The Chemical Biology of Cadmium

  • Eric Lund
  • Susan Krezoski
  • David Petering


Cadmium is a major toxic element with important and long-recognized consequences for human health. As a result, Cd2+ has been subjected to thousands of toxicological studies that reveal its complex and wide-ranging impacts on cellular processes. Nevertheless, as with other toxic metals, it has been difficult to extend this research to the molecular level, where Cd2+ binds to particular molecules and initiates mechanisms of cell injury. This chapter sets forth a framework for considering the molecular interactions of Cd2+ with biomolecules, principally proteins. The paradigm is developed that at the proteomic level, Cd2+ may undergo metal exchange reactions with many Zn-proteins. In some cases, protein functions are perturbed and toxicity results. In others, as with its reaction with Zn-metallothionein, Cd2+ is inactivated. In all cases, the important role of adventitious binding of Cd2+ and Zn2+ within the proteome is emphasized. These ideas are given specificity in research into the molecular involvement of Cd2+ in nephrotoxicity and carcinogenesis. Examples of the chemical participation of Cd2+ in cell signaling are described. These include the activation of MTF-1 transcription factor and the stimulation of complex apoptotic pathways that may depend on the initial production of reactive oxygen species. With little information that Cd2+ interacts directly with proteins involved in the trafficking or function of other metals (Fe, Cu, Ca), the chapter concludes with a discussion of analytical methods to determine the speciation of cadmium within the proteome and particularly the zinc proteome.



Some of the research reported in this review was supported by NIH grant ES-024509 and by a Research Growth Initiative grant from the University of Wisconsin-Milwaukee.


  1. 1.
    Tarakina NV, Verberck B (2016) A portrait of cadmium. Nat Chem 9:96PubMedCrossRefGoogle Scholar
  2. 2.
    NTP (National Toxicology Program) (2016) Report on carcinogens, cadmium and cadmium compounds. Fourteenth edition, Research Triangle Park, NC, U.S. Department of Health and Human Services, Public Health Service.
  3. 3.
    Nordberg GF (2009) Historical perspectives on cadmium toxicology. Toxicol Appl Pharmacol 238:192–200PubMedCrossRefGoogle Scholar
  4. 4.
    Yoshida F, Hata A, Tonegawa Haruo (1999) Itai-Itai disease and the countermeasures against cadmium pollution by the Kamioka mine. Environ Econ Policy Studies 2:215–229CrossRefGoogle Scholar
  5. 5.
    Margoshes M, Vallee BL (1957) A cadmium protein from equine kidney cortex. J Am Chem Soc 79:4813–4814CrossRefGoogle Scholar
  6. 6.
    Kagi JH, Vallee BL (1960) Metallothionein: a cadmium- and zinc-containing protein from equine renal cortex. J Biol Chem 235:3460–3465PubMedGoogle Scholar
  7. 7.
    Piscator M (1964) On cadmium in normal human kidneys with a report on the isolation of metallothioneine from cadmium-exposed rabbit livers. Nord Hyg Tidskr 45:76–82PubMedGoogle Scholar
  8. 8.
    Nordberg GF, Nordberg M, Piscator M, Vesterberg O (1972) Separation of two forms of rabbit metallothionein by isoelectric focusing. Biochem J 126:491–498PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Thevenod F, Lee WK (2013) Toxicology of cadmium and its damage to mammalian organs. In: Sigel A, Sigel H, Sigel RKO (ed) Cadmium: from toxicity to essentiality. Met ions life sci, vol 11. Springer, Heidelberg, pp 415–490Google Scholar
  10. 10.
    Hartwig A (2013) Cadmium and cancer. In: Sigel A, Sigel H, Sigel RKO (ed) Cadmium: from toxicity to essentiality. Met ions life sci, vol 11. Springer, Heidelberg, pp 491–528Google Scholar
  11. 11.
    Thevenod F, Lee WK (2013) Cadmium and cellular signaling cascades: interactions between cell death and survival pathways. Arch Toxicol 87:1743–1786PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Templeton DM, Liu Y (2010) Multiple roles of cadmium in cell death and survival. Chem Biol Interact 188:267–275PubMedCrossRefGoogle Scholar
  13. 13.
    Maret W, Moulis JM (2013) The bioinorganic chemistry of cadmium in the context of its toxicity. In: Sigel A, Sigel H, Sigel RKO (ed) Cadmium: from toxicity to essentiality. Met ions life sci, vol 11. Springer, Heidelberg, pp 1–29Google Scholar
  14. 14.
    Sovago I, Varnagy K (2013) Cadmium (II) complexes of amino acids and peptides. In: Sigel A, Sigel H, Sigel RKO (ed) Cadmium: from toxicity to essentiality. Met ions life sci, vol 11. Springer, Heidelberg, pp 275–302Google Scholar
  15. 15.
