cadmium-metallothionein level following an injection of CdCl2 in mice. Toxicol Appl Pharmacol 134:235–240PubMedCrossRefGoogle Scholar
  71. Moffatt P, Denizeau F (1997) Metallothionein in physiological and physiopathological processes. Drug Metab Rev 29:261–307PubMedCrossRefGoogle Scholar
  72. Moffatt P, Seguin C (1998) Expression of the gene encoding metallothionein-3 in organs of the reproductive system. DNA Cell Biol 17:501–510PubMedCrossRefGoogle Scholar
  73. Mohmand J, Eqani SA, Fasola M, Alamdar A, Mustafa I, Ali N, Liu L, Peng S, Shen H (2015) Human exposure to toxic metals via contaminated dust: bio-accumulation trends and their potential risk estimation. Chemosphere 132:142–151. doi: 10.1016/j.chemosphere.2015.03.004 PubMedCrossRefGoogle Scholar
  74. Moleirinho A, Carneiro J, Matthiesen R, Silva RM, Amorim A, Azevedo L (2011) Gains, losses and changes of function after gene duplication: study of the metallothionein family. PLoS One 6:e18487PubMedPubMedCentralCrossRefGoogle Scholar
  75. Nagamine T, Nakajima K (2013) Development of a high sensitivity ELISA for the assay of metallothionein. Curr Pharm Biotechnol 14(4):427–431PubMedCrossRefGoogle Scholar
  76. Nakajima K, Kodaira T, Kato M, Nakazato K, Tokita Y, Kikuchi H, Sekine H, Suzuki K, Nagamine T (2010) Development of an enzyme-linked immunosorbent assay for metallothionein-I and -II in plasma of humans and experimental animals. Clin Chim Acta 2411(9–10):758–761. doi: 10.1016/j.cca.2010.02.058 CrossRefGoogle Scholar
  77. Nakazato K, Tomioka S, Nakajima K, Saito H, Kato M, Kodaira T, Yatsuzuka S, Shimomura Y, Hiroki T, Motoyama K, Kodama H, Nagamine T (2014) Determination of the serum metallothionein (MT)1/2 concentration in patients with Wilson’s disease and Menkes disease. J Trace Elem Med Biol 28(4):441–447. doi: 10.1016/j.jtemb.2014.07.013 PubMedCrossRefGoogle Scholar
  78. Neal JW, Singhrao SK, Jasani B, Newman GR (1996) Immunocytochemically detectable metallothionein is expressed by astrocytes in the ischaemic human brain. Neuropathol Appl Neurobiol 22:243–247PubMedCrossRefGoogle Scholar
  79. Nordberg GF, Kjellström T (1979) Metabolic model for cadmium in man. Environ Health Perspect 28:211–217PubMedPubMedCentralCrossRefGoogle Scholar
  80. Nordberg M, Nordberg GF (2000) Toxicological aspects of metallothionein. Cell Mol Biol 46:451–463PubMedGoogle Scholar
  81. Nourani MR, Ebrahimi M, Roudkenar MH, Vahedi E, Ghanei M, Imani Fooladi AA (2011) Sulfur mustard induces expression of metallothionein-1a in human airway epithelial cells. Int J Gen Med 4:413–419PubMedPubMedCentralCrossRefGoogle Scholar
  82. Oda N, Sogawa CA, Sogawa N, Onodera K, Furuta H, Yamamoto T (2001) Metallothionein expression and localization in rat bone tissue after cadmium injection. Toxicol Lett 123:143–150PubMedCrossRefGoogle Scholar
  83. Oh KB, Watanabe T, Matsuoka H (1999) A novel copper-binding protein with characteristics of a metallothionein from a clinical isolate of Candida albicans. Microbiology 145(Pt 9):2423–2429PubMedCrossRefGoogle Scholar
  84. Pauwels M, van Weyenbergh J, Soumillion A, Proost P, De Ley M (1994) Induction by zinc of specific metallothionein isoforms in human monocytes. Eur J Biochem 220:105–110PubMedCrossRefGoogle Scholar
  85. Phillippi JA, Klyachko EA, Kenny JP IV, Eskay MA, Gorman RC, Gleason TG (2009) Basal and oxidative stress-induced expression of metallothionein is decreased in ascending aortic aneurysms of bicuspid aortic valve patients. Circulation 119:2498–2506PubMedPubMedCentralCrossRefGoogle Scholar
  86. Prozialeck WC, Wellington DR, Lamar PC (1993) Comparison of the cytotoxic effects of cadmium chloride and cadmium-metallothionein in LLC-PK1 cells. Life Sci 53:Pl337–Pl342PubMedCrossRefGoogle Scholar
