Mechanism of cadmium-induced cytotoxicity in rat hepatocytes

Cd-induced acidification causes alkalinization accompanied by membrane damage
  • Toshiaki Koizumi
  • Toshiki Yokota
  • Kazuo T. Suzuki


Exposure of rat hepatocytes to cadmium below 50 μM for a short period (10 min) resulted in cellular acidification. Conversely, exposure to Cd more than 50 μM for a long period (60 min) caused cellular alkalinization accompanied by membrane damage as reflected by decrease in cellular K content and loss of intracellular lactic dehydrogenase. In hepatocytes exposed to 5 μM Cd, a concentration sufficient to induce acidification without cytotoxicity, the metal was preferentially associated with the crude nuclei and cell debris fractions, suggesting an interaction between Cd and cell membranes to cause acidification. Omission of bicarbonate from the incubation medium induced cellular acidification. The presence of Cd in this medium did not potentiate the medium-induced acidification. Mg-ATP (25 μM) induced cellular acidification in relation to an increase in the concentration of cytosolic free Ca. The coexistence of Mg-ATP and Cd at the concentrations which had no effect on cellular pH in the presence of either agants induced cellular acidification.

These observations suggest that Cd induced cellular acidification by modulating the process connected with the rise in cytosolic free Ca via interaction with plasma membranes. This acidification had no strong immediate cytotoxic actions but led to subsequent cellular alkalinization accompanied with severe cytotoxicity and membrane breakage.

