The metabolism of 4-hydroxynonenal, a lipid peroxidation product, is dependent on tumor age in Ehrlich mouse ascites cells

  • Werner G. Siems
  • Tilman Grune
  • Beatrix Beierl
  • Helmward Zollner
  • Hermann Esterbauer
Part of the EXS book series (EXS, volume 62)


4-Hydroxynonenal is a major product formed by lipid peroxidation from omega 6-polyunsaturated fatty acids as linoleic acid and arachidonic acid. This aldehyde is cytotoxic at high concentrations (in the range of 100 μM), disturbs cell prohferation at low concentrations and exhibits genotoxic effects. Furthermore, in the submicromolar range 4-hydroxynonenal is chemotactic and stimulates phospholipase C. 4-Hydroxynonenal is rapidly metabolized in eucaryotic cells. Here the metabolism of 4-hydroxynonenal was studied in suspensions of Ehrlich mouse ascites cells at different periods of the tumor age. The Ehrlich ascites tumor is a convenient biological model for the investigation of tumor cells in different age and proliferation phases of the tumor. The main products of 4-hydroxynonenal which were identified in the Ehrlich ascites cells were glutathione-HNE-conjugate, hydroxynonenoic acid and 1,4-dihydroxynonene. The formation of glutathione conjugates following the addition of 4-hydroxynonenal was higher in cells of the early phase in comparison with cells of the late phase of tumor growth. That was in accordance with the increased consumption of the reduced form of glutathione during 4-hydroxynonenal utilization. The degradation of 4-hydroxynonenal and other aldehydic products of lipid peroxidation is postulated to be an important part of the intracellular antioxidative defense system.


Lipid Peroxidation Lipid Peroxidation Product Ehrlich Ascites Tumor Cell Pyruvate Ratio Ehrlich Ascites Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Ehrlich ascites tumor cells


glutathione (reduced form)






4-hydroxy-2-nonenoic acid


polyunsaturated fatty acids.


