Skip to main content
SpringerLink
Log in

Does mercury promote lipid peroxidation?

An in vitro study concerning mercury, copper, and iron in peroxidation of low-density lipoprotein

  • Original Articles
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

In order to explore the observed association among mercury, atherosclerosis, and coronary heart disease, the effects of mercury, copper, and iron on the peroxidation of low-density lipoprotein (LDL) and on the enzymatic activities of glutathione peroxidase and myeloperoxidase were investigated in vitro. On the basis of our nuclear magnetic resonance (NMR) experiments, we conclude that mercury does not promote the direct nonenzymatic peroxidation of LDL, like copper and iron. In our enzyme measurements, mercury inhibited slightly myeloperoxidase, although not significantly in presence of LDL. Instead, inorganic mercury, but not methylmercury chloride, inhibited glutathione peroxidase effectively and copper event at 10 μmol/L, below physiological concentrations, doubled the inhibition rate. Copper and iron had no direct effect on glutathione peroxidase, but they both seem to activate production of HOCl by myeloperoxidase. We conclude here that, first, mercury and methylmercury do not promote direct lipid peroxidation, but that, second, a simultaneous exposure to high inorganic mercury, copper, and iron and low selenium concentrations can lead to a condition in which mercury promotes lipid peroxidations. This mechanism provides a plausible molecular-level explanation for the observed association between high body mercury content and atherosclerosis.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. I. Pinchuk and D. Lichtenberg, The mechanism of action of antioxidants against lipoprotein peroxidation, evaluation based on kinetic experiments, Prog. Lipid Res. 41, 279–314 (2002).

    Article  PubMed  CAS  Google Scholar 

  2. H. Kuhn and L. Chan, The role of 15-lipoxygenase in atherogenesis: pro- and antiatherogenic actions, Curr. Opin. Lipidol. 8, 111–117 (1997).

    Article  PubMed  CAS  Google Scholar 

  3. A. Lass, J. Belkner, H. Esterbauer, and H. Kuhn, Lipoxygenase treatment renders low density lipoprotein susceptible to Cu2+-catalysed oxidation, Biochem. J. 314, 577–585 (1996).

    PubMed  CAS  Google Scholar 

  4. V. J. O’Leary, V. M. Darley-Usmar, L. J. Russell, and D. Stone, Pro-oxidant effects of lipoxygenase-derived peroxides on the copper-initiated oxidation of low density lipoprotein, Biochem. J. 282, 631–634 (1992).

    PubMed  CAS  Google Scholar 

  5. G. A. Francis, High density lipoprotein oxidation: in vitro susceptibility and potential in vivo consequences, BBA-Mol. Cell Biol. Lipids 1483, 217–235 (2000).

    CAS  Google Scholar 

  6. P. Libby, Inflammation in atherosclerosis, Nature 420, 868–874 (2002).

    Article  PubMed  CAS  Google Scholar 

  7. H. Esterbauer, J. Gebicki, H. Puhl, and G. Jurgens, The role of lipid peroxidation and antioxidants in oxidative modification of LDL, Free Radical Biol. Med. 13, 341–390 (1992).

    Article  CAS  Google Scholar 

  8. Y. Yoshida, J. Tsuchiya, and E. Niki, Interaction of alpha-tocopherol with copper and its effect on lipid peroxidation, Biochim. Biophys. Acta-Gen. Subjects 1200, 85–92 (1994).

    CAS  Google Scholar 

  9. A. Kontush, S. Meyer, B. Finckh, A. Kohlschutter, and U. Beisiegel, Alpha-tocopherol a reductant for Cu(II) in human lipoproteins: triggering role in the initiation of lipoprotein oxidation, J. Biol. Chem. 271, 11,106–11,112 (1996).

    CAS  Google Scholar 

  10. O. Ziouzenkova, A. Sevanian, P. M. Abuja, P. Ramos, and H. Esterbauer, Copper can promote oxidation of LDL by markedly different mechanisms, Free Radical Biol. Med. 24, 607–623 (1998).

    Article  CAS  Google Scholar 

  11. J. T. Salonen, K. Seppänen, K. Nyyssönen, et al., Intake of mercury from fish, lipid peroxidation, and the risk of myocardial infarction and coronary, cardiovascular, and any death in Eastern Finnish men, Circulation 91, 645–655 (1995).

    PubMed  CAS  Google Scholar 

  12. E. Guallar, M. I. Sanz-Gallardo, P. Van’t Veer, et al., Mercury, fish oils, and myocardial infarction, N. Engl. J. Med. 347, 1747–1754 (2002).