    Krezel A, Bal W (1999) Coordination chemistry of glutathione. Acta Biochim Pol 46:567–580PubMedGoogle Scholar
  16. 16.
    Andreini C, Banci L, Bertini I, Rosato A (2006) Counting the zinc-proteins encoded in the human genome. J Proteome Res 5:196–201PubMedCrossRefGoogle Scholar
  17. 17.
    Andreini C, Banci L, Bertini I, Rosato A (2006) Zinc through the three domains of life. J Proteome Res 5:3173–3178PubMedCrossRefGoogle Scholar
  18. 18.
    Maret W, Li Y (2009) Coordination dynamics of zinc in proteins. Chem Rev 109:4682–4707PubMedCrossRefGoogle Scholar
  19. 19.
    Petering DH (2017) Reactions of the Zn Proteome with Cd2+ and other xenobiotics: trafficking and toxicity. Chem Res Toxicol 30:189–202PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Armitage I, Drakenberg T, Reilly B (2013) Use of 113Cd NMR to probe the native metal binding sites in metalloproteins: an overview. In: Sigel A, Sigel H, Sigel RKO (ed) Cadmium: from toxicity to essentiality. Met ions life sci, vol 11. Springer, Heidelberg, pp 117–144Google Scholar
  21. 21.
    Krezel A, Maret W (2006) Zinc-buffering capacity of a eukaryotic cell at physiological pZn. J Biol Inorg Chem 11:1049–1062PubMedCrossRefGoogle Scholar
  22. 22.
    Colvin RA, Bush AI, Volitakis I, Fontaine CP, Thomas D, Kikuchi K, Holmes WR (2008) Insights into Zn2+ homeostasis in neurons from experimental and modeling studies. Am J Physiol Cell Physiol 294:C726–C742PubMedCrossRefGoogle Scholar
  23. 23.
    Nowakowski AB, Meeusen JW, Menden H, Tomasiewicz H, Petering DH (2015) Chemical-biological properties of zinc sensors TSQ and Zinquin: formation of sensor-Zn-protein adducts versus Zn(sensor)2 complexes. Inorg Chem 54:11637–11647PubMedCrossRefGoogle Scholar
  24. 24.
    Karim MR, Petering DH (2016) Newport Green, a fluorescent sensor of weakly bound cellular Zn2+: competition with proteome for Zn2+. Metallomics 8:201–210PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Petering DH, Krezoski S, Tabatabai NM (2009) In: Sigel A, Sigel H, Sigel RKO (ed) Metallothioneins and related chelators. Met ions life sci, vol 5. Springer, Heidelberg, pp 353–397Google Scholar
  26. 26.
    Namdarghanbari M, Wobig W, Krezoski S, Tabatabai NM, Petering DH (2011) Mammalian metallothionein in toxicology, cancer, and cancer chemotherapy. J Biol Inorg Chem 16:1087–101PubMedCrossRefGoogle Scholar
  27. 27.
    Cousins RJ (1979) Metallothionein synthesis and degradation: relationship to cadmium metabolism. Environ. Health Persp 28:131–136PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Klaassen CD, Liu J, Diwan BA (2009) Metallothionein protection of cadmium toxicity. Toxicol Appl Pharmacol 238:215–220PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Klaassen CD, Liu J, Choudhuri S (1999) Metallothionein: an intracellular protein to protect against cadmium toxicity. Annu Rev Pharmacol Toxicol 39:267–294PubMedCrossRefGoogle Scholar
  30. 30.
    Liu Y, Liu J, Habeebu SM, Waalkes MP, Klaassen CD (2000) Metallothionein-I/II null mice are sensitive to chronic oral cadmium-induced nephrotoxicity. Toxicol Sci 57:167–176PubMedCrossRefGoogle Scholar
  31. 31.
    Habeebu SS, Liu J, Liu Y, Klaassen CD (2000) Metallothionein-null mice are more susceptible than wild-type mice to chronic CdCl(2)-induced bone injury. Toxicol Sci 56:211–219PubMedCrossRefGoogle Scholar
  32. 32.
    Vasak M, Meloni G (2011) Chemistry and biology of mammalian metallothioneins. J Biol Inorg Chem 16:1067–1078PubMedCrossRefGoogle Scholar
  33. 33.
    Otvos JD, Armitage IM (1980) Structure of the metal clusters in rabbit liver metallothionein. Proc Natl Acad Sci U S A 77:7094–98CrossRefGoogle Scholar
  34. 34.
    Robbins AH, McRee DE, Williamson M, Collett SA, Xuong NH, Furey WF, Wang BC, Stout CD (1991) Refined crystal structure of Cd, Zn metallothionein at 2.0 A resolution. J Mol Biol 221:1269–1293PubMedPubMedCentralGoogle Scholar
  35. 35.
