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Molecular mechanisms of Cr(VI)-induced carcinogenesis

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Abstract

Although Cr(VI)-containing compounds are well documented carcinogens, their mechanism of action is still not well understood. Recent studies have suggested that reduction of Cr(VI) to its lower oxidation states and related free radical reactions play an important role in Cr(VI)-induced carcinogenesis. This article summarizes recent studies from our laboratory on (a) the reduction of Cr(VI) by ascorbate, diol- and thiol-containing molecules, certain flavoenzymes, cell organelles, intact cells, and whole animals; (b) free radical production in both non-cellular and cellular systems; and (c) Cr(VI)-induced DNA damage, activation of nuclear transcription factor κB (NF-κB), activator protein-1, p53, hypoxia-inducible factor-1, vascular endothelial growth factor, tyrosine phosphorylation, apoptosis, cell growth arrest, and gene expression profile.

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References

  1. Cohen MD, Kargacin B, Klein CB, Costa M: Mechanism of chromium carcinogenicity and toxicity. Crit Rev Toxicol 23: 255–281, 1993

    PubMed  Google Scholar 

  2. Costa M: Toxicity and carcinogenicity of Cr(VI) in animal models and humans. Crit Rev Toxicol 27: 431–442, 1997

    PubMed  Google Scholar 

  3. IARC: Chromium and chromium compounds: Chromium metal (group 3) trivalent compounds (group) hexavalent chromium compounds (group 1). IARC Monogr Eval Carcinogen Risk Chem Hum 7(suppl): 165–168, 1987

    Google Scholar 

  4. IARC: Chromium, nickel and welding. IARC Monogr Eval Carcinogen Risk Chem Hum 49: 55–62, 1990

    Google Scholar 

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

    PubMed  Google Scholar 

  6. De Flora S, Wetterhahn KE: Mechanisms of chromium metabolism and genotoxicity. Life Chem Rep 7: 169–244, 1989

    Google Scholar 

  7. Sugiyama M: Role of physiological antioxidants in chromium(VI)-induced cellular injury. Free Radic Biol Med 12: 397–407, 1992

    Article  PubMed  Google Scholar 

  8. Luo H, Lu YD, Shi X, Mao Y, Dalal NS: Chromium(IV)/H2O2 Fentonlike reaction causes DNA damage: Implication to chromate's genotoxicity. Ann Clin Lab Sci 26: 185–191, 1996

    PubMed  Google Scholar 

  9. Shi X, Sun X, Gannett PM, Dalal NS: Deferoxamine inhibition of Cr(V)-mediated radical generation and deoxyguanine hydroxylation: ESR and HPLC evidence. Arch Biochem Biophys 293: 281–286, 1992

    PubMed  Google Scholar 

  10. Shi X, Mao Y, Knapton AD, Ding M, Rojanasakul Y, Gannett PM, Dalal NS, Liu K: Reaction of Cr(VI) with ascorbate and hydrogen peroxide generates hydroxyl radicals and causes DNA damage: Role of Cr(IV)-mediated Fenton-like reaction. Carcinogenesis 15: 2475–2478, 1994

    PubMed  Google Scholar 

  11. Standeven AM, Wetterhahn KE: Possible role of glutathione in chromium( VI) metabolism and toxicity in rats. Pharmacol Toxicol 68: 469–476, 1991

    PubMed  Google Scholar 

  12. Connett PH, Wetterhahn KE: Metabolism of the carcinogenic chromate by cellular constituents. Struct Bond 54: 93–124, 1983

    Google Scholar 

  13. Kortenkamp A, Beyersmann D, O'Brien P: Uptake of chromium(III) complexes by erythrocytes. Toxicol Environ Chem 14: 23–29, 1987

    Google Scholar 

  14. Tsapakos MJ, Wetterhahn KE: Interaction of chromium with nucleic acids Chem Biol Interact 46: 265–277, 1983

    PubMed  Google Scholar 

  15. Jennett KW: Microsomal reduction of the carcinogen chromate produces chromium(V). J Am Chem Soc 104: 874–875, 1982

    Google Scholar 

  16. Kortenkamp A, Ozolins Z, Beyersmann D, O'Brien P: Generation of PM2 DNA breaks in the course of reduction of chromium(VI) by glutathione. Mutat Res 216: 19–26, 1989

    PubMed  Google Scholar 

  17. Rodney PF, Robert JJ, Lay PA, Dixon NE, Raker RSU, Bonin AM: Chromium(V)-induced cleavage of DNA: Are chromium(V) complexes the active carcinogens in chromium(VI)-induced cancer? Chem Res Toxicol 2: 227–229, 1989

    PubMed  Google Scholar 

  18. Shi X, Chiu A, Chen CT, Halliwell B, Castranova V, Vallyathan VJ: Reduction of chromium(VI) and its relationship to carcinogenesis. Toxicol Environ Health 2: 101–118, 1998

    Google Scholar 

  19. Shi X, Dalal NS: On the mechanism of the chromate reduction by glutathione: ESR evidence for the glutathionyl radical and an isolable Cr(V) intermediate. Biochem Biophys Res Commun 156:137–142, 1988

