Abstract
The aims of this study were to investigate the roles of iron as a catalyst in reactive oxygen metabolite-mediated cellular injury and of the endogenous antioxidant defenses against acetaminophen-induced cytotoxicity in cultured rat hepatocytes. Hepatocytes were isolated and cultured from either 3-methylcholanthrene-treated or untreated rats. Cytotoxicity was evaluated by measuring51Cr and lactate dehydrogenase release. Acetaminophen caused dose-dependent cytotoxicity in 3-methlycholanthrene-treated, but not untreated, cells. There was a good correlation between51Cr and lactate dehydrogenase release values. Pretreatment with both diethyl maleate, which covalently binds glutathione as catalyzed by glutathione-S-transferase, and bis(chloroethyl)-nitrosourea, an inhibitor of glutathione reductase, enhanced acetaminophen-induced cytotoxicity. Inhibition of endogenous catalase activity by pretreatment with aminotriazole did not affect acetaminophen-induced cellular damage. Addition of exogenous catalase failed to protect against acetaminophen-induced cytotoxicity. Preincubation with both deferoxamine, a ferric iron chelator, and phenanthroline, a ferrous iron chelator, diminished acetaminophen-induced cytotoxicity. These results indicate that iron is crucial in mediating acetaminophen-induced cytotoxicity and that the glutathione redox cycle, but not catalase, plays a critical role in the endogenous defenses against acetaminophen-induced cellular damage in cultured rat hepatocytesin vitro.
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This work was supported by the Medical Research Service of the Veterans Affairs.
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Ito, Y., Suzuki, Y., Ogonuki, H. et al. Role of iron and glutathione redox cycle in acetaminophen-induced cytotoxicity to cultured rat hepatocytes. Digest Dis Sci 39, 1257–1264 (1994). https://doi.org/10.1007/BF02093791
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DOI: https://doi.org/10.1007/BF02093791