Lipid Peroxidation: The Role of Hepatic FAD-Monooxygenase

  • Julia D. George
  • Gerald M. Rosen
  • Elmer J. Rauckman
  • Daniel M. Ziegler


Lipid peroxidation is a process which occurs in biological membranes, and which has been implicated in many instances of in vitro and in vivo damage.1 The hepatic microsomal fraction is known to readily undergo lipid peroxidation. Extensive research has been conducted to attempt to clarify this process which has been shown to involve the hepatic microsomal cytochrome P-450 mixed function oxidase system. In this review we will discuss the properties of another hepatic microsomal enzyme, FAD*-containing monooxygenase. In addition we will summarize the peroxidative mechanism as it is currently understood and present evidence that FAD-containing monooxygenase is involved in the lipid peroxidation of hepatic microsomes.


Lipid Peroxidation Liver Microsome Hepatic Microsomal Cytochrome Microsomal Oxidase Hydroxyl Radical Adduct 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    J.F. Mead, Free radical mechanisms of lipid damage and consequences for cellular membranes, in: “Free Radicals in Biology”, W.A. Pryor, ed., Vol. I, Academic Press, New York, p. 51 (1976).Google Scholar
  2. 2.
    J.R. Gillette, D.C. Davis, and H.A. Sasame, Cytochrome P-450 and its role in drug metabolism, Ann. Rev. Pharmacol. 12:57 (1972).Google Scholar
  3. 3.
    E.S. Vessell, ed., Drug metabolism in man, Ann. N.Y. Acad. Sci. 179:43 (1971).Google Scholar
  4. 4.
    G.J. Mannering, Microsomal enzymes systems which catalyze drug metabolism, in: “Fundamentals of Drug Metabolism and Disposition,” B.N. LaDu, H.G. Mandel, and E.L. Way, Eds., Williams and Wilkins, Baltimore, p. 206 (1971).Google Scholar
  5. 5.
    D.M. Ziegler and F.H. Pettit, Microsomal oxidase. I. The isolation and dialkylarylamine oxygenase activity of pork liver microsomes, Biochemistry 5: 2932 (1966).Google Scholar
  6. 6.
    M. Kiese and E. Rauscher, Isolation of phenylhydroxylamine produced from N-ethylaniline by microsomal enzyme, Biochem. 7, 338: 1 (1963).Google Scholar
  7. 7.
    M.S. Fish, C.C. Sweeley, N.M. Johnson, E.P. Laurence, and E.C. Horning, Chemical and enzymic rearrangements of N,Ndimethyl amino acid oxides, Biochem. Biophys. Acta 21:196 (1956).Google Scholar
  8. 8.
    H. Kampffineyer and M. Kiese, The hydroxylation of aniline and N-ethylaniline by microsomal enzymes at low oxygen pressures, Biochem. 7, 339: 454 (1964).Google Scholar
  9. 9.
    H. Uehleke, N-hydroxylation of arylamines by bladder mucosa, Life Sci. 5: 1489 (1966).Google Scholar
  10. 10.
    P.H. Halvica and M. Kiese, N-oxygenation of N-alkyl-and N, N-dialklanilines by rabbit liver microsomes, Biochem. Pharmacol. 18:1501 (1969).Google Scholar
  11. 11.
    D.M. Ziegler, C.A. Mitchell, and D. Jollow, The properties of a purified hepatic microsomal mixed function amine oxidase, in: “Microsomes and Drug Oxidations,” J.R. Gillette, A.H. Conney, G.J. Cosmides, R.W. Estabrook, J.R. Fouts, and G.J. Mannering, Eds., Academic Press, New York, p. 173 (1969).Google Scholar
  12. 12.
    D.M. Ziegler, D. Jollow, and D. Cook, Properties of a purified liver microsomal mixed function amine oxidase, in: “Flavins and Flavoproteins: Third International Symposium,” H. Kamen, ed., University Park Press, Baltimore, p. 507 (1971).Google Scholar
  13. 13.
    J.R. Gillette, B.B. Brodie, and B.N. LaDu, The oxidation of drugs by liver microsomes: on the role of TPNH and oxygen, J. Pharmacol. Exp. Therap. 119:532 (1957).Google Scholar
  14. 14.
    T. Omura, Discussion, in: Microsomes and Drug Oxidations, J.R. Gillette, A.H. Conney, G.J. Cosmides, R.W. Estabrook, J.R. Fouts, and G.S. Mannering, Eds., Academic Press, New York, p. 160 (1969).Google Scholar
  15. 15.
