The elevation of intracellular Ca2+ in various tissue through oxidative stress induced by menadione has been well documented. Increase of Ca2+ level in platelets results in aggregation of platelets. To test the hypothesis that menadione-induced Ca2+ elevations can play a role in platelet aggregation, we have studied the effect of menadione on aggregation of platelets isolated from female rats. Treatment with menadione to platelet rich plasma (PRP), which proved to be an adequate system, appeared to induce dose-dependent turbidity changes of platelets up to 60%, as determined by aggregometry. However, exposure of PRP to menadione leads to a loss of cell viability, as measured by lactate dehydrogenase (LDH) leakage, suggesting that menadione might induce cell lysis rather than aggregation of platelets. Turbidity changes induced by menadione were unaffected by addition of dicoumarol, which is a quinone reductase (QR) inhibitor. Consistent with these findings, no activity of QR was detected in any subcellular fractions of platelets. These data, which indicate an absence of the QR detoxifying pathway, suggest that platelets may be more susceptible to menadione-induced cytotoxicity than certain other cell, such as hepatocytes.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price includes VAT (USA)
Tax calculation will be finalised during checkout.
Benson, A. M., Hunkeler, M. J. and Talalay, A. P., Increase of NAD(P)H guinone reductase by dietary antioxidants: possible role in protection against carcinogenesis and toxicity.Proc. Natl. Acad. Sci. USA 77, 5216–5220 (1980).
Brass, L. F., Ca+2 homeostasis in unstimulated platelet.J. Biol. Chem., 259, 12563–12570 (1984).
Dicker, E. and Cederbaum, A. I., Requirement for iron for the production of hydroxyl radicals by rat liver quinone reductase.J. Pharmacol. Exp. Ther. 266, 1282–1290 (1993).
Di Monte, D., Ross, D., Bellomo, G., Eklow, L. and Orrenius, S., Alterations in intracellular thiol homeostasis during the metabolism of menadione isolated rat hepatocyte.Arch. Biochem. Biochem. Biophys. 235, 334–342 (1984a).
Di Monte, D., Bellomo, G., Thor, H., Nicotera, P. and Orenius, S., Menadione induced cytotoxicity is associated with thiol oxidation and alteration in intracellular Ca+2 homeostasis.Arch. Biochem. Biophys. 235, 343–350 (1984b).
Frojmovic, M. M. and Milton, J. G. Human platelet size, shape and related functions in health and disease.Physiol. Rev. 62, 185–261 (1982).
Johnson, P. C., Ware, J. A., Clivden, P. B., Smith, M., Pvorak, A. M. and Salzman, E. W., Measurement of ionized calcium in blood platelet with the photoprotein aequorin: comparison with quin 2.J. Biol. Chem. 260, 2069–2076 (1985).
Katzenschlager, R., Weiss, K., Rogatti, W., Stelzeneder, M. and Sinzinger, H., Interaction between prostaglandin E1 and nitric oxide (NO).Thomb. Res. 62, 299–304 (1991).
Kim, D. H., Ohnishi, T. and Ikemoto, N., Kinetic studies of calcium release from sarcoplasmic reticulumin vitro.J. Biol. Chem. 258, 9612–9668 (1983).
Ko, F. N., Sheu, S. J., Liu, Y. M., Huang, T. F. and Teng, C. M., Inhibition of rabbit platelet aggregation by 1,4-naphthoquinones.Thromb. Res. 57, 453–459 (1990).
Kovacs, T., Tordai, A., Szasz, I., Sarkadi, B. and Gardos, G., Membrane depolarization inhibits thrombin-induced calcium influx and aggregation in human platelets.FEBS Lett. 266, 171–174 (1989).
Lasslo, A, and Quintana, R. P., Interaction dynamics of blood plateles with medicinal agents and other chemical entities. InBlood Platelet Function and Medicinal Chemistry (A. Lasslo, Ed.) Elsevier, New York, 1984, pp. 229–315.
Lind, C., Hochstein, P. and Ernster, L., DT-diaphorase as a quinone reductase: cellular control device against semiquinone and superoxide radical formation.Arch. Biochem. Biophys, 216, 178–105 (1982).
Mirabelli, F., Salis, A., Perotti, M., Taddei, F., Bellomo, G. and Orrenius, S., Alteration of surface morphology caused by the metabolism of menadione in mammalian cells are associated with the oxidation of critical sulfhydryl groups in cytoskeletal proteins.Biochem. Pharmacol. 37, 3423–3427 (1988).
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, K. and Graham, D. G., Contemporary issues in toxicology: Quinone chemistry and toxicity.Toxicol. Appl. Pharmacol. 112, 2–16 (1992).
Mustard, J. F., Perry, D. W., Ardile, N. G. and Packman, M. A., Preparation of suspension of washed platelets from humans.Br. J. Haematol. 22, 193–204 (1972).
Mustard, J. F. and Packman, M. A., Factors influencing platelet function: Adhesion release and aggregation.Pharmacol. Rev. 22, 97–187 (1979).
Nicotera, P., Bellomo, G. and Orrenius, S., Calcium-mediated mechanisms in chemically induced cell death.Annu. Rev. Pharmacol. Toxicol. 32, 449–470 (1992).
Puri, R. N., Zhon, F., Bradford, H. and Hu, C. H., Thrombin-induced platelet aggregation involves an indirect proteolytic cleavage by calpain.Arch. Biochem. Biophys. 271, 346–358 (1989).
Radomski, M. W., Palmer, R. M. J. and Moncada, S., Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets.Br. J. Pharmac. 92, 181–187 (1987).
Rink, T. J., Smith, S. W. and Tsien, R. Y., Cytoplasmic Free Ca+2 in human platelets: Ca+2 thresholds and Ca+2-independent activation for shape change and secretion.FEBS Lett. 148, 21–26 (1982).
Rink, T. J. and Sage, S. O., Calcium signaling in human platelets.Annu. Rev. Physiol. 52, 431–439 (1990).
Smith, P. F., Alberts, D. W. and Rush, G. F., Menadione-induced oxidative stress in hepatocytes isolated from fed and fasted rat: The role of NADPH-regenerating pathways.Toxicol. Appl. Pharmacol. 89, 190–201 (1987).
Stormorken, H., Platelets in hemostasis and thrombosis. InPlatelet Responses and Metabolism (Holmsen, H. Ed.), CRC Press, Boca Raton, 1984, pp. 3–32.
Thompson, A. R. and Harker, L. A. InManual of Hemostasis and Thrombosis. F. A. Davis Co., Philadelphia, 1987, pp. 57–85.
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 rat hepatocytes.J. Biol. Chem. 257, 12419–12425 (1982).
Tsien, R. Y., Rozzan, T. and Rink, T. J., Calcium homeostasis in intact lymphocytes: Cytoplasmic free calcium monitored with a new intracellular trapped fluorescent indicator.J. Cell Biol. 94, 325–334 (1982).
Wefers, H. and Sies, H., Hepatic low-level chemiluminescence during redox cycling of menadione and the menadione-glutathione conjugate: Relation to glutathione and NAD(P)H quinone reductase (DT-diaphorase) activity.Arch. Biochem. Biophys. 224, 568–578 (1983).
About this article
Cite this article
Kim, KA., Kim, MJ., Ryu, CK. et al. Menadione-induced cytotoxicity in rat platelets: Absence of the detoxifying enzyme, quinone reductase. Arch. Pharm. Res. 18, 256–261 (1995). https://doi.org/10.1007/BF02976409
- Quinone reductase