Archives of Pharmacal Research

, Volume 23, Issue 5, pp 495–500 | Cite as

Effect of S-adenosylmethionine on hepatic injury from sequential cold and warm ischemia

  • Yu -Bum Lee
  • Sun -Mee Lee
Research Articles Pharmacology, Toxicology & Pharmaceutics


We investigated whether S-adenosylmethionine (SAM) treatment improved ischemic injury using perfused rat liver after sequential periods of 24 h cold and 20 min re-warming ischemia. SAM (100 μmol/L) was added to University of Wisconsin (UW) solution and Ringers lactate solution. After cold and sequential warm ischemia, releases of lactate dehydrogenase (LDH) and purine nucleoside phosphorylase (PNP) markedly increased during reperfusion. The increase in PNP was significantly reduced by SAM treatment. While the concentration of reduced glutathione (GSH) in ischemic livers significantly decreased, the concentration of glutathione disulfide (GSSG) increased. This decrease in GSH and increase in GSSG were suppressed by SAM treatment. Lipid peroxidation was elevated in cold and warm ischemic and reperfused livers, but this elevation was also prevented by SAM treatment. Hepatic ATP levels were decreased in the ischemic and reperfused livers to 42% of the control levels. However, treatment with SAM resulted in significantly higher ATP levels and preserved the concentration of AMP in ischemic livers. Our findings suggest that SAM prevents oxidative stress and lipid peroxidation and helps preserve hepatic energy metabolism.

Key words

S-Adenosylmethionine UW solution Total purine bases Lipid peroxidation Oxidative stress Ischemia 