    Arseniev A, Schultze P, Wörgötter E, Braun W, Wagner G, Vasák M, Kägi JH, Wüthrich K (1988) Three-dimensional structure of rabbit liver Cd7-metallothionein-2a in aqueous solution determined by nuclear magnetic resonance. J Mol Biol 201:637–657PubMedCrossRefGoogle Scholar
  36. 36.
    Ejnik JW, Muñoz A, DeRose E, Shaw CF 3rd (2003) Structural consequences of metallothionein dimerization: solution structure of the isolated Cd4-alpha-domain and comparison with the holoprotein dimer.Biochemistry. Petering DH 42:8403–8410Google Scholar
  37. 37.
    Kagi JH, Vallee BL (1961) Metallothionein: a cadmium and zinc-containing protein from equine renal cortex. II. Physico-chemical properties. J Biol Chem 236:2435–2442PubMedGoogle Scholar
  38. 38.
    Namdarghanbari MA, Meeusen J, Bachowski G, Giebel N, Johnson J, Petering DH (2010) Reaction of the zinc sensor FluoZin-3 with Zn(7)-metallothionein: inquiry into the existence of a proposed weak binding site. J Inorg Biochem 104:224–231PubMedCrossRefGoogle Scholar
  39. 39.
    Pinter TB, Stillman MJ (2014) The zinc balance: competitive zinc metalation of carbonic Anhydrase and metallothionein 1A. Biochemistry 53:6276–6285PubMedCrossRefGoogle Scholar
  40. 40.
    Karim MR, Petering DH (2017) Detection of Zn2+ release in nitric oxide treated cells and proteome: dependence on fluorescent sensor and proteomic sulfhydryl groups. Metallomics 9:391–401PubMedCrossRefGoogle Scholar
  41. 41.
    Petering DH, Mahim A (2017) Proteomic high affinity Zn2+ trafficking: where does metallothionein fit in? Int J Mol Sci 18 pii:E1289.
  42. 42.
    Kochańczyk T, Drozd A, Kręzel A (2015) Relationship between the architecture of zinc coordination and zinc binding affinity in proteins–insights into zinc regulation. Metallomics 7:244–257PubMedCrossRefGoogle Scholar
  43. 43.
    Pattanaik A, Shaw CF 3rd, Petering DH, Garvey J, Kraker AJ (1994) Basal metallothionein in tumors: widespread presence of apoprotein. J Inorg Biochem 54:91–105PubMedCrossRefGoogle Scholar
  44. 44.
    Yang Y, Maret W, Vallee BL (2001) Differential fluorescence labeling of cysteinyl clusters uncovers high tissue levels of thionein. Proc Natl Acad Sci U S A 98:5556–59CrossRefGoogle Scholar
  45. 45.
    Petering DH, Zhu J, Krezoski S, Meeusen J, Kiekenbush C, Krull S, Specher T, Dughish M (2006) Apo-metallothionein emerging as a major player in the cellular activities of metallothionein. Exp Biol Med (Maywood) 231:1528–1534CrossRefGoogle Scholar
  46. 46.
    Rana U, Kothinti R, Meeusen J, Tabatabai NM, Krezoski S, Petering DH (2008) Zinc binding ligands and cellular zinc trafficking: apo-metallothionein, glutathione, TPEN, proteomic zinc, and Zn-Sp1. J Inorg Biochem 102:489–499PubMedCrossRefGoogle Scholar
  47. 47.
    Li TY, Kraker AJ, Shaw CF 3rd, Petering DH (1980) Ligand substitution reactions of metallothioneins with EDTA and apo-carbonic anhydrase. Proc Natl Acad Sci U S A 77:6334–38CrossRefGoogle Scholar
  48. 48.
    Nielson KB, Winge DR (1983) Order of metal binding in metallothionein. J Biol Chem 258:13063–13069PubMedGoogle Scholar
  49. 49.
    Summers KL, Sutherland DE, Stillman MJ (2013) Single-domain metallothioneins: evidence of the onset of clustered metal binding domains in Zn-rhMT 1a. Biochemistry 52:2461–2471PubMedCrossRefGoogle Scholar
  50. 50.
    Sutherland DE, Summers KL, Stillman MJ (2012) Noncooperative metalation of metallothionein 1a and its isolated domains with zinc. Biochemistry 51:6690–6700PubMedCrossRefGoogle Scholar
  51. 51.
    Ejnik J, Robinson J, Zhu J, Försterling H, Shaw CF, Petering DH (2002) Folding pathway of apo-metallothionein induced by Zn2+, Cd2+ and Co2+. J Inorg Biochem 88:144–152PubMedCrossRefGoogle Scholar
  52. 52.
