Encyclopedia of Metalloproteins

2013 Edition
| Editors: Robert H. Kretsinger, Vladimir N. Uversky, Eugene A. Permyakov

Chromium(VI), Oxidative Cell Damage

Reference work entry
DOI: https://doi.org/10.1007/978-1-4614-1533-6_6



Hexavalent chromium (Cr(VI)) is a highly reactive metal capable of causing cellular oxidative damage through the generation of intracellular reactive oxygen species (ROS). ROS refers to a diverse group of reactive, short-lived, oxygen-containing species such as O2•−, H2O2, and OH. Overproduction or decreased removal of ROS leads to oxidative stress in tissues and cells. Cr(VI) can be reduced by various cellular reductants to its lower oxidation states, such as Cr(V) and Cr(VI). During the reduction process, molecular oxygen is reduced to O2•−, which reduces to H2O2 upon dismutation. H2O2 reacts with Cr(V) or Cr(IV) to generate OH radicals. Thus, Cr(VI) is...

This is a preview of subscription content, log in to check access.


  1. Chen F, Ding M, Lu Y, Leonard SS, Vallyathan V, Castranova V, Shi X (2000) Participation of MAP kinase p38 and IkappaB kinase in chromium (VI)-induced NF-kappaB and AP-1 activation. J Environ Pathol Toxicol Oncol 19:231–238PubMedGoogle Scholar
  2. Ding M, Shi X (2002) Molecular mechanisms of Cr(VI)-induced carcinogenesis. Mol Cell Biochem 234–235:293–300CrossRefPubMedGoogle Scholar
  3. Gao N, Jiang BH, Leonard SS, Corum L, Zhang Z, Roberts JR, Antonini J, Zheng JZ, Flynn DC, Castranova V et al (2002) p38 Signaling-mediated hypoxia-inducible factor 1alpha and vascular endothelial growth factor induction by Cr(VI) in DU145 human prostate carcinoma cells. J Biol Chem 277:45041–45048CrossRefPubMedGoogle Scholar
  4. Ji L, Arcinas M, Boxer LM (1994) NF-kappa B sites function as positive regulators of expression of the translocated c-myc allele in Burkitt’s lymphoma. Mol Cell Biol 14:7967–7974PubMedGoogle Scholar
  5. Kortenkamp A, Casadevall M, Da Cruz Fresco P (1996) The reductive conversion of the carcinogen chromium (VI) and its role in the formation of DNA lesions. Ann Clin Lab Sci 26:160–175PubMedGoogle Scholar
  6. Liu K, Husler J, Ye J, Leonard SS, Cutler D, Chen F, Wang S, Zhang Z, Ding M, Wang L et al (2001) On the mechanism of Cr (VI)-induced carcinogenesis: dose dependence of uptake and cellular responses. Mol Cell Biochem 222:221–229CrossRefPubMedGoogle Scholar
  7. Meplan C, Richard MJ, Hainaut P (2000) Redox signalling and transition metals in the control of the p53 pathway. Biochem Pharmacol 59:25–33CrossRefPubMedGoogle Scholar
  8. Munoz C, Pascual-Salcedo D, Castellanos MC, Alfranca A, Aragones J, Vara A, Redondo JM, de Landazuri MO (1996) Pyrrolidine dithiocarbamate inhibits the production of interleukin-6, interleukin-8, and granulocyte-macrophage colony-stimulating factor by human endothelial cells in response to inflammatory mediators: modulation of NF-kappa B and AP-1 transcription factors activity. Blood 88:3482–3490PubMedGoogle Scholar
  9. Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B (1997) A model for p53-induced apoptosis. Nature 389:300–305CrossRefPubMedGoogle Scholar
  10. Qian Y, Jiang BH, Flynn DC, Leonard SS, Wang S, Zhang Z, Ye J, Chen F, Wang L, Shi X (2001) Cr (VI) increases tyrosine phosphorylation through reactive oxygen species-mediated reactions. Mol Cell Biochem 222:199–204CrossRefPubMedGoogle Scholar
