Hepatocellular copper toxicity and its attenuation by zinc.
We studied the mechanisms by which excess copper exerts, and zinc mitigates, toxic effects on HepG2 cells. Survival and cell growth were reduced in media containing greater than 500 microM copper chloride for 48 h; LD50 was 750 microM. At 1,000 microM copper for 1 h, there was a general reduction of protein synthesis, and no recognizable changes in cellular ultrastructure. Incubation of cells with 200 microM zinc acetate before exposure to copper, raised the LD50 for confluent cells to 1,250 microM copper chloride, improved protein synthesis, and increased synthesis of a 10-kD protein, apparently metallothionein. The mitigation, by zinc, of copper's toxicity may in part be mediated through induction of this protein in the hepatocyte.
Schilsky
M L
ML
Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461.
Blank
R R
RR
Czaja
M J
MJ
Zern
M A
MA
Scheinberg
I H
IH
Stockert
R J
RJ
Sternlieb
I
I
D000255:Adenosine Triphosphate / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000473:pathology; D008668:Metallothionein / Q000096:biosynthesis; D008854:Microscopy, Electron; D014176:Protein Biosynthesis; D012313:RNA / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology*
D012313:RNA; D003300:Copper; D000255:Adenosine Triphosphate; D008668:Metallothionein; D005978:Glutathione; D015032:Zinc