  87. Qu W, Waalkes MP (2015) Metallothionein blocks oxidative DNA damage induced by acute inorganic arsenic exposure. Toxicol Appl Pharmacol 282:267–274PubMedCrossRefGoogle Scholar
  88. Qu C-S, Ma Z-W, Yang J, Liu Y, Bi J, Huang L (2012) Human exposure pathways of heavy metals in a lead-zinc mining area, Jiangsu Province, China. PLoS One 7(11):e46793. doi: 10.1371/journal.pone.0046793 PubMedPubMedCentralCrossRefGoogle Scholar
  89. Quaife C, Hammer RE, Mottet NK, Palmiter RD (1986) Glucocorticoid regulation of metallothionein during murine development. Dev Biol 118:549–555PubMedCrossRefGoogle Scholar
  90. Quaife CJ, Findley SD, Erickson JC, Froelick GJ, Kelly EJ, Zambrowicz BP et al (1994) Induction of a new metallothionein isoform (MT-IV) occurs during differentiation of stratified squamous epithelia. Biochemistry 33:7250–7259PubMedCrossRefGoogle Scholar
  91. Rahman MT, De Ley M (2001) Metallothionein isogene transcription in red blood cell precursors from human cord blood. Eur J Biochem 268:849–856PubMedCrossRefGoogle Scholar
  92. Rahman MT, De Ley M (2008) Metallothionein in human thrombocyte precursors, CD61+ megakaryocytes. Cell Biol Toxicol 24:19–25PubMedCrossRefGoogle Scholar
  93. Rahman MT, De Ley M (2016) Arsenic induction of metallothionein and metallothionein induction against arsenic cytotoxicity. Rev Environ Contam Toxicol 240:151–168. doi: 10.1007/398_2016_2 Google Scholar
  94. Rahman MT, Vandingenen A, De Ley M (2000) Metallothionein biosynthesis in human RBC precursors. Cell Physiol Biochem 10:237–242PubMedCrossRefGoogle Scholar
  95. Rigby DKE, Stillman MJ (2006) Metal-dependent protein folding: metallation of metallothionein. J Inorg Biochem 100:2101–2107CrossRefGoogle Scholar
  96. Robinson JM (2008a) Reactive oxygen species in phagocytic leukocytes. Histochem Cell Biol 130:281–297PubMedPubMedCentralCrossRefGoogle Scholar
  97. Robinson NJ (2008b) A bacterial copper metallothionein. Nat Chem Biol 4:582–583PubMedCrossRefGoogle Scholar
  98. Robinson NJ, Whitehall SK, Cavet JS (2001) Microbial metallothioneins. Adv Microb Physiol 44:183–213PubMedCrossRefGoogle Scholar
  99. Ronchetti SA, Bianchi MS, Duvilanski BH, Cabilla JP (2016) In vivo and in vitro arsenic exposition induces oxidative stress in anterior pituitary gland. Int J Toxicol 35(4):463–475. doi: 10.1177/1091581816645797 PubMedCrossRefGoogle Scholar
  100. Ruttkay-Nedecky B, Nejdl L, Gumulec J, Zitka O, Masarik M, Eckschlager T et al (2013) The role of metallothionein in oxidative stress. Int J Mol Sci 14:6044–6066PubMedPubMedCentralCrossRefGoogle Scholar
  101. Sabolic I, Breljak D, Skarica M, Herak-Kramberger CM (2010) Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. Biometals 23:897–926PubMedCrossRefGoogle Scholar
  102. Sánchez-Rodríguez JE, Bartolomé M, Cañas AI, Huetos O, Navarro C, Rodríguez AC et al (2015) Anti-smoking legislation and its effects on urinary cotinine and cadmium levels. Environ Res 136:227–233PubMedCrossRefGoogle Scholar
  103. Santos SS, Brunialti MK, Rigato O, Machado FR, Silva E, Salomao R (2012) Generation of nitric oxide and reactive oxygen species by neutrophils and monocytes from septic patients and association with outcomes. Shock 38:18–23PubMedCrossRefGoogle Scholar
  104. Satarug S, Garrett SH, Sens MA, Sens DA (2010) Cadmium, environmental exposure, and health outcomes. Environ Health Perspect 118:182–190PubMedCrossRefGoogle Scholar
  105. Sato M, Bremner I (1993) Oxygen free radicals and metallothionein. Free Radic Biol Med 14:325–337PubMedCrossRefGoogle Scholar
  106. Sato M, Mehra RK, Bremner I (1984) Measurement of plasma metallothionein-I in the assessment of the zinc status of zinc-deficient and stressed rats. J Nutr 114:1683–1689PubMedGoogle Scholar