    Article  PubMed  Google Scholar 

  20. Dalal NS, Shi X: ESR evidence for the glutathionyl radical in the reduction of chromium(VI) by glutathione. In: Medical, Biomedical and Chemical Aspects of Free Radicals. Elsevier Science Publishers, Amsterdam, 1989, pp 547–550

    Google Scholar 

  21. Shi X, Dong Z, Dalal NS, Gannett P: Chromate-mediated free radical generation from cysteine, penicillamine, hydrogen peroxide, and lipid hydroperoxides. Biophys Acta 1226: 65–72, 1994

    Google Scholar 

  22. Chen F, Ye J, Zhang X, Rojanasakul Y, Shi X: One-electron reduction of chromium(VI) by alpha-lipoic acid and related hydroxyl radical generation, dG hydroxylation and nuclear transcription factor-κB activation. Arch Biochem Biophys 338: 165–172, 1997

    PubMed  Google Scholar 

  23. Shi X, Dalal NS: ESR spin trapping detection of hydroxyl radicals in the reaction of Cr(V) complexes with hydrogen peroxide. Free Radic Res Commun 10: 17–26, 1990

    PubMed  Google Scholar 

  24. Shi X, Dalal NS: On the hydroxyl radical formation in the reaction between hydrogen peroxide and biologically generated chromium(V) species. Arch Biochem Biophys 277: 342–350, 1990

    Article  PubMed  Google Scholar 

  25. Liu KJ, Shi X, Dalal NS: Synthesis of Cr(VI)-GSH, its identification and its free hydroxyl generation: A model compound for Cr(VI) carcinogenicity. Biochem Biophys Res Commun 235: 54–58, 1997

    PubMed  Google Scholar 

  26. Suzuki Y, Fukuda K: Reduction of hexavalent chromium by ascorbic acid and glutathione with special reference to the rat lung. Arch Toxicol 64: 169–176, 1994

    Google Scholar 

  27. Shi X, Dalal NS, Vallyathan V: One electron reduction of carcinogen chromate by microsomes, mitochondria and E. coli: Identification of Cr(V) and ·OH radical. Arch Biochem Biophys 290: 381–386, 1991

    PubMed  Google Scholar 

  28. Shi X, Dalal NS: Chromium(V) and hydroxyl radical formation during the glutathione reductase-catalyzed reduction of chromium(VI). Biochem Biophys Res Commun 163: 627–634, 1989

    PubMed  Google Scholar 

  29. Shi X, Dalal NS: NADPH dependent flavoenzymes catalyze one electron reduction of metal ions and molecular oxygen and generate hydroxyl radical. FEBS Lett 276: 189–191, 1990

    Article  PubMed  Google Scholar 

  30. Shi X, Dalal NS: Free radical generation by mineral ions adsorbed on mineral dust: A mechanism for chronic lung injury. Respirable dust in the mineral industries. Society for Mining, Metallurgy and Exploration, Inc., Littleton, Colorado, 38: 307–311, 1991

    Google Scholar 

  31. Liu K, Jiang J, Swartz HM, Shi X: Low frequency EPR detection of chromium(V) formation by chromium(VI) reduction in whole live mice. Arch Biochem Biophys 313: 248–255, 1995

    Google Scholar 

  32. Liu KJ, Shi X, Jiang JJ, Goda F, Dalal NS, Swartz HM: Chromateinduced chromium(V) formation in live mice and its control by cellular antioxidants: An L-band EPR study. Arch Biochem Biophys 323: 33–39, 1995

    PubMed  Google Scholar 

  33. Liu KJ, Shi X, Jian JJ, Doda F, Dalal NS, Swartz HM: Low frequency electron paramagnetic resonance investigation on metabolism of chromium( VI) by whole mice. Annu Clin Lab Sci 26:176–184, 1996

    Google Scholar 

  34. Barton JP, Packer JE: Radiolysis of oxygenated cysteine solutions at neutral pH. The role of RSSR and O2-. Int J Rad Phys Chem 23: 159–166, 1970

    Google Scholar 

  35. Quintiliani M, Badiello R, Tamba M, Esfendi A, Gorin G: Radiolysis of glutathione in oxygen-containing solutions of pH 7. Int J Rad Phys Chem 32: 159–166, 1997

    Google Scholar 

  36. Shi X, Dalal NS: Evidence for a fenton-type mechanism for the generation of ·OH radicals in the reduction of Cr(VI) in cellular media. Arch Biochem Biophys 281: 90–95, 1990

    PubMed  Google Scholar 

  37. Shi X, Dalal NS: On the mechanism of generation of hydroxyl radical by chromate in biologically relevant systems: Role of Cr(V) complexes vs. tetraperoxochromate(V). Environ Health Perspect 102: 231–236, 1994

    PubMed  Google Scholar 

  38. Shi X, Dalal NS, Kasprzak KS: Generation of free radicals from hydrogen peroxide and lipid hydroperoxides in the presence of Cr(III). Arch Biochem Biophys 302: 294–299, 1993