    Vasak M, Kagi JH (1981) Metal thiolate clusters in cobalt(II)-metallothionein. Proc Natl Acad Sci U S A 78:6709–13CrossRefGoogle Scholar
  53. 53.
    Irvine GW, Stillman MJ (2016) Cadmium binding mechanisms of isolated domains of human MT isoform 1a: Non-cooperative terminal sites and cooperative cluster sites. J Inorg Biochem 158:115–121PubMedCrossRefGoogle Scholar
  54. 54.
    Blumenthal S, Lewand D, Sochanik A, Krezoski S, Petering DH (1994) Inhibition of Na1+-glucose cotransport in kidney cortical cells by cadmium and copper: protection by zinc. Toxicol Appl Pharmacol 29:177–187CrossRefGoogle Scholar
  55. 55.
    Nettesheim DG, Engeseth HR, Otvos JD (1985) Products of metal exchange reactions of metallothionein. Biochemistry 24:6744–6751PubMedCrossRefGoogle Scholar
  56. 56.
    Petering DH, Loftsgaarden J, Schneider J, Fowler B (1984) Metabolism of cadmium, zinc and copper in the rat kidney: the role of metallothionein and other binding sites. Environ Health Perspect 54:73–81PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Otvos JD, Petering DH, Shaw CF (1989) Structure-reactivity relationships of metallothionein, a unique metal binding protein. Comments Inorg Chem 9:1–35CrossRefGoogle Scholar
  58. 58.
    Ejnik J, Shaw CF 3rd, Petering DH (2010) Mechanism of cadmium ion substitution in mammalian zinc metallothionein and metallothionein alpha domain: kinetic and structural studies. Inorg Chem 49:6525–6534PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Namdarghanbari MA, Bertling J, Krezoski S, Petering DH (2014) Toxic metal proteomics: reaction of the mammalian zinc proteome with Cd2+. J Inorg Biochem 136:115–121PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Roesijadi G, Bogumil R, Vasak M, Kagi JH (1998) Modulation of DNA binding of a tramtrack zinc finger peptide by the metallothionein-thionein conjugate pair. J Biol Chem 273:17425–17432PubMedCrossRefGoogle Scholar
  61. 61.
    Ejnik J, Muñoz A, Gan T, Shaw CF 3rd, Petering DH (1999) Interprotein metal ion exchange between cadmium-carbonic anhydrase and apo- or zinc-metallothionein. J Biol Inorg Chem 4:784–790PubMedCrossRefGoogle Scholar
  62. 62.
    Friberg L (1984) Cadmium and the kidney. Environ Health Perspect 54:1–11PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Nowakowski, A, Karim, MR, Petering DH (2015) Zinc proteomics. In: RA Scott (ed) Encyclopedia of inorganic and bioinorganic chemistry. Wiley, Chichester. eibc2332.
  64. 64.
    Li TY, Minkel DT, Shaw CF 3rd, Petering DH (1981) On the reactivity of metallothioneins with 5,5′-dithiobis-(2-nitrobenzoic acid). Biochem J 193:441–446PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Maret W (1994) Oxidative metal release from metallothionein via zinc-thiol/disulfide interchange. Proc Natl Acad Sci U S A 91:237–241CrossRefGoogle Scholar
  66. 66.
    Quesada AR, Byrnes RW, Krezoski SO, Petering DH (1996) Direct reaction of H2O2 with sulfhydryl groups in HL-60 cells: zinc-metallothionein and other sites. Arch Biochem Biophys 334:241–250PubMedCrossRefGoogle Scholar
  67. 67.
    Savas MM, Shaw CF 3rd, Petering DH (1993) The oxidation of rabbit liver metallothionein-II by 5,5′-dithiobis(2-nitrobenzoic acid) and glutathione disulfide. J Inorg Biochem 52:235–249PubMedCrossRefGoogle Scholar
  68. 68.
    Zhu J, Meeusen J, Krezoski S, Petering DH (2010) Reactivity of Zn-, Cd-, and apo-metallothionein with nitric oxide compounds: in vitro and cellular comparison. Chem Res Toxicol 23:422–431PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Gan T, Munoz A, Shaw CF 3rd, Petering DH (1995) Reaction of 111Cd7-metallothionein with EDTA. A reappraisal. J Biol Chem 270:5339–5345PubMedCrossRefGoogle Scholar
  70. 70.
    Laity JH, Andrews GK (2007) Understanding the mechanisms of zinc-sensing by metal-response element binding transcription factor-1 (MTF-1). Arch Biochem Biophys 463:201–210PubMedCrossRefGoogle Scholar
  71. 71.
    Günther V, Lindert U, Schaffner W (2012) The taste of heavy metals: gene regulation by MTF-1. Biochim Biophys Acta 1823:1416–1425PubMedCrossRefGoogle Scholar
  72. 72.
