Toxicity of t-butylhydroperoxide in hepatocyte monolayers exposed to hypoxia and reoxygenation.

Inasmuch as it is known that the toxicity of anesthetic agents is potentiated by hypoxia and that the reductive metabolism of these agents results in the formation of lipid hydroperoxides, we investigated the toxicity of hydroperoxides under low-oxygen concentrations. We found that hypoxia exacerbates the toxicity of t-butyl hydroperoxide, shifting the dose-response curve of t-butyl hydroperoxide vs. lysis of hepatocytes approximately an order of magnitude to the left. Furthermore, although at the end of a 4-h exposure to 0.5% O2 hepatocyte monolayers seemed normal by three indices (release of 51Cr and serum glutamate transaminase or exclusion of trypan blue), they were completely lysed after an additional 20 h reoxygenation at 20% O2. In contrast, monolayers exposed to 2% O2 for 4 h seemed normal after 20 h reoxygenation. However, cells exposed to both a subtoxic dose of hydroperoxide and 4 h of 2% O2, although seeming healthy at the end of the hypoxic period, were completely lysed within 20 h after reoxygenation.