  107. Schwarz MA, Lazo JS, Yalowich JC, Reynolds I, Kagan VE, Tyurin V et al (1994) Cytoplasmic metallothionein overexpression protects NIH 3T3 cells from tert-butyl hydroperoxide toxicity. J Biol Chem 269:15238–15243PubMedGoogle Scholar
  108. Selvaraj A, Balamurugan K, Yepiskoposyan H, Zhou H, Egli D, Georgiev O et al (2005) Metal-responsive transcription factor (MTF-1) handles both extremes, copper load and copper starvation, by activating different genes. Genes Dev 19:891–896PubMedPubMedCentralCrossRefGoogle Scholar
  109. Shi M, Wang X, Yamanaka T, Ogita F, Nakatani K, Takeuchi T (2007) Effects of anaerobic exercise and aerobic exercise on biomarkers of oxidative stress. Environ Health Prev Med 12:202–208PubMedPubMedCentralCrossRefGoogle Scholar
  110. Slusser A, Zheng Y, Zhou XD, Somji S, Sens DA, Sens MA et al (2015) Metallothionein isoform 3 expression in human skin, related cancers and human skin derived cell cultures. Toxicol Lett 232:141–148PubMedCrossRefGoogle Scholar
  111. Smirnova IV, Bittel DC, Ravindra R, Jiang HM, Andrews GK (2000) Zinc and cadmium can promote rapid nuclear translocation of metal response element-binding transcription factor-1. J Biol Chem 275:9377–9384PubMedCrossRefGoogle Scholar
  112. Souza V, Escobar Mdel C, Bucio L, Hernández E, Gutiérrez-Ruiz MC (2004) Zinc pretreatment prevents hepatic stellate cells from cadmium-produced oxidative damage. Cell Biol Toxicol 20:241–251PubMedCrossRefGoogle Scholar
  113. Spiering R, van der Zee R, Wagenaar J, Kapetis D, Zolezzi F, van Eden W et al (2012) Tolerogenic dendritic cells that inhibit autoimmune arthritis can be induced by a combination of carvacrol and thermal stress. PLoS One 7:e46336PubMedPubMedCentralCrossRefGoogle Scholar
  114. Spiering R, Wagenaar-Hilbers J, Huijgen V, van der Zee R, van Kooten PJ, van Eden W et al (2014) Membrane-bound metallothionein 1 of murine dendritic cells promotes the expansion of regulatory T cells in vitro. Toxicol Sci 138:69–75PubMedCrossRefGoogle Scholar
  115. Sullivan VK, Cousins RJ (1997) Competitive reverse transcriptase–polymerase chain reaction shows that dietary zinc supplementation in humans increases monocyte metallothionein mRNA levels. J Nutr 127:694–698PubMedGoogle Scholar
  116. Sullivan VK, Burnett FR, Cousins RJ (1998) Metallothionein expression is increased in monocytes and erythrocytes of young men during zinc supplementation. J Nutr 128:707–713PubMedGoogle Scholar
  117. Suzuki K, Nakajima K, Otaki N, Kimura M (1994) Metallothionein in developing human brain. Biol Signals 3:188–192PubMedCrossRefGoogle Scholar
  118. Tanaka K, Nomura H, Onosaka S, Min K (1981) Release of hepatic cadmium by carbon tetrachloride treatment. Toxicol Appl Pharmacol 59:535–539PubMedCrossRefGoogle Scholar
  119. Tanaka K, Min KS, Onosaka S, Fukuhara C, Ueda M (1985) The origin of metallothionein in red blood cells. Toxicol Appl Pharmacol 78:63–68PubMedCrossRefGoogle Scholar
  120. Tanaka K, Min KS, Ohyanagi N, Onosaka S, Fukuhara C (1986) Fate of erythrocyte Cd-metallothionein in mice. Toxicol Appl Pharmacol 83:197–202PubMedCrossRefGoogle Scholar
  121. Tanaka K, Min K, Onosaka S, Fukuhara C (1987) Synthesis and degradation of erythrocyte metallothionein in cadmium-administered mice. Experientia Suppl 52:525–532PubMedCrossRefGoogle Scholar
  122. Thornalley PJ, Vašák M (1985) Possible role for metallothionein in protection against radiation-induced oxidative stress. Kinetics and mechanism of its reaction with superoxide and hydroxyl radicals. Biochim Biophys Acta 827:36–44PubMedCrossRefGoogle Scholar
  123. Tsantes AE, Bonovas S, Travlou A, Sitaras NM (2006) Redox imbalance, macrocytosis, and RBC homeostasis. Antioxid Redox Signal 8:1205–1216PubMedCrossRefGoogle Scholar
