Abstract
Our previous studies demonstrate that menadione (MEN) is cytotoxic to platelets of rats by depleting glutathione (GSH). In order to clarify whether GSH has a role in protecting against menadione-induced cytotoxicity, the effect of GSH depletors as well as GSH precusors on menadione-induced cytotoxicity was investigated. Cysteine and dithiothreitol (DTT) prevent MEN-induced cytotoxicity in a dose-dependent manner, as determined by LDH leakage and change in turbidity. When platelets were treated with 1-chloro-2,4-dinitrobenzene (CNDB) and diethylmaleate (DEM), both of which deplete intracellular GSH, MEN-induced cytotoxicity was potentiated in the CDNB-treated platelets, but not in the DEM-treated platelets. These data suggest that the GSH in platelets plays an important role in protecting against cytotoxicity induced by menadione.
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References Cited
Beatty, W. P. and Reed, J. D., Involvement of the cystathionine pathway in the biosynthesis of glutathione by isolated rat hepatocytes.Arch. Biochem. Biophys. 204, 80–87 (1980).
Bergmeyer, H.U., Bernt, E. and Hess, B., Lactate dehydrogenase. InMethods in Enzymatic Analysis (H.U. Bergmeyer, ed.), Academic Press, New York, 1965, pp. 736.
Bosia, A., Spangenberg, P., Ghogo, D., Heller, R., Losche, W., Perscarmona, G. P., and Till, U., Effect of GSH depletion by 1-chloro-2,4-dinitrobenzene on human platelet aggregation, arachidonic acid oxidative metabolic and cytoskeleton proteins.Throm. Res. 37, 423–434 (1985).
Bryant, R. W., Simon, T. C. and Bailey, J. M., Role of hexose monophosphate shunt in the platelet lipoxygenase pathway.J. Biol. Chem. 257, 14937–14943 (1982).
Di Monte, D., Ross, D., Bellomo, G., Eklow, L. and Orrenius, S., Alteration in intracellular thiol homeostasis during the metabolism of menadione by isolated rat hepatocytes.Arch. Biochem. Biophys. 235, 334–342 (1984a).
Di Monte, D., Bellomo, G., Thor, H., Nicotera, P. and Orrenius, S., Menadione-induced cytotoxicity is associated with thiol oxidation and alteration in intracellular Ca2+ homeostasis.Arch. Biochem. Biophys. 235, 343–350 (1984b).
Hill, T. D., White, J. G. and Rao, G. H. R., Role of glutathione peroxidase in human platelet arachidonic acid metabolism.Prostaglandins 38, 21–32 (1989).
Kim, K. A. Lee, J. Y., Park, K. S., Kim, M. J. and Chung, J. H., Mechanism of menadione-induced cytotoxicity in rat platelets.Toxicol. Appl. Pharmacol., in press (1995a).
Kim, K. A., Kim, M. J., Ryu, C. K., Chang, M. J. and Chung, J. H., Menadione-induced cytotoxicity in rat platelets: Absence of the detoxifying enzyme, quinone reductase.Arch. Pharm. Res. 18, 256–261 (1995b).
Mirabelli, F., Salis, A., Vairetti, M., Bellomo, G., Thor, H. and Orrenius, S., Cytoskeletal alterations in human platelets exposed to oxidative stress are mediated by oxidative and Ca2+-dependent mechanisms.Arch. Biochem. Biophys. 270, 478–488 (1989).
Monks, T. J., Hanzlik, R. P., Cohen, G. M., Ross, D. and Graham, D. G., Contemporary issues in toxicology: Quinone chemistry and toxicity.Toxicol. Appl. Pharmacol. 112, 2–16 (1992).
Nicotera, P., Bellomo, G. and Orrenius, S., Inhibition of hepatocyte plasma membrane Ca2+-ATPase activity by menadione metabolism and its restoration by thiols.FEBS lett. 181, 149–153 (1985).
Orrenius, S., Ormsrad, K., Thor, H. and Jewel, S. A., Turnover and functions of glutathione studied with isolated hepatic and renal cells.FASEB J. 42, 3177–3188 (1983).
Redegeld, R. A., Hofman, G. A., van de Loo, P. G. F., Koater, A. S. and Noordfoek, J., Nephrotoxicity of the glutathione conjugate of menadione (2-methyl-1,4-naphthoquinone) in the isolated perfused rat kidney.J. Pharmacol. Exp. Ther. 242, 741–748 (1989).
Straat, R., Vries, J. and Vermeulen, N.P.E., Role of hepatic microsomal and purified cytochrome P-450 in one-electron reduction of two quinone imines and concomitant reduction of molecular oxygen.Biochem. Pharmacol. 36, 613–619 (1987).
Thor, H., Moldeus, P., Hermanson, R., Hogberg, J., Reed, D. J. and Orrenius, S., Toxicity of bromobenzene in hepatocytes isolated from phenobarbital and diethylmaleate treated rats.Arch. Biochem. Biophys. 188, 122–129 (1978).
Thor, H., Moldeus, P. and Orrenius, S., Metabolic activation and hepatotoxicity: Effect of cysteine, N-acetylcysteine and methionine on glutathione biosynthesis and bromobenzene toxicity in isolated rat hepatocytes.Arch. Biochem. Biophys. 192, 405–413 (1979).
Thor, H., Smith, M. T., Hartzell, P., Bellomo, G., Jewell, S. A. and Orrenius, S., The metabolism of menadione (2-methyl-1,4-naphthoquinone) by isolated hepatocytes.J. Biol. Chem. 257., 12419–12425 (1982).
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Cho, YS., Seung, SA., Kim, MJ. et al. Important role of glutathione in protecting against menadione-induced cytotoxicity in rat platelets. Arch. Pharm. Res. 19, 12–17 (1996). https://doi.org/10.1007/BF02976813
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DOI: https://doi.org/10.1007/BF02976813