Abstract
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.
Similar content being viewed by others
References
R. E. Dudley, D. J. Svoboda, and C. D. Klaassen,Toxicol. Appl. Pharmacol. 65, 302–313 (1982).
R. E. Dudley, D. J. Svoboda, and C. D. Klaassen,Toxicol. Appl. Pharmacol. 76, 150–160 (1984).
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.
Y. Yamane, M. Fukuchi, Zhi Gang Li, and T. Koizumi,Toxicology 60, 235–243 (1990).
T. Koizumi, T. Yokota, M. Fukuch, H. Tasumoto, and Y. Yamane,Cell Biol. Toxicol. 7, 357–369 (1991).
C. Frelin, P. Vinge, A. Ladoux, and M. Lazdunsky,Eur. J. Biochem. 174, 3–14 (1988).
E. K. Hofman and L. O. Simonsen,Physiol. Rev. 69, 315–382 (1989).
W. B. Busa and R. Nuccitelli,Am. J. Physiol. 246, R409-R438 (1984).
A. F. Stein, W. M. Bracken, and C. D. Klaassen,Toxicol. Appl. Pharmacol. 87, 276–283 (1987).
I. S. Ambudkar, M. W. Smith, P. C. Phelps, A. L. Regec, and B. F. Trump,Environ. Ind. Health 4, 107–123 1988).
W. C. Schneider and G. H. Hogeboom,J. Biol. Chem. 183, 123–130 (1950).
C. Juel,Acta Physiol. Scand. 132, 363–371 (1988).
A. Livne and K. Hofman,J. Membrane Biol. 114 153–157 (1990).
L. O. Kristensen,Am. J. Physiol. 251, G575-G584 (1986).
E. L. Renner, J. R. Lake, J. R. Scharschmidt, P. J. Meir, and B. Zimmerli,J. Clin. Invest. 83, 1225–1235 (1989).
E. L. Renner, J. R. Lake, M. Persico, and J. R. Scharschmidt.Am. J. Physiol. 256, G44-G52 (1990).
T. I. Tonnessen, J. Ludt, K. Sandvig, and S. Olsnes,J. Cell Physiol. 132, 183–191 (1987).
J. R. Chailet, K. Amsler, and W. F. Boron,Proc. Natl. Acad. Sci. USA 83, 522–526 (1986).
D. Gleen, J. G. Gorasanti, and J. L. Boyer,Am. J. Physiol. 258, G299-G307 (1990).
J. Green, D. T. Yamaguchi, C. R. Kleeman, and S. Muallem,J. Biol. Chem. 263, 5012–5015 (1988).
V. L. Lew and R. M. Bookchin,J. Membr. Biol. 92, 57–74 (1986).
R. B. Jennings,Acta Med. Scand. 587, 83–92 (1975).
D. A. Whalen, Jr., D. G. Hamilton, C. E. Ganote, and R. B. Jennings,Am. J. Pathol. 74, 381–398 (1974).
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).
G. J. Gores, A.-L. Nieminen, T. L. Dawson, B. Herman, and J. J. Lemasters,Am. J. Physiol. 24, C315-C322 (1988).
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).
A. D. C. McNight and A. Leaf,Physiol. Rev.,57, 519–573 (1977).
A. Rothstein and M. Esther,Am. J. Physiol. 260, C113-C121 (1991).
L. O. Kristensen and M. Folke,Biochem. J. 221, 265–268 (1984).
E. Frei and P. Zahler,Biochim. Biophys Acta 550, 450–455 (1979).
M. Puceat, O. Clement, F. Scamps, and G. Vassort,Biochem. J. 274, 55–62 (1991).
J. B. Smith, S. D. Dwyer, and L. Smith,J. Biol. Chem. 264, 7115–7118 (1989).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Koizumi, T., Yokota, T. & Suzuki, K.T. Mechanism of cadmium-induced cytotoxicity in rat hepatocytes. Biol Trace Elem Res 42, 31–41 (1994). https://doi.org/10.1007/BF02990486
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02990486