The Mechanisms of Metal Carcinogenicity

Chromium(VI)-induced Genotoxicity: Direct and Indirect Pathways
  • Diane M. Stearns
  • Karen E. Wetterhahn
Part of the NATO ASI Series book series (ASEN2, volume 26)


Metal carcinogens may act through both genotoxic and non-genotoxic pathways. Chromium(VI) (Cr(VI)) is an example of a genotoxic metal carcinogen. People can be exposed to Cr(VI) in the environment, from chromium-contaminated lands, and workers can be exposed in occupations that produce, refine, or use Cr(VI), for example in the manufacture of stainless steel, paints and pigments; and in chrome plating, leather tanning, and wood preserving industries. Toxic effects of acute exposure to Cr(VI) include perforation of the nasal septum, ulcerations of the skin, and contact dermatitis. Exposure of human populations to chronic high levels of Cr(VI) has been correlated with an increased incidence of lung cancer [1].


Electron Paramagnetic Resonance Strand Break Electron Paramagnetic Resonance Signal Electron Paramagnetic Resonance Spectroscopy Strand Breakage 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Langård, S. (1990) One hundred years of chromium and cancer: a review of epidemiological evidence and selected case reports. Am. J. Indust. Med. 17, 189–215.CrossRefGoogle Scholar
  2. 2.
    Standeven, A.M. and Wetterhahn, K.E. (1989) Chromium(VI) toxicity: uptake, reduction and DNA damage. J. Am. Coll. Toxicol. 8, 1275–1282.CrossRefGoogle Scholar
  3. 3.
    De Flora, S., Bagnasco, M., Serra, D., and Zanacchi, P. (1990) Genotoxicity of chromium compounds. A review. Mutat. Res. 238, 99–172.CrossRefGoogle Scholar
  4. 4.
    Connett, P.H. and Wetterhahn, K.E. (1985) In vitro reaction of the carcinogen chromate with cellular thiols and carboxylic acids. J. Am. Chem. Soc. 107, 4282–4288.CrossRefGoogle Scholar
  5. 5.
    Meister, A. and Anderson, M.E. (1983) Glutathione. Ann. Rev. Biochem. 52, 711–760.CrossRefGoogle Scholar
  6. 6.
    Misra, M., Alcedo, J.A., and Wetterhahn, K.E. (1994) Two pathways for chromium(VI)-induced DNA damage in 14 day chick embryos: Cr-DNA binding in liver and 8-oxo-2’-deoxyguanosine in red blood cells. Carcinogenesis 15, 2911–2917.CrossRefGoogle Scholar
  7. 7.
    Levine, M., Conry-Cantilena, C., Wang, Y., Welch, R.W., Washko, P.W., Dhariwal, K.R., Park, J.B., Lazarev, A., Graumlich, J.F., King, J., and Cantilena, L.R. (1996) Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance. Proc. Natl. Acad. Sci. USA 93, 3704–3709.CrossRefGoogle Scholar
  8. 8.
    Toth, I., Rogers, J.T., McPhee, J.A., Elliott, S.M., Abramson, S.L., and Bridges, K.R. (1995) Ascorbic acid enhances iron-induced ferritin translation in human leukemia and hepatoma cells. J. Biol. Chem. 270, 2846–2852.CrossRefGoogle Scholar
  9. 9.
    Standeven, A.M. and Wetterhahn, K.E. (1991) Tissue-specific changes in glutathione and cysteine after buthionine sulfoximine treatment of rats and the potential for artifacts in thiol levels resulting from tissue preparation. Toxicol. Appl. Pharmacol. 107, 269–284.CrossRefGoogle Scholar
  10. 10.
    Ames, B.N., Shigenaga, M.K., and Hagen, T.M. (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc. Natl. Acad. Sci. USA 90, 7915–7922.CrossRefGoogle Scholar
  11. 11.
    Aiyar, J., Berkovits, H.J., Floyd, R.A., and Wetterhahn, K.E. (1991) Reaction of chromium(VI) with glutathione or with hydrogen peroxide: identification of reactive intermediates and their role in chromium(VI)-induced DNA damage. Env. Health Perspect. 92, 53–62.CrossRefGoogle Scholar
