Destruction of Microsomal Calcium Pump Activity: A Possible Secondary Mechanism in BrCCl3 and CCl4 Liver Cell Injury

  • Richard O. Recknagel
  • Karen Lowrey
  • Robert L. Waller
  • Eric A. GlendeJr.
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


In vitro rat liver microsomes free of Fe2+ ions peroxidize minimally at 37° when NADPH and either CC14 or BrCC13 are added. Although the lipid peroxidation dependent on toxigenic haloalkanes in these Fe2+-free microsome systems is very low, it is considerably more efficient in causing loss of cytochrome P-450 and glucose6-phosphatase than is the far more vigorous lipid peroxidation dependent on presence of Fe2+ ions. In particular, the Ca2+-pump activity of isolated microsomes was almost completely destroyed when malonic dialdehyde (MDA) production was as little as 8 pg per gram equivalent microsomes. Moore et al. (1976) had shown previously that the capacity of liver microsomes to sequester Ca2+ was severely depressed 30 min after CC14 administration to rats. We have shown that this effect is already manifested within 3 min after CC14 administration, by which time peroxidative decomposition of microsomal lipids can be detected. The time course of the destruction of the liver microsomal Ca2+ pump after CC14 administration to rats was essentially identical to the time course of microsomal lipid peroxidation, as revealed by the appearance of conjugated diene configurations in microsomal lipids.


