Evidence for the participation of activated oxygen species and the resulting peroxidation of lipids in the killing of cultured hepatocytes by aryl halides.
Primary cultures of rat hepatocytes were used to explore the mechanisms of the toxicity of aryl halides. The sensitivity of the hepatocytes to chloro-, bromo-, and iodobenzene was enhanced by inhibition of glutathione reductase with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). In each case, the increased cell killing depended on the metabolism of the toxicant, a result shown by the protective effect of SKF-525A, an inhibitor of mixed function oxidation. BCNU decreased the metabolism of [14C]bromobenzene and the covalent binding of its metabolites by 20%. Chelation by deferoxamine of a cellular source of ferric iron prevented the cell killing in the presence or absence of BCNU. Deferoxamine had no effect on the metabolism or the covalent binding of [14C]bromobenzene. Similarly, the antioxidant N,N'-diphenyl-p-phenylenediamine (DPPD) reduced the cell killing and had no effect on the metabolism of [14C]bromobenzene. Thus, the toxicity of the three aryl halides was manipulated in ways that modify the sensitivity of hepatocytes to an oxidative stress, and the changes in cell killing occurred without parallel changes in the metabolism of [14C]bromobenzene or the covalent binding of its metabolites.
Coleman
J B
JB
Department of Pathology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Casini
A F
AF
Serroni
A
A
Farber
J L
JL
D000818:Animals; D001969:Bromobenzenes / Q000378:metabolism / Q000633:toxicity*; D002330:Carmustine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002722:Chlorobenzenes / Q000633:toxicity*; D003676:Deferoxamine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007462:Iodobenzenes / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010100:Oxygen / Q000378:metabolism*; D010655:Phenylenediamines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001969:Bromobenzenes; D002722:Chlorobenzenes; D007462:Iodobenzenes; D010655:Phenylenediamines; D011725:Pyridines; C013109:metapyrone; C031905:iodobenzene; D006861:Hydrogen Peroxide; C032036:bromobenzene; C004845:N,N'-diphenyl-4-phenylenediamine; D003676:Deferoxamine; C031294:chlorobenzene; D010100:Oxygen; D002330:Carmustine