Cytochrome P-450 and Vitamin E Free Radical Reductase: Formation of and Protection Against Free Radicals

  • Aalt Bast
  • Guido R. M. M. Haenen
Part of the NATO ASI Series book series (NSSA, volume 189)


In studies on lipid peroxidation, liver microsomes are frequently employed. Already in 1963, Hochstein and Ernstere1 reported that in their experiments lipid peroxidationin rat liver microsomes required molecular oxygen and NADPH and that lipid peroxidation intensified by the availability of ADP and Fe2+. This process is referred to as enzymic lipid peroxidation since it appears to depend on the presence of the haemoprotein cytochrome P-450 and the flavoprotein NADPH cytochrome P-450 reductase, both residing in the microsomal membrane2. The precise contribution of both proteins to NADPH dependent microsomal lipid peroxidation is still a matter of debate2. We described that cytochrome P-450 might be involved in both lipid hydroperoxide (LOOH) independent and LOOH dependent lipid peroxidation2.


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  1. 1.
    P. Hochstein and L. Ernster, ADP-activated lipid peroxidation coupled to the TPNH oxidase system of microsomes. Biochem, Biophys. Res, Commun. 12: 388 (1963).CrossRefGoogle Scholar
  2. 2.
    A. Bast and G.R.M.M. Haenen, Cytochrome P-450 and glutathione: What is the significance of their interrelationship in lipid peroxidation? Trends Biochem. Sci. 9: 510 (1984).CrossRefGoogle Scholar
  3. 3.
    A. Bast, Is formation of reactive oxygen by cytochrome P-450 perilous and predictable? Trends Pharmacol. Sci. 7: 266 (1986).CrossRefGoogle Scholar
  4. 4.
    G. R.M.M. Haenen and A. Bast, Protection against lipid peroxidation by a microsomal glutathione-dependent labile factor. FEBS Lett. 159: 24 (1983).CrossRefGoogle Scholar
  5. 5.
    D. W. Nebert, M. Adesnik, M.J. Coon, R.W. Estabrook, F.J. Gonzalez, F.P. Guengerich, I.C. Gunsalus, E.F. Johnson, B. Kemper, W. Levin, I.R. Phillips, R. Sato and M.R. Waterman, The P-450 gene superfamily: recommended nomenclature. DNA 6: 1 (1987).PubMedGoogle Scholar
  6. 6.
    Y. Terelius and M. Ingelman-Sundberg, Cytochrome P-450-dependent oxidase activity and hydroxyl radical production in micellar and membranous types of reconstituted systems. Biochem. Pharmacol, 37: 1383 (1988).CrossRefGoogle Scholar
  7. 7.
    G. Powis and I. Jansson, Stoichiometry of the mixed function oxidase. Pharmac. Ther. 7: 297 (1979).CrossRefGoogle Scholar
  8. 8.
    L. D. Gorsky, D.R. Koop and M.J. Coon, On the stoichiometry of the oxidase and monooxygenase reactions catalyzed by liver microsomal cytochrome P-450. Products of oxygen production. J. Biol. Chem. 259: 6812 (1984).PubMedGoogle Scholar
  9. 9.
    A. Bast, E.M. Savenije-Chapel and B.H. Kroes, Inhibition of mono-oxygenase and oxidase activity of reat-hepatic cytochrome P-450 by H2-receptor blockers. Xenobiotica 14: 399 (1984).CrossRefGoogle Scholar
  10. 10.
    A. Bast, J.W. Brenninkmeijer, E.M. Savenije-Chapel and J. Noordhoek, Cytochrome P-450 oxidase activity and its role in NADPH dependent lipil peroxidation. FEBS Lett. 151: 185 (1983).CrossRefGoogle Scholar
  11. 11.
    A. Bast and M.H.M. Steeghs, Hydroxyl radicals are not involved in NADPH dependent microsomal lipid peroxidation. Experientia 42: 555 (1986).CrossRefGoogle Scholar
  12. 12.
    L. A. Morehouse, M. Tien, J.R. Bucher and S.D. Aust, Effect of hydrogen peroxide on the initiation of microsomal lipid peroxidation. Biochem, Pharmacol. 32: 123 (1983).CrossRefGoogle Scholar
