Toxicity of calcium ionophore A23187 in monolayers of hypoxic hepatocytes.
Increased cytoplasmic calcium has been implicated in hepatic necrosis induced by cytochrome P-450-mediated halocarbon metabolism; hepatic necrosis is exacerbated hypoxia. It is known that addition of the calcium ionophore A23187 to a cell can mimic the metabolic causes of increased cytoplasmic calcium. In the present experiments, confluent monolayers of rat hepatocytes were exposed to A23187 (0.5-50 microM) under conditions of normoxia and 18-fold during a 4-h incubation at 0.5% (5 microM) O2 compared with 20% (212 microM) O2. The ED50 values of A23187 were 0.92, 1.84, 10.98, and 16.81 microM at 0.5, 1, 2, and 20% O2, respectively. The results demonstrate that small reductions in the oxygen concentrations normally encountered by pericentral hepatocytes (i.e., below 28 microM) may severely decrease the ability of these already compromised hepatocytes to manage perturbations in calcium homeostasis.
D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D000001:Calcimycin / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002478:Cells, Cultured; D002860:Chromium Radioisotopes; D003593:Cytoplasm / Q000201:enzymology; D008099:Liver / Q000187:drug effects*; D008297:Male; D010100:Oxygen / Q000502:physiology*; D051381:Rats; D011919:Rats, Inbred Strains
D002860:Chromium Radioisotopes; D000001:Calcimycin; D001219:Aspartate Aminotransferases; D010100:Oxygen; D002118:Calcium