    Article  PubMed  CAS  Google Scholar 

  13. J. T. Salonen, K. Seppänen, T. A. Lakka, R. Salonen, and G. A. Kaplan, Mercury accumulation and accelerated progression of carotid atherosclerosis: a population-based prospective 4-year follow-up study in men in Eastern Finland, Atherosclerosis 148, 265–273 (2000).

    Article  PubMed  CAS  Google Scholar 

  14. Y. L. Huang, S. L. Cheng, and T. H. Lin, Lipid peroxidation in rats administrated with mercuric chloride, Biol. Trace Element Res. 52, 193–206 (1996).

    CAS  Google Scholar 

  15. T. H. Lin, Y. L. Huang, and S. F. Huang, Lipid peroxidation in liver of rats administrated with methyl mercuric chloride, Biol. Trace Element Res. 54, 33–41 (1996).

    CAS  Google Scholar 

  16. K. Takahashi, N. Avissar, J. Whitin, and H. Cohen, Purification and characterization of human plasma glutathione peroxidase: a selenoglycoprotein distinct from the known cellular enzyme, Arch. Biochem. Biophys. 256, 677–686 (1987).

    Article  PubMed  CAS  Google Scholar 

  17. J. Gailer, G. N. George, I. J. Pickering, et al., Structural basis of the antagonism between inorganic mercury and selenium in mammals, Chem. Res. Toxicol. 13, 1135–1142 (2000).

    Article  PubMed  CAS  Google Scholar 

  18. H. J. Raderecht, Molecular biology in the interpretation of metabolic toxic mechanisms and possibilities for estimating the potential toxicity of metals, illustrated by the example of mercury and iron, Clin. Lab. 44, 33–50 (1998).

    CAS  Google Scholar 

  19. S. J. Klebanoff, Myeloperoxidase, Proc. Assoc. Am. Physician 111, 383–389 (1999).

    CAS  Google Scholar 

  20. R. Laatikainen, M. Niemitz, W. J. Malaisse, M. Biesemans, and R. Willem, A computational strategy for the deconvolution of NMR spectra with multiplet structures and constraints: analysis of overlapping C-13-H-2 multiplets of C-13 enriched metabolites from cell suspensions incubated in deuterated media, Magn. Reson. Med. 36, 359–365 (1996).

    Article  PubMed  CAS  Google Scholar 

  21. S. Blankenberg, H. J. Rupprecht, C. Bickel, et al., Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease, N. Engl. J. Med. 349, 1605–1613 (2003).

    Article  PubMed  CAS  Google Scholar 

  22. M. L. Brennan, M. S. Penn, F. Van Lente, et al., Prognostic value of myeloperoxidase in patients with chest pain, N. Engl. J. Med. 349, 1595–1604 (2003).

    Article  PubMed  CAS  Google Scholar 

  23. S. Baldus, C. Heeschen, T. Meinertz, et al., Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes, Circulation 108, 1440–1445 (2003).

    Article  PubMed  CAS  Google Scholar 

  24. G. V. Iyengar, Reevaluation of the trace element content in reference man, Radiat. Phys. Chem. 51, 545–560 (1998).

    Article  CAS  Google Scholar 

  25. D. Metodiewa and H. B. Dunford, The reactions of horseradish peroxidase, lactoperoxidase, and myeloperoxidase with enzymatically generated superoxide, Arch. Biochem. Biophys. 272, 245–253 (1989).

    Article  PubMed  CAS  Google Scholar 

  26. Y. Z. Fang, S. Yang, and G. Wu, Free radicals, antioxidants, and nutrition, Nutrition 18, 872–879 (2002).

    Article  PubMed  CAS  Google Scholar 

  27. A. G. Splittgerber and A. L. Tappel, Inhibition of glutathione peroxidase by cadmium and other metal ions, Arch. Biochem. Biophys. 197, 534–542 (1979).

    Article  PubMed  CAS  Google Scholar 

  28. E. M. Bem, K. Mailer, and C. M. Elson, Influence of mercury(II), cadmium(II), methylmercury, and phenylmercury on the kinetic properties of rat liver glutathione peroxidase, Can. J. Biochem. Cell Biol. 63, 1212–1216 (1985).

    Article  PubMed  CAS  Google Scholar 

  29. Y. Hirota, Effect of methylmercury on the activity of glutathione peroxidase in rat liver, Am. Ind. Hyg. Assoc. J. 47, 556–558 (1986).

    PubMed  CAS  Google Scholar 

  30. J. A. Berliner and J. W. Heinecke, The role of oxidized lipoproteins in atherogenesis, Free Radical Biol. Med. 20, 707–727 (1996).