  12. 12.
    Kawanishi, S., Inoue, S., and Sano, S. (1986) Mechanism of DNA cleavage induced by sodium chromate(VI) in the presence of hydrogen peroxide. J. Biol. Chem. 261, 5952–5958.Google Scholar
  13. 13.
    Dalai, N.S., Millar, J.M., Jagadeesh, M.S., and Seehra, M.S. (1981) Paramagnetic resonance, magnetic susceptibility, and antiferromagnetic exchange in a Cr5+ paramagnet: potassium perchromate (K3CrO8). J. Chem. Phys. 74, 1916–1923.CrossRefGoogle Scholar
  14. 14.
    Borges, K.M. and Wetterhahn, K.E. (1989) Chromium cross-links glutathione and cysteine to DNA. Carcinogenesis 10, 2165–2168.CrossRefGoogle Scholar
  15. 15.
    Hneihen, A.S., Standeven, A.M., and Wetterhahn, K.E. (1993) Differential binding of chromium(VI) and chromim(III) complexes to salmon sperm nuclei and nuclear DNA and isolated calf thymus DNA. Carcinogenesis 14, 1795–1803.CrossRefGoogle Scholar
  16. 16.
    Aiyar, J., Borges, K.M., Floyd, R.A., and Wetterhahn, K.E. (1989) Role of chromium(V), glutathione thiyl radical and hydroxyl radical intermediates in chromium(VI)-induced DNA damage. Toxicol. Environ. Chem. 22, 135–148.CrossRefGoogle Scholar
  17. 17.
    Borges, K.M., Boswell, J.S., Liebross, R.H., and Wetterhahn, K.E. (1991) Activation of chromium(VI) by thiols results in chromium(V) formation, chromium binding to DNA and altered DNA conformation. Carcinogenesis 12, 551–561.CrossRefGoogle Scholar
  18. 18.
    Kortenkamp, A., Oetken, G., and Beyersmann, D. (1990) The DNA cleavage induced by a chromium(V) complex and by chromate and glutathione is mediated by activated oxygen species. Mutat.Res. 232, 155–161.CrossRefGoogle Scholar
  19. 19.
    Kortenkamp, A., Ozolins, Z., Beyersmann, D., and O’Brien, P. (1989) Generation of PM2 DNA breaks in the course of reduction of chromium(VI) by glutathione. Mutai. Res. 216, 19–26.CrossRefGoogle Scholar
  20. 20.
    Casadevall, M. and Kortenkamp, A. (1994) The generation of apurinic/apyrimidinic sites in isolated DNA during the reduction of chromate by glutathione. Carcinogenesis 15, 407–409.CrossRefGoogle Scholar
  21. 21.
    Casadevall, M. and Kortenkamp, A. (1995) The formation of both apurinic/apyrimidinic sites and single-strand breaks by chromate and glutathione arises from attack by the same reactive species and is dependent on molecular oxygen. Carcinogenesis 16, 805–809.CrossRefGoogle Scholar
  22. 22.
    Kitagawa, S., Seki, H., Kametani, F., and Sakurai, H. (1988) EPR study on the interaction of hexavalent chromium with glutathione or cysteine: production of pentavalent chromiium and its stability. Inorg. Chim. Acta 152, 251–255.CrossRefGoogle Scholar
  23. 23.
    Sevilla, M.D., Becker, D., Swarts, S., and Herrington, J. (1987) Sulfinyl radical formation from the reaction of cysteine and glutathione thiyl radicals with molecular oxygen. Biochem. Biophys. Res. Commun. 144, 1037–1042.CrossRefGoogle Scholar
  24. 24.
    Sevilla, M.D., Becker, D., and Yan, M. (1990) The formation and structure of the sulfoxyl radicals RSO, RSOO, RSO2 and RSO2OO from the reaction of cysteine, glutathione and penicillamine thiyl radicals with molecular oxygen. Int. J. Radiat. Biol. 57, 65–81.CrossRefGoogle Scholar
  25. 25.
    Bose, R.N., Moghaddas, S., and Gelerinter, E. (1992) Long-lived chromium(IV) and chromium(V) metabolites in the chromium(VI)-glutathione reaction: NMR, ESR, HPLC and kinetic characterization. Inorg. Chem. 31, 1987–1994.CrossRefGoogle Scholar
  26. 26.
    Zhitkovich, A., Voitkun, V., and Costa, M. (1995) Glutathione and free amino acids form stable complexes with DNA following exposure of intact mammalian cells to chromate. Carcinogenesis 16, 907–913.CrossRefGoogle Scholar
  27. 27.
    Sugiyama, M. and Tsuzuki, K. (1994) Effect of glutathione depletion on formation of paramagnetic chromium in Chinese hamster V-79 cells. FEBS Lett. 341, 273–276.CrossRefGoogle Scholar
  28. 28.
    Cupo, D.Y. and Wetterhahn, K.E. (1985) Modification of chromium(VI)-induced DNA damage by glutathione and cytochromes P-450 in chicken embryo hepatocytes. Proc. Natl. Acad. Sci. USA 82, 6755–6759.CrossRefGoogle Scholar
  29. 29.
    Sugiyama, M., Ando, A., Furuno, A., Furlong, N.B., Hidaka, T., and Ogura, R. (1987) Effects of vitamin E, vitamin B2 and selenite on DNA single strand breaks induced by sodium chromate(VI). Cancer Lett. 38, 1–7.CrossRefGoogle Scholar
  30. 30.
    Stearns, D.M., Kennedy, L.J., Courtney, K.D., Giangrande, P.H., Phieffer, L.S., and Wetterhahn, K.E. (1995) Reduction of chromium(VI) by ascorbate leads to chromium-DNA binding and DNA stand breaks in vitro. Biochemistry 34, 910–919.CrossRefGoogle Scholar
  31. 31.
    Bridgewater, L.C., Manning, F.C.R., and Patierno, S.R. (1994) Base-specific arrest of in vitro DNA replication by carcinogenic chromium: relationship to DNA interstrand crosslinking. Carcinogenesis 15, 2421–2427.CrossRefGoogle Scholar
  32. 32.
    da Cruz Fresco, P. and Kortenkamp, A. (1994) The formation of DNA cleaving species during the reduction of chromate by ascorbate. Carcinogenesis 15, 1773–1778.CrossRefGoogle Scholar
  33. 33.
    da Cruz Fresco, P., Shacker, F., and Kortenkamp, A. (1995) The reductive conversion of chromium(VI) by ascorbate gives rise to apurinic/apyrimidinic sites in isolated DNA. Chem. Res. Toxicol. 8, 884–890.CrossRefGoogle Scholar
  34. 34.
    Stearns, D.M. and Wetterhahn, K.E. (1994) Reaction of chromium(VI) with ascorbate produces chromium(V), chromium(IV), and carbon-based radicals. Chem. Res. Toxicol. 7, 219–230.CrossRefGoogle Scholar
  35. 35.
    Lefebvre, Y. and Pézerat, H. (1992) Production of activated species of oxygen during the chromate(VI)-ascorbate reaction: implication in carcinogenesis. Chem. Res. Toxicol. 5, 461–463.CrossRefGoogle Scholar
  36. 36.
    Sugiyama, M., Tsuzuki, K., and Ogura, R. (1991) Effect of ascorbic acid on DNA damage, cytotoxicity, glutathione reductase, and formation of paramagnetic chromium in Chinese hamster V-79 cells treated with sodium chromate(VI). J. Biol. Chem. 266, 3383–3386.Google Scholar
  37. 37.
    Wise, J.P., Orenstein, J.M., and Patierno, S.R. (1993) Inhibition of lead chromate clastogenesis by ascorbate: relationship to particle dissolution and uptake. Carcinogenesis 14, 429–434.CrossRefGoogle Scholar
  38. 38.
    Hamilton, J.W. and Wetterhahn, K.E. (1986) Chromium(VI)-induced DNA damage in chick embryo liver and blood cells in vivo. Carcinogenesis 7, 2085–2088.CrossRefGoogle Scholar
  39. 39.
    Hamilton, J.W. and Wetterhahn, K.E. (1989) Differential effects of chromium(VI) on constitutive and inducible gene expression in chick embryo liver in vivo and correlation with chromium(VI)-induced DNA damage. Mol. Carcinogen. 2, 274–286.CrossRefGoogle Scholar
  40. 40.
    Liebross, R.H. and Wetterhahn, K.E. (1992) In vivo formation of chromium(V) in chick embryo liver and red blood cells. Carcinogenesis 13: 2113–2120.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 1997

Authors and Affiliations

  • Diane M. Stearns
    • 1
  • Karen E. Wetterhahn
    • 1
  1. 1.Department of ChemistryDartmouth CollegeHanoverUSA

Personalised recommendations