Differential effects of extracellular calcium on lipid peroxidation dependent (ethacrynic acid and allyl alcohol) and lipid peroxidation independent (disulfiram)-induced cytotoxicity in normal and vitamin E-deficient rat hepatocytes.
Hepatocytes have been isolated from normal and vitamin E-deficient rats in which the hepatic vitamin E level was less than 6% that of controls. The hypothesis was tested that extracellular calcium ameliorates chemical-induced cell killing because it decreases the extent of vitamin E loss induced by oxidative stress: such a retarding effect of calcium on cytotoxicity should be lost in hepatocytes from vitamin E-deficient rats. In normal hepatocytes, allyl alcohol and ethacrynic acid induced oxidative stress as indicated by GSH depletion, lipid peroxidation and cell death. Extracellular calcium retarded the induction of lipid peroxidation and cell death without affecting the GSH depletion. In vitamin E-deficient cells, extracellular calcium had lost its protective effect on ethacrynic acid- and allyl-alcohol induced cytotoxicity; it did not affect the GSH depletion and subsequent induction of lipid peroxidation and cell death by ethacrynic acid. However, in vitamin E-deficient hepatocytes, extracellular calcium even potentiated the cytotoxicity of allyl alcohol; under those conditions it also increased GSH loss. Neither in normal, nor in vitamin E-deficient hepatocytes, extracellular calcium had an effect on disulfiram-induced cytotoxicity, i.e. cell death in the absence of lipid peroxidation. These results support the hypothesis that the protecting effect of extracellular calcium on cytotoxicity, associated with lipid peroxidation in normal hepatocytes, is mediated by its protection against intracellular vitamin E loss.
Dogterom
P
P
Institute of Toxicology, Swiss Federal Institute of Technology, Schwerzenbach.
Mulder
G J
GJ
D000433:1-Propanol / Q000633:toxicity; D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D004221:Disulfiram / Q000633:toxicity; D004976:Ethacrynic Acid / Q000633:toxicity; D005260:Female; D005978:Glutathione / Q000032:analysis; D066298:In Vitro Techniques; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D020005:Propanols; D011506:Proteins / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D014811:Vitamin E Deficiency / Q000378:metabolism*
D020005:Propanols; D011506:Proteins; C006463:allyl alcohol; D000433:1-Propanol; D005978:Glutathione; D004976:Ethacrynic Acid; D002118:Calcium; D004221:Disulfiram