title: Thiols, thiol depletion, and thermosensitivity.
abstract: Hyperthermia sensitization or tolerance is subject to cellular events that may occur at membrane, nuclear, and cytoplasmic sites. We have studied the effects of elevated temperatures on the oxidative-reductive state of the cell by measuring and altering glutathione (GSH) concentrations. GSH plays a pivotal role in maintaining the overall cellular redox state and detoxification of peroxides. Continuous heating at 42.5 degrees C or acute exposure at 43 degrees C or 45.5 degrees C resulted in rapid elevations of cellular GSH to 120-200% of control values. Qualitatively, the more severe the heat exposure, the quicker the maximal GSH levels are attained. Ethanol, a compound that also induces thermal tolerance, likewise increases intracellular GSH concentrations. GSH depletion by two different modalities, diethylmaleate (DEM) and buthionine sulfoximine (BSO), results in thermal sensitization. It was demonstrated that once thermotolerance has been induced, depletion of GSH has minimal effects on subsequent heating and thermotolerance. Heat shock protein (HSP) synthesis is lessened by treatment with buthionine sulfoximine; the extent of the decrease in HSP production correlates with the decrease in thermotolerance. The exogenous thiol cysteine combined with heat treatment results in thermosensitization. Exogenous cysteine is found to oxidize to cysteine and to enhance oxygen consumption. The use of N-acetylcysteine resulted in less oxygen consumption and less thermosensitization. A proposed mechanism of peroxide-induced cell damage is suggested by exogenous thiols, as well as an involvement of GSH in the initial aspects of thermotolerance induction.
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D019328:Buthionine Sulfoximine; D002470:Cell Survival; D002478:Cells, Cultured; D006224:Cricetinae; D003545:Cysteine / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis / Q000378:metabolism*; D006360:Heat-Shock Proteins; D006358:Hot Temperature; D008298:Maleates / Q000494:pharmacology; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D014176:Protein Biosynthesis; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D013997:Time Factors
chemical_list: D006360:Heat-Shock Proteins; D008298:Maleates; D013438:Sulfhydryl Compounds; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C014476:diethyl maleate; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine