Lysosomal involvement in hepatocyte cytotoxicity induced by Cu2+ but not Cd2+
Identifieur interne : 002359 ( Main/Exploration ); précédent : 002358; suivant : 002360Lysosomal involvement in hepatocyte cytotoxicity induced by Cu2+ but not Cd2+
Auteurs : Jalal Pourahmad [Canada] ; Steve Ross [Canada] ; Peter J. O Rien [Canada]Source :
- Free Radical Biology and Medicine [ 0891-5849 ] ; 2001.
Descripteurs français
- Wicri :
- topic : Cuivre.
English descriptors
- KwdEn :
- ANOVA, BAPTA, BSA, Copper, Cytotoxicity, DMSO, EGTA, Free radicals, HEPES, Hepatocyte, Lysosomes, Proteases, ROS, Redox cycling, SD, SOD, rpm.
- Teeft :
- Acridine, Aurothioglucose, Cadmium, Cell lysis, Cell viability, Chloroquine, Control hepatocytes, Copper chloride, Cysteine, Cytotoxic, Cytotoxic mechanism, Cytotoxicity, Dimethyl sulfoxide, Gentamicin, Hepatic, Hepatocyte, Hepatocyte cytotoxicity, Hepatocyte proteolysis, Hepatocytes, Inhibitor, Leupeptin, Lipid, Lipid peroxidation, Lysis, Lysosomal, Lysosomal enzymes, Lysosomal involvement, Lysosomal membrane damage, Lysosomal protease inhibitors, Lysosomal proteases, Lysosome, Methylamine, Mitochondrial membrane, Monensin, Oxidative, Oxidative stress, Pepstatin, Peroxidation, Pourahmad, Preincubated, Protease, Proteolysis, Redox, Redox cycling, Separate experiments, Superoxide dismutase, Toxicity, Trypan, Uorescence.
Abstract
Abstract: Previously we showed that the redox active Cu2+ was much more effective than Cd2+ at inducing reactive oxygen species (“ROS”) formation in hepatocytes and furthermore “ROS” scavengers prevented Cu2+-induced hepatocyte cytotoxicity (Pourahmad and O’Brien, 2000). In the following it is shown that hepatocyte cytotoxicity induced by Cu2+, but not Cd2+, was preceded by lysosomal membrane damage as demonstrated by acridine orange release. Cytotoxicity, “ROS” formation, and lipid peroxidation were also readily prevented by methylamine or chloroquine (lysosomotropic agents) or 3-methyladenine (an inhibitor of autophagy). Hepatocyte lysosomal proteolysis was also activated by Cu2+, but not Cd2+, as tyrosine was released from the hepatocytes and was prevented by leupeptin and pepstatin (lysosomal protease inhibitors). Cu2+-induced cytotoxicity was also prevented by leupeptin and pepstatin. A marked increase in Cu2+-induced hepatocyte toxicity also occurred if the lysosomal toxins gentamicin or aurothioglucose were added at the same time as the Cu2+. Furthermore, destabilizing lysosomal membranes beforehand by preincubating the hepatocytes with gentamicin or aurothioglucose prevented Cu2+-induced hepatocyte cytotoxicity. It is proposed that Cu2+-induced cytotoxicity involves lysosomal damage that causes the release of cytotoxic digestive enzymes as a result of lysosomal membrane damage by “ROS” generated by lysosomal Cu2+ redox cycling.
Url:
DOI: 10.1016/S0891-5849(00)00450-0
Affiliations:
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Le document en format XML
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<front><div type="abstract" xml:lang="en">Abstract: Previously we showed that the redox active Cu2+ was much more effective than Cd2+ at inducing reactive oxygen species (“ROS”) formation in hepatocytes and furthermore “ROS” scavengers prevented Cu2+-induced hepatocyte cytotoxicity (Pourahmad and O’Brien, 2000). In the following it is shown that hepatocyte cytotoxicity induced by Cu2+, but not Cd2+, was preceded by lysosomal membrane damage as demonstrated by acridine orange release. Cytotoxicity, “ROS” formation, and lipid peroxidation were also readily prevented by methylamine or chloroquine (lysosomotropic agents) or 3-methyladenine (an inhibitor of autophagy). Hepatocyte lysosomal proteolysis was also activated by Cu2+, but not Cd2+, as tyrosine was released from the hepatocytes and was prevented by leupeptin and pepstatin (lysosomal protease inhibitors). Cu2+-induced cytotoxicity was also prevented by leupeptin and pepstatin. A marked increase in Cu2+-induced hepatocyte toxicity also occurred if the lysosomal toxins gentamicin or aurothioglucose were added at the same time as the Cu2+. Furthermore, destabilizing lysosomal membranes beforehand by preincubating the hepatocytes with gentamicin or aurothioglucose prevented Cu2+-induced hepatocyte cytotoxicity. It is proposed that Cu2+-induced cytotoxicity involves lysosomal damage that causes the release of cytotoxic digestive enzymes as a result of lysosomal membrane damage by “ROS” generated by lysosomal Cu2+ redox cycling.</div>
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