    Berg JM, Godwin HA (1997) Lessons from zinc-binding peptides. Annu Rev Biophys Biomol Struct 26:357–371PubMedCrossRefGoogle Scholar
  73. 73.
    Cox EH, McLendon GL (2000) Zinc-dependent protein folding. Curr Opin Chem Biol 4:162–165PubMedCrossRefGoogle Scholar
  74. 74.
    Dalton TP, Bittel D, Andrews GK (1997) Reversible activation of mouse metal response element-binding transcription factor 1 DNA binding involves zinc interaction with the zinc finger domain. Mol Cell Biol 17:2781–2789PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Guerrerio AL, Berg JM (2004) Metal ion affinities of the zinc finger domains of the metal responsive element-binding transcription factor-1 (MTF1). Biochemistry 43:5437–5444PubMedCrossRefGoogle Scholar
  76. 76.
    Bittel D, Dalton T, Samson SL, Gedamu L, Andrews GK (1998) The DNA binding activity of metal response element-binding transcription factor-1 is activated In vivo and in vitro by zinc, but not by other transition metals. J Biol Chem 273:7127–7133PubMedCrossRefGoogle Scholar
  77. 77.
    Huang M, Krepkiy D, Hu W, Petering DH (2004) Zn-, Cd-, and Pb-transcription factor IIIA: properties, DNA binding, and comparison with TFIIIA-finger 3 metal complexes. J Inorg Biochem 98:775–785PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Krepkiy D, Forsterling FH, Petering DH (2004) Interaction of Cd2+ with Zn finger 3 of transcription factor IIIA: structures and binding to cognate DNA. Chem Res Toxicol 17:863–870PubMedCrossRefGoogle Scholar
  79. 79.
    Namdarghanbari M, Wobig W, Krezoski S, Tabatabai NM, Petering DH (2011) Mammalian metallothionein in toxicology, cancer, and cancer chemotherapy. J Biol Inorg Chem 16:1087–1101PubMedCrossRefGoogle Scholar
  80. 80.
    Berg JM (1988) Proposed structure for the zinc-binding domains from transcription factor IIIA and related proteins. Proc Natl Acad Sci U S A 85:99–102CrossRefGoogle Scholar
  81. 81.
    Lee MS, Gippert GP, Soman KV, Case DA, Wright PE (1989) Three-dimensional solution structure of a single zinc finger DNA-binding domain. Science 245:635–637PubMedCrossRefGoogle Scholar
  82. 82.
    Zhang B, Georgiev O, Hagmann M, Günes C, Cramer M, Faller P, Vasak M, Schaffner W (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
  83. 83.
    Jarup L, Akesson A (2009) Current status of cadmium as an environmental health problem. Toxicol Appl Pharmacol 238:201–208PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Maitani T, Cuppage FE, Klaassen CD (1988) Nephrotoxicity of intravenously injected cadmium-metallothionein: critical concentration and tolerance. Fundam Appl Toxicol 10:98–108PubMedCrossRefGoogle Scholar
  85. 85.
    Dorian C, Gattone VH 2nd, Klaassen CD (1992) Accumulation and degradation of the protein moiety of cadmium-metallothionein (CdMT) in the mouse kidney. Toxicol Appl Pharmaco 117:242–248CrossRefGoogle Scholar
  86. 86.
    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 23:897–926PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Liu J, Habeebu SS, Liu Y, Klaassen CD (1998) Acute CdMT injection is not a good model to study chronic Cd nephropathy: comparison of chronic CdCl2 and CdMT exposure with acute CdMT injection in rats Toxicol. Appl. Pharmacol. 153:48–58CrossRefGoogle Scholar
  88. 88.
    Blumenthal S, Lewand D, Krezoski SK, Petering DH (1996) Comparative effects of Cd2+ and Cd-metallothionein on cultured kidney tubule cells. Toxicol Appl Pharmacol 136:220–228PubMedCrossRefGoogle Scholar
  89. 89.
    Satarug S, Moore MR (2004) Adverse health effects of chronic exposure to low-level cadmium in foodstuffs and cigarette smoke. Environ Health Perspect 112:1099–1103PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Thevenod F (2003) Nephrotoxicity and the proximal tubule. Insights from cadmium. Nephron Physiol 93:87–93CrossRefGoogle Scholar
  91. 91.
    Blumenthal SS, Lewand DL, Buday MA, Kleinman JG, Krezoski SK, Petering DH (1990) Cadmium inhibits glucose uptake in primary cultures of mouse cortical tubule cells. Am J Physiol 258:F1625–F1633PubMedGoogle Scholar
  92. 92.
    Tabatabai NM, Blumenthal SS, Lewand DL, Petering DH (2001) Differential regulation of mouse kidney sodium-dependent transporters mRNA by cadmium. Toxicol Appl Pharmacol 177:163–173PubMedCrossRefGoogle Scholar
  93. 93.
