Toxicological Research

Korean Society of Toxicology & Korea Environmental Mutagen Society (한국독성학회)
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Impaired Metabolomics of Sulfur-Containing Substances in Rats Acutely Treated with Carbon Tetrachloride

  • Published : 2008.12.01
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Abstract

Impairment of hepatic metabolism of sulfur-containing amino acids has been known to be linked with induction of liver injury. We determined the early changes in the transsulfuration reactions in liver of rats challenged with a toxic dose of $CCl_4$ (2 mmol/kg, ip). Both hepatic methionine concentration and methionine adenosyltransferase activity were increased, but S-adenosylmethionine level did not change. Hepatic cysteine was increased significantly from 4 h after $CCl_4$ treatment. Glutathione (GSH) concentration in liver was elevated in $4{\sim}8$ h and then returned to normal in accordance with the changes in glutamate cysteine ligase activity. Cysteine dioxygenase activity and hypotaurine concentration were also elevated from 4 h after the treatment. However, plasma GSH concentration was increased progressively, reaching a level at least several fold greater than normal in 24 h. ${\gamma}$-Glutamyltransferase activity in kidney or liver was not altered by $CCl_4$, suggesting that the increase in plasma GSH could not be attributed to a failure of GSH cycling. The results indicate that acute liver injury induced by $CCl_4$ is accompanied with extensive alterations in the metabolomics of sulfurcontaining amino acids and related substances. The major metabolites and products of the transsulfuration pathway, including methionine, cysteine, hypotaurine, and GSH, are all increased in liver and plasma. The physiological significance of the change in the metabolomics of sulfur-containing substances and its role in the induction of liver injury need to be explored in future studies.