  11. Shi XL, Dalal NS (1990) NADPH-dependent flavoenzymes catalyze one electron reduction of metal ions and molecular oxygen and generate hydroxyl radicals. FEBS Lett 276:189–191CrossRefPubMedGoogle Scholar
  12. Shi XL, Dalal NS (1992) The role of superoxide radical in chromium (VI)-generated hydroxyl radical: the Cr(VI) Haber-Weiss cycle. Arch Biochem Biophys 292:323–327CrossRefPubMedGoogle Scholar
  13. Shi X, Dong Z, Dalal NS, Gannett PM (1994a) Chromate-mediated free radical generation from cysteine, penicillamine, hydrogen peroxide, and lipid hydroperoxides. Biochim Biophys Acta 1226:65–72CrossRefPubMedGoogle Scholar
  14. Shi X, Mao Y, Knapton AD, Ding M, Rojanasakul Y, Gannett PM, Dalal N, Liu K (1994b) Reaction of Cr(VI) with ascorbate and hydrogen peroxide generates hydroxyl radicals and causes DNA damage: role of a Cr(IV)-mediated Fenton-like reaction. Carcinogenesis 15:2475–2478CrossRefPubMedGoogle Scholar
  15. Shi X, Leonard SS, Wang S, Ding M (2000) Antioxidant properties of pyrrolidine dithiocarbamate and its protection against Cr(VI)-induced DNA strand breakage. Ann Clin Lab Sci 30:209–216PubMedGoogle Scholar
  16. Singh J, McLean JA, Pritchard DE, Montaser A, Patierno SR (1998) Sensitive quantitation of chromium-DNA adducts by inductively coupled plasma mass spectrometry with a direct injection high-efficiency nebulizer. Toxicol Sci 46:260–265PubMedGoogle Scholar
  17. Son YO, Hitron JA, Wang X, Chang Q, Pan J, Zhang Z, Liu J, Wang S, Lee JC, Shi X (2010) Cr(VI) induces mitochondrial-mediated and caspase-dependent apoptosis through reactive oxygen species-mediated p53 activation in JB6 Cl41 cells. Toxicol Appl Pharmacol 245:226–235CrossRefPubMedGoogle Scholar
  18. Son YO, Hitron JA, Cheng S, Budhraja A, Zhang Z, Shi X (2011) The dual roles of c-Jun NH2-terminal kinase signaling in Cr(VI)-induced apoptosis in JB6 cells. Toxicol Sci 119:335–345CrossRefPubMedGoogle Scholar
  19. Wang S, Shi X (2001) Mechanisms of Cr(VI)-induced p53 activation: the role of phosphorylation, mdm2 and ERK. Carcinogenesis 22:757–762CrossRefPubMedGoogle Scholar
  20. Wang S, Leonard SS, Ye J, Ding M, Shi X (2000) The role of hydroxyl radical as a messenger in Cr(VI)-induced p53 activation. Am J Physiol Cell Physiol 279:C868–C875PubMedGoogle Scholar
  21. Yao H, Guo L, Jiang BH, Luo J, Shi X (2008) Oxidative stress and chromium(VI) carcinogenesis. J Environ Pathol Toxicol Oncol 27:77–88CrossRefPubMedGoogle Scholar
  22. Ye J, Zhang X, Young HA, Mao Y, Shi X (1995) Chromium(VI)-induced nuclear factor-kappa B activation in intact cells via free radical reactions. Carcinogenesis 16:2401–2405CrossRefPubMedGoogle Scholar
  23. Ye J, Wang S, Leonard SS, Sun Y, Butterworth L, Antonini J, Ding M, Rojanasakul Y, Vallyathan V, Castranova V et al (1999) Role of reactive oxygen species and p53 in chromium(VI)-induced apoptosis. J Biol Chem 274:34974–34980CrossRefPubMedGoogle Scholar
  24. Zhang Z, Leonard SS, Wang S, Vallyathan V, Castranova V, Shi X (2001) Cr (VI) induces cell growth arrest through hydrogen peroxide-mediated reactions. Mol Cell Biochem 222:77–83CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Young-Ok Son
    • 1
  • John Andrew Hitron
    • 1
  • Xianglin Shi
    • 1
  1. 1.Graduate Center for ToxicologyUniversity of KentuckyLexingtonUSA