tert-butyl hydroperoxide kills cultured hepatocytes by peroxidizing membrane lipids.
The killing of cultured hepatocytes by tert-butyl hydroperoxide was dissociated from the changes both in glutathione metabolism and in intracellular calcium homeostasis that accompany the metabolism of this toxin. Deferoxamine, a ferric iron chelator, keto-methiolbutyric acid, a radical scavenger, and the antioxidants N,N'-diphenyl-p-phenylenediamine (DPPD) and catechol prevented the cell killing without effect on glutathione or calcium metabolism. Malondialdehyde, formed as a result of the peroxidation of cellular lipids, accumulated before any loss of viability. Prevention of the lipid peroxidation paralleled the prevention of cell killing. As much as 25 microM DPPD or 1 mM catechol did not prevent the iron-dependent, catalase-insensitive formation of tert-butyl alkoxyl radicals. Thus, DPPD and catechol do not detoxify a radical species that kills the cells and initiates lipid peroxidation as an epiphenomenon. Furthermore, lipid peroxidation cannot be dismissed as simply a consequence of the cell killing. It is concluded that low concentrations of tert-butyl hydroperoxide (less than 1.0 mM) lethally injure cultured hepatocytes by a mechanism that depends on the peroxidation of cellular lipids.
Masaki
N
N
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Kyle
M E
ME
Farber
J L
JL
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D007700:Kinetics; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010545:Peroxides / Q000494:pharmacology*; D010762:Phosphorylase a / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D020122:tert-Butylhydroperoxide
D010545:Peroxides; D020122:tert-Butylhydroperoxide; D010762:Phosphorylase a; D005978:Glutathione; D003676:Deferoxamine; D019803:Glutathione Disulfide