  124. Uchida Y, Takio K, Titani K, Ihara Y, Tomonaga M (1991) The growth inhibitory factor that is deficient in Alzheimer’s disease is a 68 amino acid metallothionein-like protein. Neuron 7(2):337–347PubMedCrossRefGoogle Scholar
  125. Vandeghinste N, Proost P, De Ley M (2000) Metallothionein isoform gene expression in zinc-treated human peripheral blood lymphocytes. Cell Mol Biol 46:419–433PubMedGoogle Scholar
  126. Vasak M (2005) Advances in metallothionein structure and functions. J Trace Elem Med Biol 19:13–17PubMedCrossRefGoogle Scholar
  127. Vašák M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16:1067PubMedCrossRefGoogle Scholar
  128. Waldron KJ, Rutherford JC, Ford D, Robinson NJ (2009) Metalloproteins and metal sensing. Nature 460:823–830PubMedCrossRefGoogle Scholar
  129. Werynska B, Pula B, Muszczynska-Bernhard B, Gomulkiewicz A, Jethon A, Podhorska-Okolow M et al (2013) Expression of metallothionein-III in patients with non-small cell lung cancer. Anticancer Res 33:965–974PubMedGoogle Scholar
  130. Wittman R, Hu H (2002) Cadmium exposure and nephropathy in a 28-year-old female metals worker. Environ Health Perspect 110:1261–1266PubMedPubMedCentralCrossRefGoogle Scholar
  131. Yamada H, Koizumi S (1991) Metallothionein induction in human peripheral blood lymphocytes by heavy metals. Chem Biol Interact 78:347–354PubMedCrossRefGoogle Scholar
  132. Yamada H, Koizumi S (2001) Lymphocyte metallothionein-mRNA as a sensitive biomarker of cadmium exposure. Ind Health 39:29–32PubMedCrossRefGoogle Scholar
  133. Yang M, Chitambar CR (2008) Role of oxidative stress in the induction of metallothionein-2A and heme oxygenase-1 gene expression by the antineoplastic agent gallium nitrate in human lymphoma cells. Free Radic Biol Med 45:763–772PubMedPubMedCentralCrossRefGoogle Scholar
  134. Youn J, Lynes MA (1999) Metallothionein-induced suppression of cytotoxic T lymphocyte function: an important immunoregulatory control. Toxicol Sci 52:199–208PubMedCrossRefGoogle Scholar
  135. Youn J, Borghesi LA, Olson EA, Lynes MA (1995) Immunomodulatory activities of extracellular metallothionein. II. Effects on macrophage functions. J Toxicol Environ Health 45:397–413PubMedCrossRefGoogle Scholar
  136. Zalups RK, Ahmad S (2003) Molecular handling of cadmium in transporting epithelia. Toxicol Appl Pharmacol 186:163–188PubMedCrossRefGoogle Scholar
  137. Zhang B, Georgiev O, Hagmann M, Gunes C, Cramer M, Faller P et al (2003) Activity of metal-responsive transcription factor 1 by toxic heavy metals and H2O2 in vitro is modulated by metallothionein. Mol Cell Biol 23:8471–8485PubMedPubMedCentralCrossRefGoogle Scholar
  138. Zhou P, Kalakonda N, Comenzo RL (2005) Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol 128:636–644PubMedCrossRefGoogle Scholar
  139. Zhou XD, Sens DA, Sens MA, Namburi VBRK, Singh RK, Garrett SH et al (2006) Metallothionein-1 and -2 expression in cadmium- or arsenic-derived human malignant urothelial cells and tumor heterotransplants and as a prognostic indicator in human bladder cancer. Toxicol Sci 91:467–475PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Mohammad Tariqur Rahman
    • 1
    Email author
  • Nazmul Haque
    • 2
    • 3
  • Noor Hayaty Abu Kasim
    • 2
    • 3
  • Marc De Ley
    • 4
  1. 1.Faculty of DentistryUniversity of MalayaKuala LumpurMalaysia
  2. 2.Department of Restorative Dentistry, Faculty of DentistryUniversity of MalayaKuala LumpurMalaysia
  3. 3.Regenerative Dentistry Research Group, Faculty of DentistryUniversity of MalayaKuala LumpurMalaysia
  4. 4.Laboratorium voor BiochemieKU LeuvenHeverleeBelgium

Personalised recommendations