    Article  CAS  Google Scholar 

  31. J. W. Heinecke, W. Li, G. A. Francis, and J. A. Goldstein, Tyrosyl radical generated by myeloperoxidase catalyzes the oxidative cross-linking of proteins, J. Clin. Invest. 91, 2866–2872 (1993).

    Article  PubMed  CAS  Google Scholar 

  32. J. W. Heinecke, W. Li, H. L. Daehnke, and J. A. Goldstein, Dityrosine, a specific marker of oxidation, is synthesized by the myeloperoxidase-hydrogen peroxide system of human neutrophils and macrophages, J. Biol. Chem. 268, 4069–4077 (1993).

    PubMed  CAS  Google Scholar 

  33. M. I. Savenkova, D. M. Mueller, and J. W. Heinecke, Tyrosyl radical generated by myeloperoxidase is a physiological catalyst for the initiation of lipid peroxidation in low density lipoprotein, J. Biol. Chem. 269, 20,394–20,400 (1994).

    CAS  Google Scholar 

  34. A. Jerlich, J. S. Fabjan, S. Tschabuschnig, et al., Human low density lipoprotein as a target of hypochlorite generated by myeloperoxidase, Free Radical Biol. Med. 24, 1139–1148 (1998).

    Article  CAS  Google Scholar 

  35. G. M. Chisolm, S. L. Hazen, P. L. Fox, and M. K. Cathcart, The oxidation of lipoproteins by monocytes-macrophages, J. Biol. Chem. 274, 25,959–25,962 (1999).

    Article  CAS  Google Scholar 

  36. C. C. Winterbourn, J. J. M. Vandenberg, E. Roitman, and F. A. Kuypers, Chlorohydrin formation from unsaturated fatty acids reacted with hypochlorous acid, Arch. Biochem. Biophys. 296, 547–555 (1992).

    Article  PubMed  CAS  Google Scholar 

  37. J. W. Heinecke, Oxidants and antioxidants in the pathogenesis of atherosclerosis: implications for the oxidiized low density lipoprotein hypothesis, Atherosclerosis 141, 1–15 (1998).

    Article  PubMed  CAS  Google Scholar 

  38. M. O. Pentikäinen, K. Oorni, and P. T. Kovanen, Myeloperoxidase and hypochlorite, but not copper ions, oxidize heparin-bound LDL particles and release them from heparin, Arteriosclosis Thromb. Vasc. 21, 1902–1908 (2001).

    Google Scholar 

  39. S. L. Hazen, J. P. Gaut, J. R. Crowley, F. F. Hsu, and J. W. Heinecke, Elevated levels of protein-bound p-hydroxyphenylacetaldehyde, an amino acid derived aldehyde generated by myeloperoxidase, are present in human fatty streaks, intermediate lesions and advanced atherosclerotic lesions, Biochem. J. 352, 693–699 (2000).

    Article  PubMed  CAS  Google Scholar 

  40. P. Leppänen, K. Seppänen, J. T. Salonen, and S. Ylä-Herttuala, Effects of mercury, iron and antioxidants on atherosclerosis in LDLR-deficient mice, in XIIth International Symposium on Atherosclerosis, 2000.

  41. J. Parizek and I. Ostadalova, The protective effect of small amounts of selenite in sublimate intoxication, Experientia 23, 142–143 (1967).

    Article  PubMed  CAS  Google Scholar 

  42. K. Seppänen, R. Laatikainen, J. T. Salonen, et al., Mercury-binding capacity of organic and inorganic selenium in rat blood and liver, Biol. Trace Element Res. 65, 197–210 (1998).

    Google Scholar 

  43. K. Seppänen, M. Kantola, R. Laatikainen, et al., Effect of supplementation with organic selenium on mercury status as measured by mercury in pubic hair, J. Trace Elements Med. Bio. 14, 84–87 (2000).

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, University of Kuopio, P.O. Box 1627, FIn-70211, Kuopio, Finland

    Kari Seppänen, Pasi Soininen, Simo Lötjönen & Reino Laatikainen

  2. Research Institute of Public Health, University of Kuopio, P.O. Box 1627, FIN-70211, Kuopio, Finland

    Jukka T. Salonen

Authors
  1. Kari Seppänen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pasi Soininen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jukka T. Salonen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simo Lötjönen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Reino Laatikainen
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Seppänen, K., Soininen, P., Salonen, J.T. et al. Does mercury promote lipid peroxidation?. Biol Trace Elem Res 101, 117–132 (2004). https://doi.org/10.1385/BTER:101:2:117

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/BTER:101:2:117

Index Entries

Search

Navigation