Mechanism of cadmium-induced cytotoxicity in rat hepatocytes. Cd-induced acidification causes alkalinization accompanied by membrane damage.
Exposure of rat hepatocytes to cadmium below 50 microM for a short period (10 min) resulted in cellular acidification. Conversely, exposure to Cd more than 50 microM 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 microM 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 microM) 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.
Koizumi
T
T
Faculty of Pharmaceutical Sciences, Chiba University, Japan.
Yokota
T
T
Suzuki
K T
KT
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D002104:Cadmium / Q000378:metabolism / Q000633:toxicity*; D019256:Cadmium Chloride; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D002712:Chlorides / Q000633:toxicity*; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D002712:Chlorides; D002104:Cadmium; D000255:Adenosine Triphosphate; D019256:Cadmium Chloride; D002118:Calcium