    Tabatabai NM, Blumenthal SS, Petering DH (2005) Adverse effect of cadmium on binding of transcription factor Sp1 to the GC-rich regions of the mouse sodium-glucose cotransporter 1, SGLT1, promoter. Toxicology 207:369–382PubMedCrossRefGoogle Scholar
  94. 94.
    Youn CK, Kim SH, Lee DY, Song SH, Chang IY, Hyun JW, Chung MH, You HJ (2005) Cadmium down-regulates human OGG1 through suppression of Sp1 activity. J Biol Chem 280:25185–25195PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Kothinti RK, Blodgett AB, Petering DH, Tabatabai NM (2010) Cadmium down-regulation of kidney Sp1 binding to mouse SGLT1 and SGLT2 gene promoters: possible reaction of cadmium with the zinc finger domain of Sp1. Toxicol Appl Pharmaco 244:254–262CrossRefGoogle Scholar
  96. 96.
    Kothinti R, Blodgett A, Tabatabai NM, Petering DH (2010) Zinc finger transcription factor Zn3-Sp1 reactions with Cd2+. Chem Res Toxicol 23:405–412PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Anderegg G (1964) Komplexone XXXVI. Reaktionsenthalpie rind -entropie bei der Bildung der Metallkomplexe der hoheren EDTA-Homologen. Helv Chim Acta 50:1801–1815CrossRefGoogle Scholar
  98. 98.
    Kothinti R, Tabatabai NM, Petering DH (2011) Electrophoretic mobility shift assay of zinc finger proteins: competition for Zn(2+) bound to Sp1 in protocols including EDTA. J Inorg Biochem 105:569–576PubMedCrossRefGoogle Scholar
  99. 99.
    Huff J, Lunn RM, Waalkes MP, Tomatis L, Infante PF (2007) Cadmium-induced cancers in animals and in humans. Int J Occup Environ Health 13:202–212PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Miller J, McLachlan AD, Klug A (1985) Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes. EMBO J 4:1609–1614PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Sunderman FW Jr, Barber AM (1988) Finger-loops, oncogenes, and metals. Claude Passmore Brown memorial lecture. Ann Clin Lab Sci 18:267–288PubMedGoogle Scholar
  102. 102.
    Hanas JS, Gunn CG (1996) Inhibition of transcription factor IIIA-DNA interactions by xenobiotic metal ions. Nucleic Acids Res 24:924–930PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Asmuss M, Mullenders LH, Hartwig A (2000) Interference by toxic metal compounds with isolated zinc finger DNA repair proteins. Toxicol Lett 112–113:227–231PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Buchko GW, Hess NJ, Kennedy MA (2000) Cadmium mutagenicity and human nucleotide excision repair protein XPA: CD, EXAFS and (1)H/(15)N-NMR spectroscopic studies on the zinc(II)- and cadmium(II)-associated minimal DNA-binding domain (M98-F219). Carcinogenesis 21:1051–1057PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Hartwig A (2001) Zinc finger proteins as potential targets for toxic metal ions: differential effects on structure and function. Antioxid Redox Signal 3:625–634PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Kopera E, Schwerdtle T, Hartwig A, Bal W (2004) Co(II) and Cd(II) substitute for Zn(II) in the zinc finger derived from the DNA repair protein XPA, demonstrating a variety of potential mechanisms of toxicity. Chem Res Toxicol 17:1452–1458PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Mustra DJ, Warren AJ, Wilcox DE, Hamilton JW (2007) Preferential binding of human XPA to the mitomycin C-DNA interstrand crosslink and modulation by arsenic and cadmium. Chem Biol Interact 168:159–168PubMedCrossRefGoogle Scholar
  108. 108.
    Verhaegh GW, Parat MO, Richard MJ, Hainaut P (1998) Modulation of p53 protein conformation and DNA-binding activity by intracellular chelation of zinc. Mol Carcinog 21:205–214PubMedCrossRefGoogle Scholar
  109. 109.
    Meplan C, Mann K, Hainaut P (1999) Cadmium induces conformational modifications of wild-type p53 and suppresses p53 response to DNA damage in cultured cells. J Biol Chem 274:31663–31670CrossRefGoogle Scholar
  110. 110.
    Wang J, Zhu H, Liu X, Liu Z (2014) Oxidative stress and Ca2+ signals involved on cadmium-induced apoptosis in rat hepatocyte. Biol Trace Elem Res 161:180–189PubMedCrossRefGoogle Scholar
  111. 111.
    Hu KH, Li WX, Sun MY, Zhang SB, Fan CX, Wu Q, Zhu W, Xu X (2015) Cadmium induced apoptosis in MG63 cells by increasing ROS, activation of p38 MAPK and inhibition of ERK 1/2 pathways. Cell Physiol Biochem 36:642–654PubMedCrossRefGoogle Scholar
  112. 112.