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  1. Benndorf, R., Nürnberg, P., and Bielka, H. (1988) Growth phase-dependent proteins of the Ehrlich ascites tumor analyzed by one- and two-dimensional electrophoresis. Exp. Cell Res. 174: 130–138.PubMedCrossRefGoogle Scholar
  2. Bize, J. B., Overley, L. W., and Morris, H. P. (1980) Superoxide dismutase and superoxide radical in Morris hepatoma. Cancer Res. 40: 3686–3693.PubMedGoogle Scholar
  3. Borrello, S., Minotti, G., Palombini, G., Grattagliano, A., and Galeotti, T. (1985) Superoxide- dependent lipid peroxidation and vitamin E content of microsomes from hepatomas with different growth rates. Archs Biochem. Biophys. 238: 588–595.CrossRefGoogle Scholar
  4. Burdon, R. H., and Rice-Evans, C. (1989) Free radicals and the regulation of mammalian cell proHferation. Free Radical Res. Commun. 6: 345–358.CrossRefGoogle Scholar
  5. Cerutti, P. A. (1985) Prooxidant states and tumor promotion. Science 227: 375–381.PubMedCrossRefGoogle Scholar
  6. Cheeseman, K. H., Burton, G. W., Ingold, K. U., and Slater, T. F. (1984) Lipid peroxidation and lipid antioxidants in normal and tumor cells. Toxicol. Pathol. 12: 552–557.CrossRefGoogle Scholar
  7. Cheeseman, K. H., Collins, M., Proudfoot, K., Slater, T. F., Burton, G. W., Webb, A. C., and Ingold, K. U. (1986) Studies on lipid peroxidation in normal and tumor tissues. Biochem. J. 235: 507–514.PubMedGoogle Scholar
  8. Devasagayam, T. P. A. (1986) Low level of lipid peroxidation in new born rats. FEBS Lett. 199: 203–207.PubMedCrossRefGoogle Scholar
  9. Emerit, I. (1987a) Icosanoids, chromosome damage and cancer, in: Prostaglandins in Cancer Research, pp. 29–34. Eds E. Garaci, R. Paoletti and M. G. Santoro. Springer-Verlag, Berlin, Heidelberg.CrossRefGoogle Scholar
  10. Emerit, I. (1987b) Clastogenic factors, a link between chronic inflammation and carcinogenesis, in: Anticarcinogenesis and Radiation Protection, pp. 59–62. Eds P. A. Cerutti, O. F. Nygaard and M. G. Simic. Plenum Press, New York.Google Scholar
  11. Emerit, I., Khan, S. H., and Esterbauer, H. (1991) Hydroxynonenal, a component of clastogenic factors? Free Radical Biol. Med. 10: 371–377.CrossRefGoogle Scholar
  12. Esterbauer, H. (1982) Aldehydic products of lipid peroxidation, in: Free Radicals, Lipid Peroxidation and Cancer, pp. 101–128. Eds D. C. H. McBrien and T. F. Slater. Academic Press, New York.Google Scholar
  13. Esterbauer, H., Zollner, H., and Lang, J. (1985) Metabolism of the lipid peroxidation product 4-hydroxynonenal by isolated hepatocytes and by liver cytosolic fractions. Biochem. J. 228: 363–373.PubMedGoogle Scholar
  14. Esterbauer, H., Zollner, H., and Schaur, R. J. (1988) Hydroxyalkenals: cytotoxic products of lipid peroxidation. ISI Atlas Sci. Biochem. 1: 311–317.Google Scholar
  15. Esterbauer, H., Zollner, H., and Schaur, R. J. (1989) Aldehydes formed by lipid peroxidation: mechanisms of formation, occurrence, and determination, in: Membrane Lipid Oxidation, vol. 1, pp. 239–283. Ed. C. Vigo-Pelfrey. CRC Press, Boca Raton, FL.Google Scholar
  16. Fauler, G. (1987) Investigations on the metabolism of 4-hydroxy-alkenals. Austria: Univ. Graz; Ph.D. Thesis.Google Scholar
  17. Ferro, M., Marinari, U. M., Poli, G., Dianzani, M. U., Fauler, G., Zollner, H., and Esterbauer, H. (1988) Metabolism of 4-hydroxynonenal by the rat hepatoma cell line MHICI. Cell Biochem. Funct. 6: 245–250.PubMedCrossRefGoogle Scholar
  18. Galeotti, T., Borrello, S., Minotti, G., Palombini, G., Masotti, L., Sartor, G., Cavatorta, P., Arcioni, A., and Zannoni, C. (1984) Lipid composition, physical state, and Hpid peroxidation of tumor membranes. Toxicol. Pathol. 12: 324–330.PubMedCrossRefGoogle Scholar
  19. Grune, T., Siems, W., Kowalewski, J., Zollner, H., and Esterbauer, H. (1991) Identification of metabolic pathways of the lipid peroxidation product 4-hydroxynonenal by enterocytes of rat small intestine. Biochem. Int. 25: 963–971.PubMedGoogle Scholar
  20. Hauptlorenz, S., Esterbauer, H., Moll, W., Pümpel, R., Schauenstein, E., and Puschendorf, B. (1985) Effects of the lipid peroxidation product 4-hydroxynonenal and related aldehydes on proliferation and viability of cultured Ehrlich ascites tumor cells. Biochem. Pharmacol. 34: 3803–3809.PubMedCrossRefGoogle Scholar
