copper;
cadmium;
mitochondrial injury;
ion homeostasis;
cell swelling;
hepatocytes;
D O I:
10.1016/S0009-2797(00)00162-9
中图分类号:
Q5 [生物化学];
Q7 [分子生物学];
学科分类号:
071010 ;
081704 ;
摘要:
Previously we showed that hepatocyte lysis induced by Cu+2/Cd+2 could be partly attributed to membrane lipid peroxidation induced by Cu+2 Or mitochondrial toxicity induced by Cd+2 [5]. Changes in Na+ and Ca+2 homeostasis induced when Cu+2 was incubated with hepatocytes markedly differed from that induced by Cd+2. Na+ omission from the media or addition of the Na+/H+ exchange inhibitor 5-(N,N-dimethyl)-amiloride markedly increased Cu+2 cytotoxicity even though Cu+2 did not increase hepatocyte Na+ when the media contained Na+. Intracellular Ca+2 levels however were markedly increased when the hepatocytes were incubated with Cu+2 in a Na+ free media and removing media Ca+2 with EGTA also prevented Cu+2 induced hepatocyte cytotoxicity. This suggests that intracellular Ca+2 accumulation contributes to Cu+2 induced cytotoxicity and a Na+-dependent Ca+2 transporter is involved in controlling excessive Ca+2 accumulation caused by Cu+2. The omission of Cl- from the media or addition of glycine, a Cl- channel blocker also enhanced Cu induced cytotoxicity. By contrast Cd+2 induced cytotoxicity was prevented by Na+ omission from the media or by the addition of 5-(N,N-dimethyl)-amiloride. Furthermore the omission of Cl- from the media or addition of glycine also prevented Cd+2 induced hepatocyte toxicity. A hypotonic media also increased Cd+2 but not Cu+2 induced hepatocyte cytotoxicity. This suggests that Cd+2 but not Cu+2 cytotoxicity could be partly attributed to disruption of cell volume regulation mechanisms. The increased osmotic load caused by the uncontrolled accumulation of intracellular Na+ in Cd+2 treated hepatocytes likely resulted from the activation of Na+/H+ exchanger and the Na+/HCO3- cotransporter by the acidosis and ATP depletion caused by mitochondrial toxicity. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.