Abstract
Glutathione (GSH) is the major nonprotein thiol that can protect cells from damage due to electrophilic alkylating agents by forming conjugates with the agent. Sulfur mustard (HD) is an electrophilic alkylating agent that has potent mutagenic, carcinogenic, cytotoxic, and vesicant properties. Compounds that elevate or reduce intracellular levels of GSH may produce changes in cytotoxicity induced by sulfur mustard. Pretreatment of human peripheral blood lymphocytes (PBL) for 72 hr with 1 mM buthionine sulfoximine (BSO), which reduces intracellular GSH content to approximately 26% of control, appears to sensitize these in vitro cells to the cytotoxic effects of 10 μM HD but not to higher HD concentrations. Pretreatment of PBL for 48 hr with 10 mM N-acetyl cysteine (NAC), which elevates intracellular glutathione levels to 122% of control, appears to partially protect these in vitro cells from the cytotoxic effects of 10 μM HD but not to higher HD concentrations. Augmentation of intracellular levels of glutathione may provide partial protection against cytotoxicity of sulfur mustard.
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Abbreviations
- BSO:
-
L-buthionine (S,R)-sulfoximine
- GSH:
-
glutathione
- HD:
-
sulfur mustard
- NAC:
-
N-acetyl-L-cysteine
- PBL:
-
peripheral blood lymphocytes
References
AHMAD, S., OKINE, L., LE, B., NALARIAN, P., and VISTICA, D.T. (1987). “Elevation of glutathione in phenylalanine mustard-resistant murine L1210 leukemia cells” J. Biol. Chem. 262: 15048–15053.
AUERBACH, C. (1949). “Chemical mutagenesis”. Biol. Rev. 24: 355–391.
BELLOMO, G., VAITETTI, M., STIVALA, L., MIRABELLA, F., RICHELEMI, P., and ORRENIUS, S. (1992). “Demonstration of nuclear compartmentalization of glutathione in hepatocytes”. Proc. Natl. Acad. Sci. USA 89: 4412–4416.
BLACK, R.M., BREWSTER, L., CLARKE, R.J., HAMBROOKE, J.L., HARRISON, J.M., and HOWELLS, D.J., (1992). “Biological fate of sulphur mustard 1,1′-thiobis (2-chloethane): isolation and identification of urinary metabolites following intraperitoneal administration to rat”. Xenobiotica 22: 405–418.
DAVISON, C., ROZMAN, R.S., and SMITH, P.K. (1961). “Metabolism of bis-β-chloroethyl sulfide (sulfur mustard gas)”. Biochem. Pharmacol. 7: 64–74.
DETHMERS, J.K., and MEISTER, A. (1981). “Glutathione export by human lymphoid cells: Depletion of glutathione by inhibition of its synthesis decreases export and increases sensitivity to irradiation. Proc. Natl. Acad. Sci. USA 78: 7492–7495.
ELSAYED, N.B., OMAYE, S.T., KLAIN, G.J., INASE, J.L., DAHLBERG, E.T., WHEELER, C.R. KORTE, D.W. (1989) “Response of mouse brain to a single subcutaneous injection of the monofunctional sulfur mustard, butyl 2-chloroethyl sulfide (BCS)”. Toxicology. 58: 11–20.
GENTILHOMME, E., NEVEUX, Y., TUA, A., THIRIOT, M., FAURE, M., and THIVOLET, J. (1992). “Action of bis (betachloroethyl) sulfide (BCES) on human epidermis reconstituted in culture: Morphological alterations and biochemical depletion of glutathione”. Toxicol. in Vitro 6: 139–147.
GRIFFITH, O.W. (1980). “Determination of glutathione and glutathione disulfide using glutathione reductase and 2-vinylpyridine”. Anal. Biochem. 106: 207–212.
GRIFFITH, O. W., and MEISTER, A. (1979). “Potent and specific inhibition of glutathione synthesis by buthionine sulfoximine (S-n-butyl homocysteine sulfoximine)”. J. Biol. Chem. 254: 7558–7560.
HESTON, W.E. (1953). “Occurrence of tumors in mice injected subcutaneously with sulfur mustard and nitrogen mustard”. J. Natl. Cancer Inst. 14: 131–140.
