Skip to main content
SpringerLink
Log in

The Mechanisms of Metal Carcinogenicity

Chromium(VI)-induced Genotoxicity: Direct and Indirect Pathways

  • Chapter
Cytotoxic, Mutagenic and Carcinogenic Potential of Heavy Metals Related to Human Environment

Part of the book series: NATO ASI Series ((ASEN2,volume 26))

Abstract

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].

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 54.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  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.

    Article  Google Scholar 

  2. Standeven, A.M. and Wetterhahn, K.E. (1989) Chromium(VI) toxicity: uptake, reduction and DNA damage. J. Am. Coll. Toxicol. 8, 1275–1282.

    Article  Google Scholar 

  3. De Flora, S., Bagnasco, M., Serra, D., and Zanacchi, P. (1990) Genotoxicity of chromium compounds. A review. Mutat. Res. 238, 99–172.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  5. Meister, A. and Anderson, M.E. (1983) Glutathione. Ann. Rev. Biochem. 52, 711–760.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  Google Scholar 

  14. Borges, K.M. and Wetterhahn, K.E. (1989) Chromium cross-links glutathione and cysteine to DNA. Carcinogenesis 10, 2165–2168.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, Dartmouth College, 6128 Burke Laboratory, Hanover, NH, 03755-3564, USA

    Diane M. Stearns & Karen E. Wetterhahn

Authors
  1. Diane M. Stearns
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Karen E. Wetterhahn
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Laboratory of Inorganic and General Chemistry, Department of Chemistry, University of Ioannina, Ioannina, Greece

    Nick D. Hadjiliadis

Rights and permissions

Reprints and permissions

Copyright information

© 1997 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Stearns, D.M., Wetterhahn, K.E. (1997). The Mechanisms of Metal Carcinogenicity. In: Hadjiliadis, N.D. (eds) Cytotoxic, Mutagenic and Carcinogenic Potential of Heavy Metals Related to Human Environment. NATO ASI Series, vol 26. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-5780-3_4

Download citation

  • DOI: https://doi.org/10.1007/978-94-011-5780-3_4

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-010-6440-8

  • Online ISBN: 978-94-011-5780-3

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation