Protective effect of metallothionein on intracellular pH changes induced by cadmium.

In order to gain further insight into the protective mechanism of metallothionein (MT) against Cd cytotoxicity, the effects of in vivo Zn- or Cd-pretreatment on the cytotoxicity and alteration in cellular pH induced by Cd were examined in isolated rat hepatocytes and testicular Leydig cells. These pretreatments both induced the synthesis of MT in the hepatocytes, but not in the Leydig cells. Both pretreatments alleviated Cd cytotoxicity in the hepatocytes. Cd- or Zn-pretreatment was also effective in preventing Cd-induced cellular acidification in hepatocytes but neither pretreatment was effective in Leydig cells. In fact, Cd-pretreatment stimulated acidification in Leydig cells. Exposure in vitro of hepatocytes from untreated rats to probenecid, an inhibitor of HCO3-/Cl- exchange, also ameliorated Cd-induced cellular acidification, suggesting an involvement of HCO3-/Cl- exchange in the preventive action of MT against Cd-induced acidification. These results suggest that Cd cytotoxicity in various cells may be initiated by alterations in plasma membrane ion transport systems such as the HCO3-/Cl- exchange and consequential cellular acidification. Induction of MT, therefore, may prevent Cd cytotoxicity, at least in rat hepatocytes, by preventing an alteration in ion transport at the plasma membrane as well as by intracytoplasmic binding of the metal molecules.