  13. 13.
    G. Minotti and S.D. Aust, The role of iron in the initiation of lipid peroxidation. Chem. Physics of Lipids 44: 191 (1987).CrossRefGoogle Scholar
  14. 14.
    H. Wefers and H. Sies, The protection by ascorbate and glutathione against microsomal lipid peroxidation is dependent on vitamin E. Eur. J. Biochem. 174: 353 (1988).CrossRefGoogle Scholar
  15. 15.
    A. Bast, G.R.M.M. Haenen and E.M. Savenije-Chapel, Inhibition of rat hepatic microsomal lipid peroxidation by mesna via glutathione. Arzneim.-Forsch./Drug Res. 37: 1043 (1987).Google Scholar
  16. 16.
    L. G. Forni and R.L. Willson, Vitamin C and consecutive hydrogen atom and electron transfer reactions in free radical protection: A novel catalytic role for glutathione, in: “Protective agents in cancer”, D.C. McBrien and T.F. Slater eds., Academic Press, New York (1983).Google Scholar
  17. 17.
    R. Morgenstern, G. Lundqvist, V. Hancock and J.W. DePierre, Studies on the activity and activation of rat liver microsomal glutathione transferase, in particular with a substrate analogue series. J, Biol. Chem, 263: 6671 (1988).Google Scholar
  18. 18.
    E. Mousialou and R. Morgenstern, Studies on the glutathione dependent inhibition of lipid peroxidation. Abstract 3.15 in Eur. Workshop on Drug Metab., Univ. of Konstanz, F.R.G. (1988).Google Scholar
  19. 19.
    G. R.M.M. Haenen, J.N.L. Tai Tin Tsoi, N.P.E. Vermeulen, H. Timmerman and A. Bast, 4-Hydroxy-2,3-trans-nonenal stimulates microsomal lipid peroxidation by reducing the gluthathione-dependent protection. Arch, Biochem. Biophys, 259: 449 (1987).CrossRefGoogle Scholar
  20. 20.
    R. Morgenstern, H. Wallin and J.W. DePierre, Mechanisms of activation of the microsomal glutathione transferase, in “Glutathione S-transferases and carcinogenesis”, T.J. Mantle, C.B. Pickett and J.D. Hayes eds., Taylor and Francis, London, New York and Philadelphia (1987).Google Scholar
  21. 21.
    R. F. Burk, Glutathione-dependent protection by rat liver microsomal protein against lipid peroxidation. Biochim. Biophys. Acta 757: 21 (1983).Google Scholar
  22. 22.
    M. Yonaha and Y. Tampo, Studies on protection by glutahione against lipid peroxidation in rat liver microsomes. Effect of bromosulfophtalein. Chem, Pharm. Bud. 34: 4195 (1986).Google Scholar
  23. 23.
    F. Ursini, M. Maiorino, M. Valente, L. Ferri and C. Gregolin. Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activïiy on phosphatidylcholine hydroperoxides. Biochim. Biophys. Acta 710: 197 (1982).CrossRefGoogle Scholar
  24. 24.
    F. Ursini and A. Bindoli, The role of selenium peroxidases in the protection against oxidative damage of membranes. Chem. Physics of Lipids. 44: 255 (1987).CrossRefGoogle Scholar
  25. 25.
    C. C. Reddy, R.W. Scholz, C.E. Thomas and E.J. Massaro, Vitamin E dependent reduced glutathione inhibition of rat liver microsomal lipid peroxidation. Life Sci. 31: 571 (1982).Google Scholar
  26. 26.
    M. E. Murphy and J.P. Kehrer, Simultaneous measurement of tocopherols and tocopheryl quinones in tissue fractions using high-performance liquid chrom atography with redoxcycling electrochemical detection. J. Chromatogr. (Biomed. Anplicat.) 421: 71 (1987).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • Aalt Bast
    • 1
  • Guido R. M. M. Haenen
    • 1
  1. 1.Department of Phannacochemistry, Faculty of ChemistryVrije UniversiteitAmsterdamThe Netherlands

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