  21. Hostetler, K. Y., Zenner, B. D., and Morris, H. P. (1979) Phospholipid content of mitochondrial and microsomal membranes from Morris hepatomas of varying growth rates. Cancer Res. 39: 2978–2983.PubMedGoogle Scholar
  22. Ishikawa, T., Esterbauer, H., and Sies, H. (1986) Role of cardiac glutathione transferase and of the glutathione S-conjugate export system in biotransformation of 4-hydroxynonenal in the heart. J. Biol. Chem. 261: 1576–1586.PubMedGoogle Scholar
  23. Kagan, V. E., Bakalova, R. A., and Karakashev, P. H. (1991) Lipid peroxidation in the tumor cells and tissues of tumor-bearing animals, in: Membrane Lipid Oxidation, vol. 3, pp. 191–208. Ed. C. Vigo-Pelfrey. CRC Press, Boca Raton, FL.Google Scholar
  24. Kowalewski, J., Siems, W., Grune, T., Werner, A., Esterbauer, H., and Gerber, G. (1991) Nucleotide degradation and oxygen radical formation during ischemia and reperfusion of the rat small intestine, Z. Klin. Med. 46: 143–146.Google Scholar
  25. Masotti, L., Gasa, H. E., and Galeotti, T. (1988) Lipid peroxidation in tumor cells. Free Rad. Biol. Med. 4: 377–386.PubMedCrossRefGoogle Scholar
  26. Müller, M., Siems, W., Buttgereit, F., Dumdey, R., and Rapoport, S. M. (1986) Quantification of ATP-producing and consuming processes of Ehrlich ascites tumour cells. Eur. J. Biochem 161: 701–705.PubMedCrossRefGoogle Scholar
  27. Peskin, A. V., Koen, Y. M., and Zbarsky, J. B. (1977) Superoxide dismutase and glutathione peroxidase activities in tumors. FEBS Lett. 78: 41–45.PubMedCrossRefGoogle Scholar
  28. Po, H. G., Cecchini, G., Biasi, F., Chiarpotto, E., Canuto, R. A., Biocca, M. E., Muzio, G., Esterbauer, H., and Dianzani, M. U. (1986) Resistance to oxidative stress by hyperplastic and neoplastic rat liver tissue monitored in terms of production of unpolar and medium polar carbonyls. Biochim. Biophys. Acta 883: 207–214.CrossRefGoogle Scholar
  29. Schaur, R. J., Zollner, H., and Esterbauer, H. (1991) Biological effects of aldehydes with particular attention to 4-hydroxynonenal and malonaldehyde, in: Membrane Lipid Oxidation, vol. 3, pp. 141–163. Ed. C. Vigo-Pelfrey. CRC Press, Boca Raton, FL.Google Scholar
  30. Schmidt, H., Siems, W., Müller, M., Dumdey, R., Jakstadt, M., and Rapoport, S. (1989) Balancing of mitochondrial and glycolytic ATP production and of the ATP-consuming processes of Ehrlich ascites tumour cells in a high phosphate medium. Biochem. Int. 19: 985–992.PubMedGoogle Scholar
  31. Schmidt, H., Siems, W., Müller, M., Dumdey, R., and Rapoport, S. (1991) ATP-producing and consuming processes of Ehrlich mouse activities tumor cells in proliferating and resting phases. Exp. Cell Res. 194: 122–127.PubMedCrossRefGoogle Scholar
  32. Siems, W. G., Zollner, H., and Esterbauer, H. (1990) Metabolic pathways of the Hpid peroxidation product 4-hydroxynonenal in hepatocytes - quantitative assessment of an antioxidant defense system. Free Radie. Biol. Med. 9: 110.CrossRefGoogle Scholar
  33. Siems, W., Schmidt, H., Werner, A., UerHngs, L, David, H., and Gerber, G. (1989) Changes in the nucleotide metabolism of Ehrlich ascites tumour cells during their growth in vivo. Cell. Molec. Biol. 35: 255–262.Google Scholar
  34. Siems, W., Kowalewski, J., David, H., Grune, T., and Bimmler, M. (1991) Discrepancy between biochemical normaHsation and morphological recovery of jejunal mucosa during postischemic reperfusion in presence of the xanthine oxidase inhibitor oxypurinol. Cell. Molec. Biol. 37: 213–226.Google Scholar
  35. Tessitore, L., Bonelli, G., Cecchini, G., Amenta, J. S., and Baccino, F. M. (1987) Regulation of protein turnover versus growth state: Ascites hepatoma as a model for studies both in the animal and in vitro. Archs Biochem. Biophys. 255: 372–384.CrossRefGoogle Scholar
  36. Van Kuijk, F. J. G. M., Thomas, D. W., Stephens, R. J., and Dratz, E. A. (1986) Occurrence of 4-hydroxyalkenals in rat tissues determined as pentafluorobenzyl oxime derivatives by gas chromatography-mass spectrometry. Biochem. Biophys. Res. Comm. 139: 144–149.PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 1992

Authors and Affiliations

  • Werner G. Siems
    • 1
  • Tilman Grune
    • 1
  • Beatrix Beierl
    • 2
  • Helmward Zollner
    • 2
  • Hermann Esterbauer
    • 1
  1. 1.Institute of Biochemistry, Medical Faculty (Charité)Humboldt University of BerlinBerlinFederal Republic of Germany
  2. 2.Institute of BiochemistryUniversity of GrazGrazAustria

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