Pretreatment of Isolated Human Peripheral Blood Lymphocytes with L- Oxothiazolidine 4-Carboxylate Reduces Sulfur Mustard Cytotoxicity

Despite 70 years of research, there appears to be no satisfactory prophylaxis or treatment for the vesicant chemical warfare agent sulfur mustard (HD). Attempts to modify cytotoxicity of HD are now focusing on the use of intracellular 'scavengers' to interact with sulfur mustard before it...

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Bibliographic Details
Main Authors: Gross, Clark L, Smith, William J
Format: Report
Language:English
Subjects:
ADDITION
ANTIDOTES
BLOOD
BLUE(COLOR)
CARBOXYLATE/L-OXOTHIAZOLIDINE-4
CARBOXYLATES
CELLS
CHEMICAL WARFARE
CHEMICAL WARFARE AGENTS
Chemical, Biological and Radiological Warfare
CHEMICALS
COLORS
COMPONENT REPORTS
CONTROL
CYSTEINE
CYTOTOXICITY
CYTOTOXINS
DETOXIFICATION
DYES
FLOW
FOCUSING
GLUTATHIONE
HD AGENT
HUMANS
INCUBATION
IODIDES
LYMPHOCYTES
OXOTHIAZOLIDINE CARBOXYLATES
PBL(PERIPHERAL BLOOD LYMPHOCYTES)
Pharmacology
PRECURSORS
SULFUR
TARGETS
TOXICITY
Toxicology
VALUE
VESICANTS
WARFARE
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Description
Summary:Despite 70 years of research, there appears to be no satisfactory prophylaxis or treatment for the vesicant chemical warfare agent sulfur mustard (HD). Attempts to modify cytotoxicity of HD are now focusing on the use of intracellular 'scavengers' to interact with sulfur mustard before it can react with critical targets within the cell. Glutathione (GSH) is known to react readily with HD and is involved in the major metabolic pathway to HD detoxification. Glutathione level within the cell was raised 40-60% over control values by pretreatment of quiescent human peripheral blood lymphocytes (PBL) with 10 mM L-oxothiazolidine-4-carboxylate (OTC), a masked cysteine precursor. This increase in glutathione level was not toxic to the cells as judged by trypan blue dye exclusion and reached a maximum level in 48 hrs. PBL pretreated with 10 mM OTC for 48 hrs were harvested, washed, and exposed to 10, 50, or 100 uM HD. After an additional 48 hrs of incubation at 37 deg C, cytotoxicity was measured by propidium iodide dye uptake using flow cytometry. Pretreatment with OTC led to a 20% decrease in cytotoxicity with 10 uM HD, an 11% decrease in cytotoxicity with 50 uM HD, and an 8% decrease in cytotoxicity with 100 uM HD. Cytotoxicity of HD was not influenced by addition of 10 mM OTC 2 hrs after HD exposure. These results suggest that biochemical manipulation of intracellular GSH level may provide an important pretreatment regimen to reduce the cytotoxicity of HD. This article is from 'Proceedings of the Medical Defense Bioscience Review (1993) Held in Baltimore, Maryland on 10-13 May 1993. Volume 1', AD-A275 667, p141-147.