Cytotoxicity of phenazine methosulfate in isolated rat hepatocytes is associated with superoxide anion production, thiol oxidation and alterations in intracellular calcium ion homeostasis.
The metabolism of phenazine methosulfate (PMS) by isolated rat hepatocytes is associated with superoxide anion production, and with a substantial decrease in intracellular levels of reduced glutathione, most of which is oxidized to GSSG. A marked loss of protein-free sulfhydryl groups also occurs when intracellular glutathione is depleted, and cytotoxicity follows. These effects are associated with the inhibition of the plasma membrane Ca2+-ATPase and with intracellular accumulation of calcium ion which is preferentially sequestered in mitochondria. Maintenance of protein sulfhydryl groups in the reduced state by dithiothreitol (DTT) prevents the alterations in intracellular calcium homeostasis and protects against toxicity.
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002470:Cell Survival; D002851:Chromatography, High Pressure Liquid; D003574:Cytochrome c Group / Q000378:metabolism; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D006706:Homeostasis; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D008773:Methylphenazonium Methosulfate / Q000633:toxicity*; D010084:Oxidation-Reduction; D010619:Phenazines / Q000633:toxicity*; D010762:Phosphorylase a / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
D003574:Cytochrome c Group; D010619:Phenazines; D013438:Sulfhydryl Compounds; D013481:Superoxides; D008773:Methylphenazonium Methosulfate; D013482:Superoxide Dismutase; D010762:Phosphorylase a; D005978:Glutathione; D002118:Calcium; D019803:Glutathione Disulfide