Index Entries

Cadmium Mg-ATP cellular acidification cellular alkalinization 


  1. 1.
    R. E. Dudley, D. J. Svoboda, and C. D. Klaassen,Toxicol. Appl. Pharmacol. 65, 302–313 (1982).PubMedCrossRefGoogle Scholar
  2. 2.
    R. E. Dudley, D. J. Svoboda, and C. D. Klaassen,Toxicol. Appl. Pharmacol. 76, 150–160 (1984).PubMedCrossRefGoogle Scholar
  3. 3.
    B. F. Trump, I. K. Berezesky, and A. R. O.-Vargas, Cell death and the disease process. The role of calcium. In Biology and Pathology, I. D. Bowen and R. A. Lockshin (eds.), Chapman and Hall, New York, 1981, p. 209.Google Scholar
  4. 4.
    Y. Yamane, M. Fukuchi, Zhi Gang Li, and T. Koizumi,Toxicology 60, 235–243 (1990).PubMedCrossRefGoogle Scholar
  5. 5.
    T. Koizumi, T. Yokota, M. Fukuch, H. Tasumoto, and Y. Yamane,Cell Biol. Toxicol. 7, 357–369 (1991).PubMedCrossRefGoogle Scholar
  6. 6.
    C. Frelin, P. Vinge, A. Ladoux, and M. Lazdunsky,Eur. J. Biochem. 174, 3–14 (1988).PubMedCrossRefGoogle Scholar
  7. 7.
    E. K. Hofman and L. O. Simonsen,Physiol. Rev. 69, 315–382 (1989).Google Scholar
  8. 8.
    W. B. Busa and R. Nuccitelli,Am. J. Physiol. 246, R409-R438 (1984).PubMedGoogle Scholar
  9. 9.
    A. F. Stein, W. M. Bracken, and C. D. Klaassen,Toxicol. Appl. Pharmacol. 87, 276–283 (1987).PubMedCrossRefGoogle Scholar
  10. 10.
    I. S. Ambudkar, M. W. Smith, P. C. Phelps, A. L. Regec, and B. F. Trump,Environ. Ind. Health 4, 107–123 1988).Google Scholar
  11. 11.
    W. C. Schneider and G. H. Hogeboom,J. Biol. Chem. 183, 123–130 (1950).Google Scholar
  12. 12.
    C. Juel,Acta Physiol. Scand. 132, 363–371 (1988).PubMedCrossRefGoogle Scholar
  13. 13.
    A. Livne and K. Hofman,J. Membrane Biol. 114 153–157 (1990).CrossRefGoogle Scholar
  14. 14.
    L. O. Kristensen,Am. J. Physiol. 251, G575-G584 (1986).PubMedGoogle Scholar
  15. 15.
    E. L. Renner, J. R. Lake, J. R. Scharschmidt, P. J. Meir, and B. Zimmerli,J. Clin. Invest. 83, 1225–1235 (1989).PubMedCrossRefGoogle Scholar
  16. 16.
    E. L. Renner, J. R. Lake, M. Persico, and J. R. Scharschmidt.Am. J. Physiol. 256, G44-G52 (1990).Google Scholar
  17. 17.
    T. I. Tonnessen, J. Ludt, K. Sandvig, and S. Olsnes,J. Cell Physiol. 132, 183–191 (1987).PubMedCrossRefGoogle Scholar
  18. 18.
    J. R. Chailet, K. Amsler, and W. F. Boron,Proc. Natl. Acad. Sci. USA 83, 522–526 (1986).CrossRefGoogle Scholar
  19. 19.
    D. Gleen, J. G. Gorasanti, and J. L. Boyer,Am. J. Physiol. 258, G299-G307 (1990).Google Scholar
  20. 20.
    J. Green, D. T. Yamaguchi, C. R. Kleeman, and S. Muallem,J. Biol. Chem. 263, 5012–5015 (1988).PubMedGoogle Scholar
  21. 21.
    V. L. Lew and R. M. Bookchin,J. Membr. Biol. 92, 57–74 (1986).PubMedCrossRefGoogle Scholar
  22. 22.
    R. B. Jennings,Acta Med. Scand. 587, 83–92 (1975).Google Scholar
  23. 23.
    D. A. Whalen, Jr., D. G. Hamilton, C. E. Ganote, and R. B. Jennings,Am. J. Pathol. 74, 381–398 (1974).PubMedGoogle Scholar
  24. 24.
    J. Tranum-Jensen, M. J. Janes, J. W. T. Fiolet, W. J. G. Krieger, C. D. D'Alnoncourt, and D. Durrer,Cir. Res. 49, 364–381 (1981).Google Scholar
  25. 25.
    G. J. Gores, A.-L. Nieminen, T. L. Dawson, B. Herman, and J. J. Lemasters,Am. J. Physiol. 24, C315-C322 (1988).Google Scholar
  26. 26.
    M. Webb, Interactions of cadmium with cellular components. InThe Chemistry, Biochemistry and Biology of cadmium, M. Webb (ed.), Elsevier/North-Holland, Amsterdam, p. 285 (1979).Google Scholar
  27. 27.
    A. D. C. McNight and A. Leaf,Physiol. Rev.,57, 519–573 (1977).Google Scholar
  28. 28.
    A. Rothstein and M. Esther,Am. J. Physiol. 260, C113-C121 (1991).PubMedGoogle Scholar
  29. 29.
    L. O. Kristensen and M. Folke,Biochem. J. 221, 265–268 (1984).PubMedGoogle Scholar
  30. 30.
    E. Frei and P. Zahler,Biochim. Biophys Acta 550, 450–455 (1979).PubMedCrossRefGoogle Scholar
  31. 31.
    M. Puceat, O. Clement, F. Scamps, and G. Vassort,Biochem. J. 274, 55–62 (1991).PubMedGoogle Scholar
  32. 32.
    J. B. Smith, S. D. Dwyer, and L. Smith,J. Biol. Chem. 264, 7115–7118 (1989).PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 1994

Authors and Affiliations

  • Toshiaki Koizumi
    • 1
  • Toshiki Yokota
    • 1
  • Kazuo T. Suzuki
    • 1
  1. 1.Faculty of Pharmaceutical SciencesChiba UniversityChibaJapan

Personalised recommendations