    Article  PubMed  Google Scholar 

  39. Shi X, Dalal NS: The role of superoxide radical in chromium(VI) generated hydroxyl radical: The Cr(VI) Haber-Weiss cycle. Arch Biochem Biophys 292: 323–327, 1992

    PubMed  Google Scholar 

  40. Shi X, Leonard S, Zang L, Gannett P, Rojanasakul Y, Castranova V, Vallyathan V: Cr(III)-mediated hydroxyl radical generation via Haber-Weiss cycle. J Inorg Biochem 69: 263–268, 1998

    Google Scholar 

  41. Freeman BA, Crapo JD: Biology and disease: Free radicals and tissue injury. Lab Invest 47: 412–426, 1982

    PubMed  Google Scholar 

  42. Weinstein J, Bielski BHJ: Kinetics of the interaction of H2O2 and O2 - radicals with hydrogen peroxide. J Am Chem Soc 101: 58–62, 1979

    Google Scholar 

  43. Ye J, Wang S, Leonard SS, Sun Y, Butterworth L, Antonini J, Ding M, Rojanasakul R, Vallyathan V, Castranova V, Shi X: Role of reactive oxygen species and p53 in chromium(VI)-induced apoptosis. J Biol Chem 274: 34974–34980, 1999

    Article  PubMed  Google Scholar 

  44. Wang S, Leonard SS, Ye J, Ding M, Shi X: The role of hydroxyl radical as a messenger in Cr(VI)-induced p53 activation. Am J Physiol C868–C875, 2000

  45. Dizadaroglu M: Chemical determination of free radical-induced damage to DNA. Free Radic Biol Med 10: 225–242, 1991

    Article  PubMed  Google Scholar 

  46. Liu K, Husler J, Ye J, Leonard SS, Cutler D, Chen F, Wang S, Zhang Z, Ding M, Wang L, Shi X: On the mechanism of Cr(VI)-induced carcinogenesis: Dose dependence of cellular responses. Mol Cell Biochem 222: 221–229, 2001

    PubMed  Google Scholar 

  47. Chen F, Castranova, V, Shi X, Demers LM: New insights into the role of NF-κB, a ubiquitous transcription factor in initiation of diseases. Clin Chem 45: 7–17, 1999

    PubMed  Google Scholar 

  48. Baldwin AS: The NF-κB and IκB proteins: New discoveries and insights. Annu Rev Immunol 14: 649–681, 1996

    Article  PubMed  Google Scholar 

  49. Baeuerle PA, Henkel T: Function and activation of NF-κB in the immune system. Annu Rev Immunol 12: 141–179, 1994

    PubMed  Google Scholar 

  50. Ye J, Zhang X, Young HA, Mao Y, Shi X: Chromium(VI)-induced nuclear factor-κB activation in intact cells via free radical reactions. Carcinogenesis 16: 2401–2405, 1995

    PubMed  Google Scholar 

  51. Ji L, Arcinas M, Boxer LM: NF-κB sites function as positive regulators of expression of the translocated c-myc allelle in Burkitt's lymphoma. Mol Cell Biol 14: 141–179, 1994

    Google Scholar 

  52. Chen F, Ding F, Lu Y, Leonard SS, Vallyathan V, Castranova V, Shi X: Participation of MAP kinase p38 and IκB kinase in chromium(VI)-induced NF-κB and AP-1 activation. J Environ Pathol Toxicol Oncol 19: 231–238, 2000

    PubMed  Google Scholar 

  53. Wang S, Shi X: Mechanism of Cr(VI)-induced p53 activation: The role of phosphorylation, mdm2 and ERK. Carcinogenesis 22: 757–762, 2001

    PubMed  Google Scholar 

  54. Gao N, Jiang B, Leonard SS, Corum L, Zhang Z, Roberts JR, Antonini J, Zheng JZ, Flynn DC, Shi X: Induction of hypoxia-inducible factor 1 and vascular endothelial growth factor by Cr(VI) through reactive oxygen species in DU145 human prostate carcinoma cells (manuscript in preparation).

  55. Qian Y, Jiang B, Leonard SS, Wang S, Zhang Z, Ye J, Chen F, Wang L, Flynn DC, Shi X: Cr(VI) increases tyrosine phosphorylation through reactive oxygen species-mediated reactions. Mol Cell Biochem 222: 199–204, 2001

    PubMed  Google Scholar 

  56. Zhang Z, Leonard SS, Wang S, Vallyathan V, Castranova V, Shi X: Cr(VI) induces cell growth arrest through hydrogen peroxide-mediated reactions. Mol Cell Biochem 222: 77–83, 2001

    Article  PubMed  Google Scholar 

  57. Ye J, Shi X: Gene expression profile in response to chromium-induced cell stress in A549 cells. Mol Cell Biochem 222: 189–197, 2001

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, WV, 26505, USA

    Min Ding & Xianglin Shi

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  1. Min Ding
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  2. Xianglin Shi
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Ding, M., Shi, X. Molecular mechanisms of Cr(VI)-induced carcinogenesis. Mol Cell Biochem 234, 293–300 (2002). https://doi.org/10.1023/A:1015975218920

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