TY - JOUR
T1 - Protection by acidotic pH and fructose against lethal injury to rat hepatocytes from mitochondrial inhibitors, ionophores and oxidant chemicals
AU - Nieminen, Anna Liisa
AU - Dawson, Thomas L.
AU - Gores, Gregory J.
AU - Kawanishi, Toru
AU - Herman, Brian
AU - Lemasters, John J.
N1 - Funding Information:
Depletion of ATP is a typical feature of hypoxic and toxic injury (e.g., ref l-3). In hypoxia, ATP depletion is caused by inhibition of aerobic mitochondrial ATP formation, an effect which can be mimicked by the respiratory inhibitor, cyanide. Mitochondria may also be a target of injury by toxic chemicals (2-4). For example, oxidative injury by the strong oxidant, HgC12,a ppears to cause ATP depletion by depolarizing the mitochondrial membrane lThis work was supported by Grants AGO7218 and DK30874 from the National Institutes of Health and Grant J-1433 from the Office of Naval Research.
PY - 1990/3/16
Y1 - 1990/3/16
N2 - The importance of mitochondrial ATP formation and extracellular acidosis was evaluated in hepatocyte suspensions after different toxic treatments. Acidotic pH was protective against cell killing from all toxic treatments examined except for pronase, a toxic protease. Fructose, a substrate for glycolytic ATP formation, provided good protection against toxicity from cyanide, oligomycin, t-butyl hydroperoxide, menadione and cystamine. Protection by fructose against CCCP, gramicidin and Br-A23187 required oligomycin. This indicated that these ionophores were causing cytotoxicity by uncoupling oxidative phosphorylation. Fructose provided little protection against pronase and HgCl2, the latter compound being a potent inhibitor of glycolysis. In conclusion, disruption of mitochondrial ATP formation was a common event contributing to the toxicity of chemical oxidants and ionophores. Acidotic pH was generally protective under these conditions of impaired ATP generation.
AB - The importance of mitochondrial ATP formation and extracellular acidosis was evaluated in hepatocyte suspensions after different toxic treatments. Acidotic pH was protective against cell killing from all toxic treatments examined except for pronase, a toxic protease. Fructose, a substrate for glycolytic ATP formation, provided good protection against toxicity from cyanide, oligomycin, t-butyl hydroperoxide, menadione and cystamine. Protection by fructose against CCCP, gramicidin and Br-A23187 required oligomycin. This indicated that these ionophores were causing cytotoxicity by uncoupling oxidative phosphorylation. Fructose provided little protection against pronase and HgCl2, the latter compound being a potent inhibitor of glycolysis. In conclusion, disruption of mitochondrial ATP formation was a common event contributing to the toxicity of chemical oxidants and ionophores. Acidotic pH was generally protective under these conditions of impaired ATP generation.
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U2 - 10.1016/0006-291X(90)92067-A
DO - 10.1016/0006-291X(90)92067-A
M3 - Article
C2 - 2322245
AN - SCOPUS:0025267709
SN - 0006-291X
VL - 167
SP - 600
EP - 606
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -