Abstract
Equimolar concentrations of cysteamine and reduced glutathione protected against the cytotoxicity of 5 mM misonidazole (MISO), whereas 5mM ascorbate enhanced its toxicity to hypoxic CHO and HeLa cells in vitro. Protection (reappearance of a shoulder region) could also be seen when cysteamine was added at later incubation times. These changes in toxicity were accompanied by changes in drug metabolism, as evidenced by radiochromatograms of cell extracts obtained after treatment with 14C-labelled MISO. In contrast, radiochromatograms obtained from cells treated with toxic levels of MISO (75 mM) under aerobic conditions indicated no drug metabolism. Both toxicity and drug metabolism could be immediately halted by introducing O2 during hypoxic exposure to MISO. These observations are discussed in terms of a possible model for the metabolism-mediated toxicity of MISO and the roles which sulphydryls and O2 may play.
Highlights
Summary.-Equimolar concentrations of cysteamine and reduced glutathione protected against the cytotoxicity of 5mm misonidazole (MISO), whereas 5mM ascorbate enhanced its toxicity to hypoxic Chinese hamster ovary (CHO) and HeLa cells in vitro
Reduced glutathione (GxSH) on the metabolism of MISO have been investigated. These results are discussed in terms of a possible model implicating sulphydryl (R-SH) depletion in the hypoxic cell toxicity of MISO
The results in the presence of ASC indicate an enhancement of the cytotoxic effects of MISO whereas the 2 sulphydryl compounds appear to reduce this toxicity, MEA being the more effective
Summary
Summary.-Equimolar concentrations of cysteamine and reduced glutathione protected against the cytotoxicity of 5mm misonidazole (MISO), whereas 5mM ascorbate enhanced its toxicity to hypoxic CHO and HeLa cells in vitro. Ascorbate (ASC) has been shown to increase the cytotoxicity of MISO toward hypoxic Chinese hamster ovary (CHO) cells (Josephy et al, 1978) while cysteamine (MEA), a radical scavenger and radioprotector, has been shown to protect against its cytotoxic effects (Hall et al, 1977) This raises the question whether or not the ASC-enhanced toxicity of MISO (Josephy et al, 1978; Koch et al, 1979) is mediated by an increased formation of toxic drug metabolites. These results are discussed in terms of a possible model implicating sulphydryl (R-SH) depletion in the hypoxic cell toxicity of MISO
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