Cell death and lipid peroxidation in isolated hepatocytes incubated in the presence of hydrogen peroxide and iron salts.
The incubation of isolated hepatocytes in the presence of glucose plus glucose oxidase, a H2O2-generating system, resulted in extensive loss of cell viability, as expressed by the release of lactate dehydrogenase (LDH). Disturbance of metabolic functions such as glycogen and protein synthesis was also caused by H2O2, but in no case was malondialdehyde (MDA)-like products detected. The lytic effect of H2O2 was significantly enhanced by incubating hepatocytes in the presence of iron salts. Under these conditions, MDA-like products were detected, but lipid peroxidation and cell injury did not correlate. Iron chelators modulated the cytotoxicity of H2O2 in different (and opposite) ways: when iron was complexed with ADP, increased cell lysis was observed compared to uncomplexed iron plus H2O2. Iron-DTPA, on the contrary, decreased such a lytic effect. The preincubation of hepatocytes with desferrioxamine mesylate (Desferal; a strong iron chelator) abolished the cytolytic effects produced by the association of iron salts and H2O2, as well as the membrane oxidative injury due to H2O2 alone, thus suggesting the existence of an intracellular source of iron. This kind of mechanism (metal chelation rather than radical scavenging) is supported by the absence of any protective effect by some free radical scavengers against the oxidative injury induced by the association iron H2O2. Nevertheless, the glycogenolytic effects observed in the presence of H2O2 were not modified by Desferal. In our opinion, the cytotoxicity of the association H2O2 plus iron salts involves at least two different and independent mechanisms.
Latour
I
I
Unité de Biochimie Toxicologique et Cancérologique, Ecole de Pharmacie, Université Catholique de Louvain, Bruxelles, Belgium.
Pregaldien
J L
JL
Buc-Calderon
P
P
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004347:Drug Interactions; D005949:Glucose Oxidase / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007501:Iron / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D014176:Protein Biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
D008112:Liver Glycogen; D017392:Thiobarbituric Acid Reactive Substances; D006861:Hydrogen Peroxide; D007501:Iron; D007770:L-Lactate Dehydrogenase; D005949:Glucose Oxidase; D003676:Deferoxamine