Abstract
Previous studies have indicated that the generation of H2O2 may be a key step in the mechanism mediating the in vitro cytotoxicity of 3-hydroxykynurenine (3HK). An exposure protocol resulting in a delayed toxicity was utilized in order to further examine the role of H2O2 in the in vitro toxicity of 3HK in a neural hybrid cell line. 3HK-induced cell lysis was significantly attenuated by administration of catalase after termination of 3HK exposure and was abolished when intracellular peroxidase activity was elevated by pretreatment of cultures with horseradish peroxidase. In addition, a dose-dependent attenuation of 3HK toxicity was observed when cultures were exposed to 3HK in the presence of the iron chelator, desferrioxamine (DFO). Pretreatment with DFO also resulted in a significant attenuation of 3HK toxicity. These data suggest a direct role for H2O2 and metal ions in the cytotoxic action of 3HK and indicate that cell lysis results from the intracellular accumulation of toxic levels of H2O2.
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Bessey, O. A., Adams, D. J. D., and Hansen, A. E. 1957. Intake of vitamin B-6 and infantile convulsions: First approximation of requirements of pyridoxine in infants. Pediatrics 20:33–44.
Coursin, D. B. 1969. Vitamin B6 and brain function in animals and man. Ann NY Acad. Sci. 166:7–15.
Dakshinamurti, K. and Stevens, M. C. 1969. Pyridoxine deficiency in the neonatal rat. J. Neurochem. 16:1515–1522.
Guilarte T. R., Wagner, H. N. and Frost, J. J. 1987. Effects of perinatal vitamin B-6 deficiency on dopaminergic neurochemistry. J. Neurochem. 48:432–439.
Tower, D. B. 1959. Neurochemical aspects of pyridoxine metabolism and function. Am. J. Clin. Nutr. 4:329–45.
Root, E. J. and Longenecker, J. B. 1983. Brain cell alterations suggesting premature aging induced by dietary deficiency of vitamin B6 and/or copper. Am. J. Clin. Nutr. 37:540–552.
Wasynczuk, A., Kirksey, A., and Morre, D. M. 1983. Effects of vitamin B6 deficiency on specific regions of developing rat brain: the extrapyramidal motor system. J. Nutr. 113:746–754.
Bayoumi, R. A., and Smith, W. R. D. 1972. Some effects of dietary vitamin B-6 deficiency on gamma-aminobutyric acid metabolism in developing rat brain. J. Neurochem. 19:1883–1897.
Paulose, C. S., and Dakshinamurti, K. 1984. Enhancement of high affinity gamma-aminobutyric acid receptor binding in cerebellum of pyridoxine-deficient rat. Neurosci. Lett. 48:311–316.
Guilarte, T. R. 1989. Regional changes in the concentrations of glutamate, glycine, taurine, and GABA in the vitamin B-6 deficient developing rat brain: Association with neonatal seizures. Neurochem. Res. 14:889–897.
Dakshinamurti, K., LeBlanq, W. D., Herchl, R., and Havlicek, V. 1976. Nonparallel changes in brain monoamines of pyridoxinedeficient growing rats. Exp. Brain Res. 26:355–366.
Guilarte, T. R. Effect of vitamin B-6 nutrition on the levels of dopamine, dopamine metabolites, dopa decarboxylase activity, tyrosine and GABA in the developing rat corpus striatum. Neurochem. Res. 14:571–578.
Lapin, I. P. 1981. Kynurenines and seizures, Epilepsia 22:257–265.
Pinelli, A., Ossi, C., Columbo, R., Tofanetti, O., and Spazzi, L., 1984. Experimental convulsions in rats induced by intraventricular administration of kynurenine and structurally related compounds, Neuropharmacology 23:333–337.
Eastman, C. L., and Guilarte, T. R. 1989. Cytotoxicity of 3-hydroxykynurenine in a neuronal hybrid cell line. Brain Res. 495:225–231.
Reynolds, G. P., and Pearson, S. J. 1989. Increased brain 3-hydroxykynurenine in Huntington's disease. Lancet 2():979–80.
Heyes, M. P., Queany, B. J., and Markey, S. P. 1989. Systemic endotoxin increasesl-tryptophan, 5-hydroxyindoleacetic acid, 3-hydroxykynurenine and quinolinic acid content of mouse cerebral cortex. Brain Res. 491:173–179.
Guilarte, T. R., and Wagner, H. N. 1989. Increased concentrations of 3-hydroxykynurenine in vitamin B-6 deficient neonatal rat brain. J. Neurochem. 49:1918–1926.
Tomoda, A., Shirasawa, E. and Yoneyama, Y. 1986. Reactions of oxy- and methemoglobin with tryptophan metabolites, 3-hydroxyanthranilic acid and 3-hydroxykynurenine. Hemoglobin 10:33–44.
Malouf, A. T., Schnaar, R. L., and Coyle, J. T. 1984. Characterization of aglutamic acid neurotransmitter binding site on neuroblastoma hybrid cells. J. Biol. Chem. 259:12756–12762.
Schnaar, R. L., Weigel, P. H., Kuhlenschmidt, M. S., Lee, Y. C., and Roseman, S. 1978. Adhesion of chicken hepatocytes to polyacrylamide gels derivatized with N-actylglucosamine. J. Biol. Chem. 253:7940–7951.
Heimer, L., and Robards, M. J. 1981. Neuroanatomical Tract Tracing Methods, Plenum Press, NY.
Miller, D. M., Buettner, G. R., and Aust, S. D. 1990. Transition metals as catalysts of “autoxidation” reactions. Free Radical Biol. Med. 8:95–108.
Keberle, H. 1964. The biochemistry of desferrioxamine and its relation to iron metabolism. Ann. NY Acad. Sci. 119:758–768.
Cantoni, O., Fumo, M., and Cattabeni, F. 1989. Role of metal ions in oxidant cell injury. Biological Trace Element Res. 21:277–281.
Speciale, C., Hares, R., Schwarcz, and Brookes, N. 1989. Highaffinity uptake ofl-kynurenine by a Na+-independent transporter of neutral amino acids in astrocytes. J. Neurosci. 9:2066–2072.
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Eastman, C.L., Guilarte, T.R. The role of hydrogen peroxide in the in vitro cytotoxicity of 3-hydroxykynurenine. Neurochem Res 15, 1101–1107 (1990). https://doi.org/10.1007/BF01101711
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DOI: https://doi.org/10.1007/BF01101711