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  1. Adam, R., Bismuth, H. and Diamond, T., Effect of extended cold ischemia with UW solution on graft function after liver transplantation.Lancet, 340, 1373–1376 (1992).PubMedCrossRefGoogle Scholar
  2. Atkinson, D. E., Cellular energy metabolism and its regulation. New York: Academic Press, pp. 29–35, (1977).Google Scholar
  3. Bradford, M. E., A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principles of protein-dye binding.Anal. Biochem., 42, 248–254 (1976).CrossRefGoogle Scholar
  4. Brass, C. A. and Mody, M. G., Evaluation of purine nucleoside phosphorylase release as a measure of hepatic endothelial cell injury.Hepatology, 21, 174–179 (1995).PubMedGoogle Scholar
  5. Brehe, J. E. and Burch, H. B., Enzymatic assay for glutathione.Anal. Biochem., 74, 189–197 (1978).CrossRefGoogle Scholar
  6. Brunder, G., Heid, H., Jarasch, E. D., Keenan, T. W. and Mather, I. H., Characteristics of membrane-bound and soluble forms of xanthine oxidase from milk and endothelial cells of capillaries.Biochem. Biophys. Acta, 701, 357–369 (1982).Google Scholar
  7. Caldwell-Kenkel, J. C., Currin, R. T., Tanaka, Y., Thurman, R. G. and Lemasters, J. J., Kupffer cell activation and endothelial cell damage after storage of rat livers: effects of reperfusion.Hepatology, 13, 83–95 (1991).PubMedGoogle Scholar
  8. Clemens, M. G., McDonagh, P. H., Chaudry, I. H. and Baue, A. E., Hepatic microvascular protection from ischemia with ATP-MgCl2.Microvasc. Res., 3, 228–229 (1983).Google Scholar
  9. Corrales, F., Alvarez, L., Pajares, M. A., Ortiz, P. and Mato, J. M., Impairment of methionine metabolism in liver disease.Drug. Invest., 4, 8–10 (1992).Google Scholar
  10. Drugus, G. T., Paidas, C. N., Yahanda, A. M., Ferguson, D. and Clemens, M. G., Conjugated desferoxamine attenuates hepatic microvascular injury following ischemia/reperfusion.Circ. Shock, 34, 278–283 (1991).Google Scholar
  11. Dunne, J. B., Davenport, M., Williams, R. and Tredger, J. M., Evidence that S-adenosylmethionine and N-acetyl-cysteine reduce injury from sequential cold and warm ischemia in the isolated perfused rat liver.Transplantation, 57, 1161–1168 (1994).PubMedCrossRefGoogle Scholar
  12. Dunne, J. B., Piratvisuth, T., Williams, R. and Tredger, J. M., Treatment of experimental ischemia/reperfusion injury with S-adenosylmethionine.Transplantation, 63, 500–506 (1997).PubMedCrossRefGoogle Scholar
  13. Finkelstein, J. D., Kyle, W. E., Martin, J. L. and Pick, A. M., Activation of cystathione synthesis by adenosylmethionine and adenosylethionine.Biochem. Biophys. Res. Commun., 66, 81–87 (1975).PubMedCrossRefGoogle Scholar
  14. Friedel, H. A., Goa, K. L. and Benfield, P., S-adenosyl-L-methionine: A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism.Drugs, 38, 389–416 (1989).PubMedCrossRefGoogle Scholar
  15. Furukawa, H., Todo, S., Imventarza, O., Casavilla, A., Wu, Y. M., Scotti-Foglieni, C., Broznick, B., Bryant, J., Day, R. and Starzl, T. E., Effect of cold ischemia time on the early outcome of human hepatic allografts preserved with UW solution.Transplatation, 51, 1000–1004 (1991).Google Scholar
  16. Harvey, P. R. C., Iu, S., McKeown, C. M. B. and Strasberg, S. M., Adenine nucleotide tissue concentrations and liver allograft viability after cold preservation and warm ischemia.Transplantation, 45, 1016–1020 (1988).PubMedCrossRefGoogle Scholar
  17. Hoffee, P. A., May, R. and Robertson, B. D., Purine nucleoside phosphorylase fromSalmonella typhimurium and rat liver. In: Hoffee P, Jones MA, eds.Methods in enzymology. Vol 51. New York: Academic Press, pp. 517–524, (1978).Google Scholar
  18. Howard, T. K., Goran, B. and Klintmalm, G., The influence of preservation injury on rejection in the hepatic transplant recipient.Transplantation, 49, 103–107 (1990).PubMedCrossRefGoogle Scholar
  19. Ikeda, T., Yanaga, K., Kishilkawa, K., Kakizoe, S., Shimada, M. and Sugimachi, K., Ischemic injury in liver transplantation: difference in injury sites between warm and cold ischemia in rats.Hepatology, 16, 454–461 (1992).PubMedCrossRefGoogle Scholar
  20. Kamiike, W., Burdelski, M., Steinhoff, G., Ringe, B., Lauchart, W. and Pichlmayer, R., Adenine nucleotide metabolism and its relation to organ viability in human liver transplantation.Transplantation, 45, 138–143 (1988).PubMedCrossRefGoogle Scholar
  21. Kim, S. K., Belzer, F. O. and Southard, J. H., Loss of mitochondrial respiratory function and its suppression during cold ischaemic preservation of rat livers with UW solution.Hepatology, 16, 742–748 (1992).PubMedCrossRefGoogle Scholar
  22. Kobayashi, H., Nonami, T., Kurokawa, T. and Takagi, H., Mechanism and prevention of ischemia-reperfusion-induced liver injury in rats.J. Surg. Res., 51, 240–244 (1991).PubMedCrossRefGoogle Scholar
  23. Lee, S. M. and Clemens, M. G., Subacinar distribution of hepatocyte membrane potential response to stimulation of gluconeogenesis.Am. J. Physiol., 263, G319-G326 (1992).PubMedGoogle Scholar
  24. Lemasters, J. J. and Thurman, R. G., Hypoxic, ischaemic and preservation-induced injury in the liver. In: Ballet, F., Thurman, R. G., eds, Perfused liver: clinical and basic applications. London: Libbey, pp. 97, (1991).Google Scholar
  25. Maessen, J. G., Vusse, G. J., Vork, M. and Kootstra, G., Nucleotides, nucleosides and oxypurines in human kidneys measured by use of reversed phase high-performance liquid chromatography.Clin. Chem., 34, 1087–1090 (1988).PubMedGoogle Scholar
  26. Masugi, F. and Nakamura, T., Effect of vitamin E deficiency on the level of superoxide dismutase, glutathione peroxidase, catalase, and lipid peroxide in rat liver.Int. J. Vitam. Nutr. Res., 46, 187–194 (1976).PubMedGoogle Scholar
  27. Montero, C., Smolenski, R. T., Duley, J. A. and Simmonds, H. A., S-Adenosylmethionine increases erythrocyte ATP in vitro by a route independent of adenosine kinase.Biochem. Pharmacol., 40, 2617–2623 (1990).PubMedCrossRefGoogle Scholar
  28. Ponsoda, X., Jover, R., Gomez,-Lechon, M. J., Fabra, R., Trullenque, R. and Castell, J. V., Intracellular glutathione in human hepatocytes incubated with S-adenosyl-L-methionine and GSH-depleting drugs.Toxicology, 70, 293–302 (1991).PubMedCrossRefGoogle Scholar
  29. Rao, P. N., Walsh, T. R. and Makowka, L., Purine nucleoside phosphorylase: A new marker for free oxygen radical injury to the endothelial cell.Hepatology, 11, 193–198 (1990).PubMedCrossRefGoogle Scholar
  30. Rounds, S., Hsieh, L. and Agarwal, K. C., Effects of endotoxin injury on endothelial cell adenosine metabolism.J. Lab. Clin. Med., 123, 309–317 (1994).PubMedGoogle Scholar
  31. Vreugdenhil, P. K., Evans, W., Belzer, F. O. and Southard, J. H., Glutathione depletion in cold-stored organs.Transplantation Proceedings, 22, 455–457 (1990).PubMedGoogle Scholar
  32. Woods, H. F. and Krebs, H. A., Lactate production in the perfused rat liver.Biochem. J., 125, 129–139 (1971).PubMedGoogle Scholar

Copyright information

© The Pharmaceutical Society of Korea 1999

Authors and Affiliations

  1. 1.College of PharmacySungkyunkwan UniversitySuwon, Kyungki-doKorea

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