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References

  1. Adinolfi, L.E., Ingrosso, D., Cesaro, G., Cimmino, A., D'Anto, M., Capasso, R., Zappia, V. and Ruggiero, G. (2005). Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C patients. Hepatology, 41, 995-1003 https://doi.org/10.1002/hep.20664
  2. Bagley, P.J., Hirschberger, L.L. and Stipanuk, M.H. (1995). Evaluation and modification of an assay procedure for cysteine dioxygenase activity: High-performance liquid chromatography method for measurement of cysteinesulfinate and demonstration of physiological relevance of cysteine dioxygenase activity in cysteine catabolism. Anal. Biochem., 227, 40-48 https://doi.org/10.1006/abio.1995.1250
  3. Corrales, F., Gimenez, A., Alvarez, L., Caballeria, J., Pajares, M.A., Andreu, H., Pares, A., Mato, J.M. and Rodes, J. (1992). S-adenosylmethionine treatment prevents carbon tetrachloride-induced S-adenosylmethionine synthetase inactivation and attenuates liver injury. Hepatology, 16, 1022-1027 https://doi.org/10.1002/hep.1840160427
  4. Corrales, F.J., Ruiz, F. and Mato, J.M. (1999). In vivo regulation by glutathione of methionine adenosyltransferase Snitrosylation in rat liver. J. Hepatol., 31, 887-894 https://doi.org/10.1016/S0168-8278(99)80291-8
  5. Gaitonde, M.K. (1967). A spectrophotometric method for the direct determination of cysteine in the presence of other naturally occurring amino acids. Biochem. J., 104, 627-633 https://doi.org/10.1042/bj1040627
  6. Griffith, O.W. (1980). Determination of glutathione and glutathione disulfide using glutathione reductase and 2- vinylpyridine. Anal. Biochem., 106, 207-212 https://doi.org/10.1016/0003-2697(80)90139-6
  7. Hinchman, C.A. and Ballatori, N. (1999). Glutathione-degrading capacities of liver and kidney in different species. Biochem. Pharmacol., 40, 1131-1135 https://doi.org/10.1016/0006-2952(90)90503-D
  8. Horowitz, J.H., Rypins, E.B., Henderson, J.M., Heymsfield, S.B., Moffitt, S.D., Bain, R.P., Chawla, R.K., Bleier, J.C. and Rudman, D. (1981). Evidence for impairment of transsulfuration pathway in cirrhosis. Gastroenterology, 81, 668- 675
  9. Ide, T. (1997). Simple high-performance liquid chromatographic method for assaying cysteinesulfinic acid decarboxylase activity in rat tissue. J. Chromatogr. B Biomed. Sci. Appl., 694, 325-332 https://doi.org/10.1016/S0378-4347(97)00128-X
  10. Irita, K., Okabe, H., Koga, A., Kurosawa, K., Tagawa, K., Yamakawa, M., Yoshitake, J. and Takahashi, S. (1994). Carbon tetrachloride increases sinusoidal efflux of reduced and oxidized glutathione in rats. Biochem. Pharmacol., 47,447-452 https://doi.org/10.1016/0006-2952(94)90174-0
  11. Ji, C., Deng, Q. and Kaplowitz, N. (2004). Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology, 40, 442-451 https://doi.org/10.1002/hep.20309
  12. Kadiiska, M.B., Gladen, B.C., Baird, D.D., Dikalova, A.E., Sohal, R.S., Hatch, G.E., Jones, D.P., Mason, R.P. and Barrett, J.C. (2000). Biomarkers of oxidative stress study: are plasma antioxidants markers of CCl4 poisoning? Free Radic. Biol. Med., 28, 838-845 https://doi.org/10.1016/S0891-5849(00)00198-2
  13. Kashiwamata, S. and Greenberg, D.M. (1970). Studies on cystathionine synthase of rat liver. Properties of the highly purified enzyme. Biochim. Biophys. Acta, 212, 488-500 https://doi.org/10.1016/0005-2744(70)90255-X
  14. Kim, S.J., Jung, Y.S., Kwon, D.Y. and Kim, Y.C. (2008). Alleviation of acute ethanol-induced liver injury and impaired metabolomics of S-containing substances by betaine supplementation. Biochem. Biophys. Res. Commun., 368, 893- 898 https://doi.org/10.1016/j.bbrc.2008.02.003
  15. Kim, S.K. and Kim, Y.C. (2002). Attenuation of bacterial lipopolysaccharide- induced hepatotoxicity by betaine or taurine in rats. Food Chem. Toxicol., 40, 545-549
  16. Kim, S.K. and Kim, Y.C. (2005). Effects of betaine supplementation on hepatic metabolism of sulfur-containing amino acids in mice. J. Hepatol., 42, 907-913 https://doi.org/10.1016/j.jhep.2005.01.017
  17. Kim, Y.C., Jung, Y.S. and Kim, S.K. (2005). Effect of betaine supplementation on changes in hepatic metabolism of sulfur- containing amino acids and experimental cholestasis induced by alpha-nap hthylisothiocyanate. Food Chem. Toxicol., 43, 663-670 https://doi.org/10.1016/j.fct.2004.12.015
  18. Kinsell, L.W., Harper, H.A., Barton, H.C., Michaels, G.D. and Weiss, H.A. (1947). Rate of disappearance from plasma of intravenously administered methionine in patients with liver damage. Science, 106, 589-594 https://doi.org/10.1126/science.106.2763.589
  19. Kwon, D.Y., Jung, Y.S., Kim, S.J., Park, H.K., Park, J.H. and Kim, Y.C. (2008). Impaired sulfur-amino acid metabolism and oxidative stress in non-alcoholic fatty liver are alleviated by betaine supplementation in rats. J. Nutr. (in press)
