Contrasting role of Na+ ions in modulating Cu+2 or Cd+2 induced hepatocyte toxicity

被引:38
作者
Pourahmad, J [1 ]
O'Brien, PJ [1 ]
机构
[1] Univ Toronto, Fac Pharm, Toronto, ON M5S 2S2, Canada
关键词
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.
引用
收藏
页码:159 / 169
页数:11
相关论文
共 13 条
[1]   METALLOTHIONEIN AND THE TRACE MINERALS [J].
BREMNER, I ;
BEATTIE, JH .
ANNUAL REVIEW OF NUTRITION, 1990, 10 :63-83
[2]   ACIDOSIS PROTECTS AGAINST LETHAL OXIDATIVE INJURY OF LIVER SINUSOIDAL ENDOTHELIAL-CELLS [J].
BRONK, SF ;
GORES, GJ .
HEPATOLOGY, 1991, 14 (01) :150-157
[3]   Intracellular Na+ accumulation and hepatocyte injury during cold storage [J].
Carini, R ;
De Cesaris, MG ;
Bellomo, G ;
Albano, E .
TRANSPLANTATION, 1999, 68 (02) :294-297
[4]   THE OPERATION OF NA+/CA2+ EXCHANGER PREVENTS INTRACELLULAR CA2+ OVERLOAD AND HEPATOCYTE KILLING FOLLOWING IRON-INDUCED LIPID-PEROXIDATION [J].
CARINI, R ;
BELLOMO, G ;
DIANZANI, MU ;
ALBANO, E .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1995, 208 (02) :813-818
[5]   Alterations of cell volume regulation in the development of hepatocyte necrosis [J].
Carini, R ;
Autelli, R ;
Bellomo, G ;
Albano, E .
EXPERIMENTAL CELL RESEARCH, 1999, 248 (01) :280-293
[6]   ALTERATION OF NA+ HOMEOSTASIS AS A CRITICAL STEP IN THE DEVELOPMENT OF IRREVERSIBLE HEPATOCYTE INJURY AFTER ADENOSINE-TRIPHOSPHATE DEPLETION [J].
CARINI, R ;
BELLOMO, G ;
BENEDETTI, A ;
FULCERI, R ;
GAMBERUCCI, A ;
PAROLA, M ;
DIANZANI, MU ;
ALBANO, E .
HEPATOLOGY, 1995, 21 (04) :1089-1098
[7]   INTRACELLULAR ACIDIFICATION ASSOCIATED WITH CHANGES IN FREE CYTOSOLIC CALCIUM - EVIDENCE FOR CA2+/H+ EXCHANGE VIA A PLASMA-MEMBRANE CA2+-ATPASE IN VASCULAR SMOOTH-MUSCLE CELLS [J].
DAUGIRDAS, JT ;
ARRIETA, J ;
YE, MH ;
FLORES, G ;
BATLLE, DC .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 95 (04) :1480-1489
[8]   Relationship between the development of hepato-renal toxicity and cadmium accumulation in rats given minimum to large amounts of cadmium chloride in the long-term: preliminary study [J].
Mitsumori, K ;
Shibutani, M ;
Sato, S ;
Onodera, H ;
Nakagawa, J ;
Hayashi, Y ;
Ando, M .
ARCHIVES OF TOXICOLOGY, 1998, 72 (09) :545-552
[9]  
Moldeus P, 1978, Methods Enzymol, V52, P60
[10]   CONSEQUENCES OF CADMIUM TOXICITY IN RAT HEPATOCYTES - MITOCHONDRIAL DYSFUNCTION AND LIPID-PEROXIDATION [J].
MULLER, L .
TOXICOLOGY, 1986, 40 (03) :285-295