Oxygen dependence of hepatocyte susceptibility to mitochondrial respiratory inhibitors.
Most zone 3 specific hepatotoxins or their metabolites are mitochondrial toxins, and yet the susceptibility of hepatocytes to respiratory inhibitors at the low O2 concentrations found in zone 3 is not known. Potassium cyanide (CN) and antimycin A (AA) were found to be 5- and 2-fold more cytotoxic at 1% than at 95% O2, respectively. CN also inhibited the respiration of hepatocytes 36% more at 1% O2 than at 95% O2; however, AA inhibited the respiration to the same level at 1% and 95% O2. CN but not AA depleted ATP levels of hepatocytes more extensively at 1% than at 95% O2. The CN-trapping agents dihydroxyacetone, glyceraldehyde, alpha-ketoglutarate and pyruvate prevented CN-induced cytotoxicity more effectively at 95% O2 than at 1% O2. In contrast, thiosulfate was less effective in preventing CN toxicity at 95% than at 1% O2. Hepatocyte thiocyanate formation from CN and thiosulfate was much faster at 1% than at 95% O2, suggesting that rhodanese, the mitochondrial enzyme that forms thiocyanate from CN and thiosulfate, is more effective at 1% O2 than at 95% O2.
Niknahad
H
H
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Khan
S
S
O'Brien
P J
PJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D000968:Antimycin A / Q000633:toxicity*; D019069:Cell Respiration / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004098:Dihydroxyacetone / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000378:metabolism; D005985:Glyceraldehyde / Q000494:pharmacology; D007656:Ketoglutaric Acids / Q000494:pharmacology; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects; D010100:Oxygen / Q000032:analysis / Q000494:pharmacology*; D010101:Oxygen Consumption; D011190:Potassium Cyanide / Q000037:antagonists & inhibitors / Q000633:toxicity*; D013861:Thiocyanates / Q000378:metabolism; D013885:Thiosulfates / Q000494:pharmacology
D007656:Ketoglutaric Acids; D013861:Thiocyanates; D013885:Thiosulfates; D005985:Glyceraldehyde; D000968:Antimycin A; D000255:Adenosine Triphosphate; D003576:Electron Transport Complex IV; C017717:sodium thiosulfate; D011190:Potassium Cyanide; D004098:Dihydroxyacetone; C031760:thiocyanate; D010100:Oxygen