  20. Lee, S.Y. and Kim, Y.C. (2007). Effect of beta-alanine administration on carbon tetrachloride-induced acute hepatotoxicity. Amino Acids, 33, 543-546 https://doi.org/10.1007/s00726-006-0450-7
  21. Lu, S.C. (1998). Regulation of hepatic glutathione synthesis. Semin. Liver Dis., 18, 331-343
  22. Mato, J.M. and Lu, S.C. (2007). Role of S-adenosyl-L-methionine in liver health and injury. Hepatology, 45, 1306-1312 https://doi.org/10.1002/hep.21650
  23. Matsuo, Y. and Greenberg, D.M. (1957). A crystalline enzyme that cleaves homoserine and cystathionine. I. isolation procedure and some physicochemical properties. J. Biol. Chem., 230, 545-560
  24. Miyazaki, T., Karube, M., Matsuzaki, Y., Ikegami, T., Doy, M., Tanaka, N. and Bouscarel, B. (2005). Taurine inhibits oxidative damage and prevents fibrosis in carbon tetrachloride- induced hepatic fibrosis. J. Hepatol., 43, 117-125 https://doi.org/10.1016/j.jhep.2005.01.033
  25. Mudd, S.H. and Poole, J.R. (1975). Labile methyl balances for normal humans on various dietary regimens. Metabolism, 24, 721-735 https://doi.org/10.1016/0026-0495(75)90040-2
  26. Nieto, N. and Cederbaum, A.I. (2005). S-adenosylmethionine blocks collagen I production by preventing transforming growth factor-beta induction of the COL1A2 promoter. J. Biol. Chem., 280, 30963-30974 https://doi.org/10.1074/jbc.M503569200
  27. Ookhtens, M. and Kaplowitz, N. (1998). Role of the liver in interorgan homeostasis of glutathione and cyst(e)ine. Semin. Liver Dis., 18, 313-329
  28. Orlowski, M. and Meister, A. (1963). ${\gamma}$-Glutamyl-p-nitroanilide: a new convenient substrate for determination and study of L- and D-glutamyltranspeptidase activities. Biochim. Biophys. Acta, 73, 676-679 https://doi.org/10.1016/0006-3002(63)90347-0
  29. Pajares, M.A., Durán, C., Corrales, F., Pliego, M.M. and Mato, J.M. (1992). Modulation of rat liver S-adenosylmethionine synthetase activity by glutathione. J. Biol. Chem., 267, 17598-17605
  30. Rajendra, W. (1987). High performance liquid chromatographic determination of amino acids in biological samples by precolumn derivatization with O-phthaldehyde. J. Liq. Chromatogr. Relat. Technol., 10, 941-955 https://doi.org/10.1080/01483918708066746
  31. Recknagel, R.O., Glende, Jr., E.A., Dolak, J.A. and Waller, R.L. (1989). Mechanisms of carbon tetrachloride toxicity. Pharmacol. Ther., 43, 139-154 https://doi.org/10.1016/0163-7258(89)90050-8
  32. Reitman, S. and Frankel, S.A. (1957). Colorimetric method for determination of serum glutamic oxaloacetic and glutamic pyruvic transaminases. Am. J. Clin. Pathol., 28, 56-63 https://doi.org/10.1093/ajcp/28.1.56
  33. Sanchez-Gongora, E., Ruiz, F., Mingorance, J., An, W., Corrales, F.J. and Mato, J.M. (1997). Interaction of liver methionine adenosyltransferase with hydroxyl radical. FASEB J., 11, 1013-1019 https://doi.org/10.1096/fasebj.11.12.9337154
  34. Sekura, R. and Meister, A. (1977). Gamma-Glutamylcysteine synthetase. Further purification, "half of the sites" reactivity, subunits, and specificity. J. Biol. Chem., 252, 2599- 2605
  35. She, Q.B., Nagao, I., Hayakawa, T. and Tsuge, H. (1994). A simple HPLC method for the determination of S-adenosylmethionine and S-adenosylhomocysteine in rat tissues: the effect of vitamin B6 deficiency on these concentrations in rat liver. Biochem. Biophys. Res. Commun., 205, 1748- 1754 https://doi.org/10.1006/bbrc.1994.2871
  36. Simile, M.M., Banni, S., Angioni, E., Carta, G., De Miglio, M.R., Muroni, M.R., Calvisi, D.F., Carru, A., Pascale, R.M. and Feo, F. (2001). 5'-Methylthioadenosine administration prevents lipid peroxidation and fibrogenesis induced in rat liver by carbon-tetrachloride intoxication. J. Hepatol., 34, 386-394 https://doi.org/10.1016/S0168-8278(00)00078-7
  37. Stipanuk, M.H., Coloso, R.M., Garcia, R.A. and Banks, M.F. (1992). Cysteine concentration regulates cysteine metabolism to glutathione, sulfate and taurine in rat hepatocytes. J. Nutr., 122, 420-427 https://doi.org/10.1093/jn/122.3.420
  38. Volpi, N. and Tarugi, P. (1998). Improvement in the high-performance liquid chromatography malondialdehyde level determination in normal human plasma. J. Chromatogr. B Biomed. Sci. Appl., 713, 433-437 https://doi.org/10.1016/S0378-4347(98)00195-9
  39. Whitfield, J.B. (2001). Gamma glutamyl transferase. Crit. Rev. Clin. Lab. Sci., 38, 263-355 https://doi.org/10.1080/20014091084227
  40. Yan, C.C. and Huxtable, R.J. (1995). Fluorimetric determination of monobromobimane and O-phthalaldehyde adducts of gamma-glutamylcysteine and glutathione: application to assay of gamma-glutamylcysteinyl synthetase activity and glutathione concentration in liver. J. Chromatogr. B Biomed. Appl., 672, 217-224 https://doi.org/10.1016/0378-4347(95)00226-9