    Yuan Y, Jiang CY, Xu H, Sun Y, Hu FF, Bian JC, Liu XZ, Gu JH, Liu ZP (2013) Cadmium-induced apoptosis in primary rat cerebral cortical neurons culture is mediated by a calcium signaling pathway. PLoS ONE 8:e64330PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Wang L, Cao J, Chen D, Liu X, Lu H, Liu Z (2009) Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium. Biol Trace Elem Res 127:53–68PubMedCrossRefGoogle Scholar
  114. 114.
    Thévenod F (2009) Cadmium and cellular signaling cascades: to be or not to be? Toxicol Appl Pharmacol 238:221–239PubMedCrossRefGoogle Scholar
  115. 115.
    Qian C, Colvin RA (2016) Zinc flexes its muscle: correcting a novel analysis of calcium for zinc interference uncovers a method to measure zinc. J Gen Physiol 147:95–102PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Cuypers A, Plusquin M, Remans T, Jozefczak M, Keunen E, Gielen H, Opdenakker K, Nair AR, Munters E, Artois TJ, Nawrot T, Vangronsveld J, Smeets K (2010) Cadmium stress: an oxidative challenge. Biometals 23:927–940PubMedCrossRefGoogle Scholar
  117. 117.
    Walsh MJ, Ahner BA (2013) Determination of stability constants of Cu(I), Cd(II) & Zn(II) complexes with thiols using fluorescent probes. J Inorg Biochem 128:112–123PubMedCrossRefGoogle Scholar
  118. 118.
    Ishikawa T, Bao JJ, Yamane Y, Akimaru K, Frindrich K, Wright CD, Kuo MT (1996) Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem 271:14981–14988PubMedCrossRefGoogle Scholar
  119. 119.
    Wimmer U, Wang Y, Georgiev O, Schaffner W (2005) Two major branches of anti-cadmium defense in the mouse: MTF-1/metallothioneins and glutathione. Nucleic Acids Res 33:5715–5727PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Bradley LB, Jacob M, Jacobs EE, Sanadi DR (1956) Uncoupling of oxidative phosphorylation by cadmium ion. J Biol Chem 223:147–156PubMedGoogle Scholar
  121. 121.
    Mustafa MG, Cross CE (1971) Pulmonary alveolar macrophage. Oxidative metabolism of isolated cells and mitochondria and effect of cadmium ion on electron- and energy-transfer reactions. Biochemistry 10:4176–4185PubMedCrossRefGoogle Scholar
  122. 122.
    Solaiman D, Bratanow N, Dolhun P, Saryan LA, Schwarzbauer J, Wielgus S, Petering DH (1979) Early reactions of cadmium with Ehrlich cells. J Inorg Biochem 10:125–133PubMedCrossRefGoogle Scholar
  123. 123.
    Skulachev VP, Chistyakov VV, Jasaitis AA, Smirnova EG (1967) Inhibition of the respiratory chain by zinc ions. Biochem Biophys Res Commun 26:1–6PubMedCrossRefGoogle Scholar
  124. 124.
    Link TA, von Jagow G (1995) Zinc ions inhibit the QP center of bovine heart mitochondrial bc1 complex by blocking a protonatable group. J Biol Chem 270:25001–25006PubMedCrossRefGoogle Scholar
  125. 125.
    Larabee JL, Hocker JR, Hanas JS (2005) Cys redox reactions and metal binding of a Cys2His2 zinc finger. Arch Biochem Biophys 434:139–149PubMedCrossRefGoogle Scholar
  126. 126.
    Ammendola R, Mesuraca M, Russo T, Cimino F (1994) The DNA-binding efficiency of Sp1 is affected by redox changes. Eur J Biochem 225:483–489PubMedCrossRefGoogle Scholar
  127. 127.
    Kim DH, Kundu JK, Surh YJ (2011) Redox modulation of p53: mechanisms and functional significance. Mol Carcinog 50:222–234PubMedCrossRefGoogle Scholar
  128. 128.
    Hainaut P, Mann K (2001) Zinc binding and redox control of p53 structure and function. Antioxid Redox Signal 3:611–623PubMedCrossRefGoogle Scholar
  129. 129.
    Miyahara T, Katoh T, Watanabe M, Mikami Y, Uchida S, Hosoe M, Sakuma T, Nemoto N, Takayama K, Komurasaki T (2004) Involvement of mitogen-activated protein kinases and protein kinase C in cadmium-induced prostaglandin E2 production in primary mouse osteoblastic cells. Toxicology 200:159–167PubMedCrossRefGoogle Scholar
  130. 130.
