Independence and additivity of cultured hepatocyte killing by Ca2+ overload and ATP depletion.
In two competing models of toxic cell death, hepatocyte killing by chemical hypoxia (CN/IAA) is attributed to ATP depletion and killing by A23187 is attributed to Ca(2+)-induced damage. The independence of these models can be questioned because CN/IAA elevates Ca2+ before killing 1c1c7 hepatoma cells and because the ATP source fructose prevents hepatocyte killing by Br-A23187. In the present studies, cultured mouse hepatocytes were exposed to CN/IAA, A23187, or treatments in combination. A23187 produced toxicity proportional to Ca(2+)-activated DNA fragmentation. CN/IAA caused comparable toxicity but no fragmentation of DNA. Treatments in combination were more toxic than either treatment alone. Aurintricarboxylic acid, a Ca(2+)-endonuclease inhibitor, decreased DNA fragmentation and the toxicity of A23187 and combination treatment without affecting CN/IAA toxicity. ATP plus oligomycin decreased CN/IAA and combination treatment toxicity but not that of A23187. These findings indicate that cultured mouse hepatocytes are killed through mechanisms that are independent and additive in their toxicities.
Kamendulis
L M
LM
Toxicology Program, College of Pharmacy, University of New Mexico, Albuquerque 87131-1066.
Corcoran
G B
GB
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000001:Calcimycin / Q000633:toxicity; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003486:Cyanides / Q000633:toxicity; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D005632:Fructose / Q000494:pharmacology; D007461:Iodoacetates / Q000633:toxicity; D019807:Iodoacetic Acid; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009840:Oligomycins / Q000494:pharmacology
D003486:Cyanides; D007461:Iodoacetates; D009840:Oligomycins; D005632:Fructose; D000001:Calcimycin; D000255:Adenosine Triphosphate; D004247:DNA; D007770:L-Lactate Dehydrogenase; D002118:Calcium; D019807:Iodoacetic Acid