Lipid Peroxidation Carbon Tetrachloride Malonic Dialdehyde Lipid Peroxidation Process Microsomal Lipid Peroxidation 
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  1. Alpers, D.H., and Isselbacher, K.J., 1968, Biochemical effects of CC14 on rat intestinal mucosa, Biochim. Biophys. Acta, 158: 414.PubMedCrossRefGoogle Scholar
  2. Benedetti, A., Casini, A., and Ferrali, M., 1977, Red cell lysis coupled to peroxidation of liver microsomal lipids: Compartmentalization of the hemolytic system, Res. Comm. Chem. Pathol. Pharmacol., 17: 519.Google Scholar
  3. Comporti, M., Benedetti, A., Casini, A., and Ferrali, M., 1979, Extraction of dialyzable products originating from the peroxidation of liver microsomal lipids and inhibiting microsomal glucose-6-phosphatase activity, Federation Proc., 38: 916.Google Scholar
  4. Esterbauer, H., Comporti, M., and Benedetti, A., 1980, Biochemical effects of 4-hydroxyalkenals, in particular 4-hydroxynonenal produced by microsomal lipid peroxidation, J. Am. Oil Chem. Soc., 57: Abstract No. 222.Google Scholar
  5. Glende, E.A., Jr., Hruszkewycz, A.M., and Recknagel, R.O., 1976, Critical role of lipid peroxidation in CC14-induced loss of aminopyrine demethylase, cytochrome P-450, and glucose-6phosphatase, Biochem. Pharmacol., 25: 2163.PubMedCrossRefGoogle Scholar
  6. Hruszkewycz, A.M., Glende, E.A., Jr., and Recknagel, R.O., 1978, Destruction of microsomal cytochrome P-450 and glucose-6phosphatase by lipids extracted from peroxidized microsomes, Toxicol. Appl. Pharmacol., 46: 695.PubMedCrossRefGoogle Scholar
  7. Kornbrust, D.L., and Mavis, R.D., 1979, The role of iron and NADPH in microsomal lipid peroxidation, Federation Proc., 38: 649.Google Scholar
  8. Kornbrust, D.J., and Mavis, R.D., 1980a, Microsomal lipid peroxidation. I. Characterization of the role of iron and NADPH, Molecular Pharm., 17: 400.Google Scholar
  9. Kornbrust, D.J., and Mavis, R.D., 1980b, Microsomal lipid peroxidation. II. Stimulation by carbon tetrachloride, Molecular Pharm., 17: 408.Google Scholar
  10. Lai, E.K., McCay, P.B., Noguchi, T., and Fong, Kuo-Lan., 1979, In vivo spin-trapping of trichloromethyl radicals formed from CC14, Biochem. Pharmacol., 28: 2231.Google Scholar
  11. Lombardi, B., and Ugazio, G., 1965, Serum lipoproteins in rats with carbon tetrachloride induced fatty liver, J. Lipid Res., 6: 498PubMedGoogle Scholar
  12. Masuda, Y., and Murano, T., 1977, Carbon tetrachloride-induced lipid peroxidation of rat liver microsomes in vitro, Biochem. Pharmacol., 26: 2275.CrossRefGoogle Scholar
  13. Moore, L., Chen, T., Knapp, H.R., Jr., and Landon, E.J., 1975, Energy dependent calcium sequestering activity in rat liver microsomes, J. Biol. Chem., 250: 4562.PubMedGoogle Scholar
  14. Moore, L., Davenport, G.R., and Landon, E.J., 1976, Calcium uptake of a rat liver microsomal subcellular fraction in response to in vivo administration of carbon tetrachloride, J. Biol. Chem., 251: 1197.PubMedGoogle Scholar
  15. Packer, J.L., Slater, T.F., and Willson, R.L., 1978, Reactions of the carbon tetrachloride-related peroxy free radical (CC1302•) with amino acids: Pulse radiolysis evidence, Life Sci., 23: 2617.PubMedCrossRefGoogle Scholar
  16. Pesh-Imam, M., Willis, R.J., and Recknagel, R.O., 1978, Red cell damage induced by peroxidizing microsomes: The relationship between hemolytic activity and peroxide content, J. Environ. Sci. Health., C13 1: 81.Google Scholar
  17. Poyer, J.L., Floyd, R.A., McCay, P.B., Janzen, E.G., and Davis, E.R., 1978, Spin-trapping of the trichloromethyl radical produced during enzymic NADPH oxidation in the presence of carbon tetrachloride and bromotrichloromethane, Biochim. Biophys. Acta., 539: 402.PubMedCrossRefGoogle Scholar
  18. Rao, K.S., and Recknagel, R.O., 1968, Early onset of lipoperoxidation in rat liver after carbon tetrachloride administration, Exp. Molec. Path., 9: 271.PubMedCrossRefGoogle Scholar
  19. Rao, K.S., and Recknagel, R.O., 1969, Early incorporation of carbon-labeled carbon tetrachloride into rat liver particulate lipids and proteins, Exp. Molec. Path., 10: 219.PubMedCrossRefGoogle Scholar
  20. Recknagel, R.O., 1967, Carbon tetrachloride hepatotoxicity, Pharmacol. Rev., 19: 145.PubMedGoogle Scholar
  21. Recknagel, R.O., and Glende, E.A., Jr., 1973, Carbon tetrachloride hepatotoxicity: An example of lethal cleavage, CRC Critical Rev. Toxicol., 2: 263.CrossRefGoogle Scholar
  22. Recknagel, R.O., Glende, E.A., Jr., and Hruszkewycz, A.M., 1977, Chemical mechanisms in carbon tetrachloride toxicity, in: “Free Radicals in Biology,” Vol. III, W.A. Pryor, ed., Academic Press, New York.Google Scholar
  23. Recknagel, R.O., and Turocy, Y., 1977, Fatal susceptibility of a free-swimming paramecium to peroxidizing rat liver microsomes, Exp. Molec. Path., 27: 93.PubMedCrossRefGoogle Scholar
  24. Reynolds, E.S., 1963, Liver parenchymal cell injury. I. Initial alterations of the cell following poisoning with carbon tetrachloride, J. Cell Biol., 19: 139.PubMedCrossRefGoogle Scholar
  25. Reynolds, E.S., 1964, Liver parenchymal cell injury. II. Cytochemical events concerned with mitochondrial dysfunction following poisoning with carbon tetrachloride, Lab. Invest., 13: 1457.PubMedGoogle Scholar
  26. Roders, M.K., Glende, E.A., Jr., and Recknagel, R.O., 1977, Separation of a hemolytic agent from peroxidizing microsomes, Science, 196: 1221.PubMedCrossRefGoogle Scholar
  27. Roders, M.K., Glende, E.A., Jr., and Recknagel, R.O., 1978, NADPHdependent microsomal lipid peroxidation and the problem of pathological action at a distance: New data on induction of red cell damage, Biochem. Pharmacol., 27: 437.PubMedCrossRefGoogle Scholar
  28. Schanne, F.A.X., Kane, A.B., Young, E.E., and Farber, J.L., 1979, Calcium dependence of toxic cell death: A final common pathway, Science, 206: 700.PubMedCrossRefGoogle Scholar
  29. Schotz, M.C., and Recknagel, R.O., 1960, Rapid increase of rat liver triglycerides following carbon tetrachloride poisoning, Biochim. Biophys. Acta., 41: 151.PubMedCrossRefGoogle Scholar
  30. Slater, T.F., 1972, “Free Radical Mechanisms in Tissue Injury”, Pion Limited, London.Google Scholar
  31. Smuckler, E.A., 1966, Studies of carbon tetrachloride intoxication. IV. Effect of carbon tetrachloride on liver slices and isolated organelles in vitro, Lab. Invest., 15: 157.Google Scholar
  32. Thiers, R.E., Reynolds, E.S., and Vallee, B.L., 1960, The effect of carbon tetrachloride poisoning on subcellular metal distribution in rat liver, J. Biol. Chem., 235:. 2130.Google Scholar
  33. Willis, R.J., and Recknagel, R.O., 1979, Partial chemical characterization of a hemolytic lipid from peroxidized rat liver microsomes, Federation Proc., 38: 916.Google Scholar
  34. Willis, R.J., Roders, M.K., Waller, R.L., Glende, E.A., Jr., and Recknagel, R.O., 1979, Use of vitamin E deficient red cells to detect a dialyzable hemolytic factor produced by peroxidizing rat liver microsome, Life Sci., 24: 1075.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • Richard O. Recknagel
    • 1
  • Karen Lowrey
    • 1
  • Robert L. Waller
    • 1
  • Eric A. GlendeJr.
  1. 1.Department of PhysiologySchool of MedicineCase Western Reserve UniversityClevelandUSA

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