KINSEY, V.E., and GRANT, W.M. (1947). “Action of mustard gas and other poisons on yeast cells III. Distribution of fixed mustard gas in yeast.” J. Cell. Comp. Physiol. 29: 75–84.
KRAMER, R.A., GREENE, K., AHMAD, S., and VISTICA, D.T. (1987). “Chemosensitization of L-phenylalanine mustard by the thiol-modulating agent, buthionine sulfoximine.” Cancer Res. 47: 1593–1597.
MEIER, H.L., and JOHNSON, B.J. (1992). “The determination and prevention of cytotoxic effects induced in human lymphocytes by the alkylating agent 2,2′-dichlorodiethyl sulfide (sulfur mustard, HD).” Toxicol. Appl. Pharmacol. 113: 234–239.
MEIER, H.L., GROSS, C.L., and PAPIRMEISTER, B. (1987). “2,2′-Dichlorodiethyl sulfide decreases NAD+ levels in human leukocytes.” Toxicol. Lett. 39: 109–122.
MEISTER, A., and ANDERSON, M.E. (1983). “Glutathione.” Annu. Rev. Biochem. 52: 711–760.
ONO, K., SHRIEVE, D.C. (1987). “Effect of glutathione depletion byl-buthionine sulfoximine on the cytotoxicity of cyclophosphamide in single and fractionated doses to EMT6/SF mouse tumors and bone marrow.” J. Natl. Cancer Inst. 79: 811–815.
PAPIRMEISTER, B., and DAVISON, C.L. (1965). “Unbalanced growth and latent killing ofEscherichia coli following exposure to sulfur mustard.” Biochim. Biophys. Acta 103: 70–92.
PAPIRMEISTER, B., GROSS, C.L., MEIER, H.L., PETRALI, J.P., and JOHNSON, J.B. (1985). “Molecular basis for mustard-induced vesication.” Fund. Appl. Toxicol. 5: S134-S149.
PURI, R.N., MEISTER, A. (1983). “Transport of glutathione, as γ-glutamylcysteinylglycl ester, into liver and kidney.” Proc. Natl. Acad. Sci. 80: 5258–5260.
SMITH, W.J., GROSS, C.L., CHAN, P., MEIER, H.L. (1990). “The use of human epidermal keratinocytes in culture as a model for studying the biochemical mechanisms of sulfur mustard toxicity.” Cell Biol. Toxicol. 6: 285–291.
SMITH, W.J., SANDERS, K.M., GALES, Y.A., and GROSS, C.L. (1991). “Flow cytometric analysis of toxicity by vesicating agents in human cellsin vitro.” J. Toxicol.-Cutan. Ocular Toxicol. 10: 33–42.
VIJAYARAGHAVAN, R., SUGENDRAN, K., PANT, S.C., HUSAIN, K., and MALHOTRA, R.C. (1991). “Dermal intoxication of mice with bis(2-chloroethyl) sulfide and the protective effect of flavonoids.” Toxicology 69: 35–42.
VOJVODIC, V., MILOSAVLJEVIC, Z., BOSKOVIC, B., and BOJANIC, N. (1985). “The protective effect of different drugs in rats poisoned by sulfur and nitrogen mustards.” Fund. Appl. Toxicol. 5: S160–168.
WALKER, I.G., and SMITH, J.F. (1969). “Protection of L-cells by thiols against the toxicity of sulfur mustard.” Can. J. Physiol. Pharmacol. 47: 143–151.
WARTHIN, S.W., and WELLER, C.V. (1919) The Medical Aspects of Mustard Gas Poisoning. C. V. Mosby, St. Louis, MO.
WONG, B.K., CHAN, H.C., and CORCORAN, G.B. (1986). “Selective effects ofN-acetyl cysteine stereoisomers on hepatic glutathione and plasma sulfate in mice.” Toxicol. Appl. Pharmacol. 86: 421–429.
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The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
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Gross, C.L., Innace, J.K., Hovatter, R.C. et al. Biochemical manipulation of intracellular glutathione levels influences cytotoxicity to isolated human lymphocytes by sulfur mustard. Cell Biol Toxicol 9, 259–267 (1993). https://doi.org/10.1007/BF00755604
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DOI: https://doi.org/10.1007/BF00755604