    Romare A, Lundholm C (1999) Cadmium-induced calcium release and prostaglandin E2 production in neonatal mouse calvaria are dependent on cox-2 induction and protein kinase C activation. Arch Toxicol 73:223–228CrossRefGoogle Scholar
  131. 131.
    Bagchi D, Bagchi M, Tang L, Stohs SJ (1997) Comparative in vitro and in vivo protein kinase C activation by selected pesticides and transition metal salts. Toxicol Lett 91:31–37PubMedCrossRefGoogle Scholar
  132. 132.
    Long GJ (1997) The effect of cadmium on cytosolic free calcium, protein kinase C, and collagen synthesis in rat osteosarcoma (ROS 17/2.8) cells. Toxicol Appl Pharmacol 143:189–195PubMedCrossRefGoogle Scholar
  133. 133.
    Hommel U, Zurini M, Luyten M (1995) Solution structure of a cysteine rich domain of rat protein kinase C. Nat Struct Bio 1:383–387CrossRefGoogle Scholar
  134. 134.
    Zhang G, Kazanietz MG, Blumberg PM, Hurley JH (1995) Crystal structure of the cys2 activator-binding domain of protein kinase C delta in complex with phorbol ester. Cell 81:917–924PubMedCrossRefGoogle Scholar
  135. 135.
    Newton AC (2001) Protein kinase C: structural and spatial regulation by phosphorylation, cofactors, and macromolecular interactions. Chem Rev 101:2353–2364PubMedCrossRefGoogle Scholar
  136. 136.
    Fukuda H, Irie K, Nakahara A, Ohigashi H, Wender PA (1999) Solid-phase synthesis, mass spectrometric analysis of the zinc-folding, and phorbol ester-binding studies of the 116-mer peptide containing the tandem cysteine-rich C1 domains of protein kinase C gamma. Bioorg Med Chem 7:1213–1221PubMedCrossRefGoogle Scholar
  137. 137.
    Beyersmann D, Block C, Malviya AN (1994) Effects of cadmium on nuclear protein kinase C. Environ Health Perspect 102(Suppl 3):177–180PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Shindo M, Irie K, Fukuda H, Ohigashi H (2003) Analysis of the non-covalent interaction between metal ions and the cysteine-rich domain of protein kinase C eta by electrospray ionization mass spectrometry. Bioorg Med Chem 11:5075–5082PubMedCrossRefGoogle Scholar
  139. 139.
    Gopalakrishna R, Gundimeda U, Schiffman JE, McNeill TH (2008) A direct redox regulation of protein kinase C isoenzymes mediates oxidant-induced neuritogenesis in PC12 cells. J Biol Chem 283:14430–14444PubMedPubMedCentralCrossRefGoogle Scholar
  140. 140.
    Zhao F, Ilbert M, Varadan R, Cremers CM, Hoyos B, Acin-Perez R, Vinogradov V, Cowburn D, Jakob U, Hammerling U (2011) Are zinc-finger domains of protein kinase C dynamic structures that unfold by lipid or redox activation? Antioxid Redox Signal 14:757–766PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Moulis JM (2010) Cellular mechanisms of cadmium toxicity related to the homeostasis of essential metals. Biometals 23:877–896PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Zanello P (2017) Structure and electrochemistry of proteins harboring iron-sulfur clusters of different nuclearities. Part I. [4Fe-4S] + [2Fe-2S] iron-sulfur proteins. J Struct Biol 200:1–19PubMedCrossRefGoogle Scholar
  143. 143.
    Hatori Y, Inouye S, Akagi R (2017) Thiol-based copper handling by the copper chaperone Atox1. IUBMB Life 69:246–254PubMedCrossRefGoogle Scholar
  144. 144.
    Choong G, Liu Y, Templeton DM (2014) Interplay of calcium and cadmium in mediating cadmium toxicity. Chem Biol Interact 211:54–65PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Lippard SJ, Berg JM (1994) Principles of bioinorganic chemistry. University Science Books, Mill Valley, California, pp 184–188Google Scholar
  146. 146.
    Linse S, Helmersson A, Forsen S (1991) Calcium binding to calmodulin and its globular domains. J Biol Chem 266:8050–8054PubMedGoogle Scholar
  147. 147.
    Sussulini A, Becker JS (2011) Combination of PAGE and LA-ICP-MS as an analytical workflow in metallomics: state of the art, new quantification strategies, advantages and limitations. Metallomics 3:1271–1279PubMedCrossRefGoogle Scholar
  148. 148.
    Nowakowski AB, Wobig WJ, Petering DH (2014) Native SDS-PAGE: high resolution electrophoretic separation of proteins with retention of native properties including bound metal ions. Metallomics 6:1068–1078PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of Wisconsin-MilwaukeeMilwaukeeUSA

Personalised recommendations