Cells enriched for catalase are sensitized to the toxicities of bleomycin, adriamycin, and paraquat.
L cells were enriched about 100-fold for catalase by the transcription of the transfected cDNA for human catalase. In spite of substantial enrichment for catalase, the transfected cells (LFN7C/B3) were not resistant to the cytotoxicity of a variety of agents which reduce dioxygen, including paraquat, menadione, adriamycin, phenazine methosulfate, and bleomycin. Instead, they were more sensitive to paraquat, bleomycin, and adriamycin than the untransfected cells from which they derived. Desferrioxamine afforded the cells enriched for catalase modest protection from the toxicities of bleomycin, paraquat, or adriamycin, suggesting that enrichment for iron as a consequence of the increased cellular content of catalase accounted for some of the increased sensitivities. The increased sensitivity of the LFN7C/B3 cells to bleomycin and paraquat was also attributed to the ability of catalase in cells to prevent the drug-induced consumption of O2; by capturing H2O2 before it can escape the cell and converting it to O2, catalase can maintain the concentration of O2 either for repeated rounds of chemical reduction or for direct interaction with the toxin. As predicted by this formulation, the toxicities of paraquat and of bleomycin were increased in an atmosphere of 40% dioxygen in comparison with an atmosphere of 20% dioxygen.
Speranza
M J
MJ
Research Service, Veterans Administration Medical Center, Salt Lake City, Utah 84148.
Bagley
A C
AC
Lynch
R E
RE
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology / Q000633:toxicity*; D002374:Catalase / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology / Q000633:toxicity*; D015870:Gene Expression; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D007501:Iron / Q000378:metabolism; D007739:L Cells / Q000201:enzymology; D051379:Mice; D010100:Oxygen / Q000378:metabolism / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010269:Paraquat / Q000494:pharmacology / Q000633:toxicity*; D010957:Plasmids; D014162:Transfection
D001761:Bleomycin; D004317:Doxorubicin; D006861:Hydrogen Peroxide; D007501:Iron; D002374:Catalase; D003676:Deferoxamine; D010269:Paraquat; D010100:Oxygen