The Role of Glycolysis and Hexose Monophosphate Pathway in the Hypoxic Toxicity of Misonidazole

The metabolic activation of misonidazole (MISO) and its effects on the hexose monophosphate pathway (HMP) and clonogenicity were studied in hypoxic EMT6/R0, wildtype Chinese hamster ovary (CHO) and mutant CHO cells deficient in glucose-6-phosphate dehydrogenase. In all three cell lines metabolic activation of MISO, as indicated by the binding of ^l4C-MISO to the acid-insoluble fraction of these cells, was increased by the presence of glucose. In EMT6/R0 cells and wildtype CHO cells, MISO caused a significant stimulation of the activity of the HMP while in the mutant CHO cells no HMP activity was measurable, even in the presence of MISO. Loss of clonogenicity induced by MISO occurred markedly earlier in EMT6/R0 cells than in the CHO cells. In the latter cells, however, only a small difference was observed between the wildtype and mutant cell line. From these results it is concluded that not only the HMP but also glycolysis and other, glucose-independent, metabolic pathways are able to provide electrons for the reductive activation of MISO and hence contribute to the hypoxic toxicity of this compound.     

The Role of Glycolysis and Hexose Monophosphate Pathway in the Hypoxic Toxicity of Misonidazole

The metabolic activation of misonidazole (MISO) and its effects on the hexose monophosphate pathway (HMP) and clonogenicity were studied in hypoxic EMT6/R0, wildtype Chinese hamster ovary (CHO) and mutant CHO cells deficient in glucose-6-phosphate dehydrogenase. In all three cell lines metabolic activation of MISO, as indicated by the binding of ^l4C-MISO to the acid-insoluble fraction of these cells, was increased by the presence of glucose. In EMT6/R0 cells and wildtype CHO cells, MISO caused a significant stimulation of the activity of the HMP while in the mutant CHO cells no HMP activity was measurable, even in the presence of MISO. Loss of clonogenicity induced by MISO occurred markedly earlier in EMT6/R0 cells than in the CHO cells. In the latter cells, however, only a small difference was observed between the wildtype and mutant cell line. From these results it is concluded that not only the HMP but also glycolysis and other, glucose-independent, metabolic pathways are able to provide electrons for the reductive activation of MISO and hence contribute to the hypoxic toxicity of this compound.