    B.S.S. Masters and D.M. Ziegler, The distinct nature and function of NADPH-cytochrome c reductase and the NADPH-dependent mixed function amine oxidase of porcine liver microsomes, Arch. Biochem. Biophys. 145:358 (1971).Google Scholar
  16. 16.
    D.M. Ziegler and C.H. Mitchell, Microsomal oxidase IV: properties of a mixed function amine oxidase isolated from pig liver microsomes, Arch. Biochem. Biophys. 150:116 (1972).Google Scholar
  17. 17.
    M.S. Gold and D.M. Ziegler, Dimethylaniline N-oxidase and aminopyrine N-demethylase activities of human liver tissue, Xenobiotica 3: 179 (1973).Google Scholar
  18. 18.
    L.L. Poulsen, F.F. Kadlubar, and D.M. Ziegler, Role of the microsomal mixed function amine oxidase in the oxidation of N,N-disubstituted hydroxylamines, Arch. Biochem. Biophys. 164:774 (1974).Google Scholar
  19. 19.
    L.L. Poulsen, R.M. Hyslop, and D.M. Ziegler, S-oxidation of thioureylenes catalyzed by a microsomal flavoprotein mixed function oxidase, Biochem. Pharmacol. 23:3431 (1974).CrossRefGoogle Scholar
  20. 20.
    L.L. Poulsen, R.M. Hyslop, and D.M. Ziegler, S-oxygenation of N-substituted thioureas catalyzed by the pig liver microsomal FAD-containing monooxygenase, Arch. Biochem. Biophys. 198:78 (1979).Google Scholar
  21. 21.
    L.L. Poulsen and D.M. Ziegler, Microsomal mixed function oxidase-dependent renaturation of reduced ribonuclease, Arch. Biochem. Biophys. 183:563 (1977).Google Scholar
  22. 20.
    I.E. Balaban and H. King, Gold and mercury derivations of 2thioglyoxalines. Mechanism of the oxidation of 2-thioglyoxalines to glyoxalines, J. Chem. Soc. 1858 (1927).Google Scholar
  23. 23.
    L.E. Zhislin, and N.M. Ovetskaya, Gig. Yr. Prof. Zabol. 16: 52 (1972), as cited in reference 20.Google Scholar
  24. 24.
    L.L. Poulsen, B.S.S. Masters, and D.M. Ziegler, Mechanism of 2-naphthylamine oxidation catalyzed by pig liver microsomes, Xenobiotica 6: 481 (1976).Google Scholar
  25. 25.
    D.M. Ziegler and L.L. Poulsen, Protein disulfide bond synthesis; a possible intracellular mechanism, Trends Biochem. Sci., 2: 79 (1977).CrossRefGoogle Scholar
  26. 26.
    J.W. Gorrod, P. Jenner, G. Keysell, and A.H. Beckett, Selective inhibition of alternative oxidative pathways of nicotine metabolism in vitro, Chem.-Biol. Interactions 3: 269 (1971).Google Scholar
  27. 27.
    R.A. Prough and D.M. Ziegler, The relative participation of liver microsomal amine oxidase and cytochrome P-450 in N-demethylation reactions, Arch. Biochem. Biophys. 180:363 (1977).CrossRefGoogle Scholar
  28. 28.
    S.E. Patton, G.M. Rosen, E.J. Rauckman, B.G. Graham, B. Small, and D.M. Ziegler, Hamster hepatic nuclear mixed function amine oxidase: location and specific activity, Mol. Pharmacol. in press.Google Scholar
  29. 29.
    H. Uehleke, 0. Reiner, and K.H. Hellman, Perinatal development of tertiary amine N-oxidation and NADPH cytochrome c reduction in rat liver microsomes, Res. Commun. Chem. Pathol. Pharmacol. 2:793 (1971).Google Scholar
  30. 30.
    D.M. Ziegler, Microsomal Oxidases, in: “Molecular Biology of Membranes,” S. Fleischer, ed., Plenum Press, New York, p. 193 (1978).Google Scholar
  31. 31.
    Greengard, Enzymic Differentiation in Mammalian Tissues, in “Essays in Biochemistry,” P.N. Campbell and F. Dickens, Eds., Academic Press, New York, p. 159 (1971).Google Scholar
  32. 32.
    A. Rane, N-oxidation of a tertiary amine (N,N-dimethylaniline) by human fetal liver microsomes, Clinical Pharm. Ther., 15: 32 (1974).Google Scholar
  33. 33.
    W.R. Bidlack and A.L. Tappel, Damage to microsomal membrane by lipid peroxidation, Lipids 8: 177 (1973).Google Scholar
  34. 34.
    S.E. Lewis and E.D. Wills, The destruction of -SH groups of proteins and amino acids by peroxides of unsaturated fatty acids, Biochem. Pharmacol. 11:901 (1962).Google Scholar
  35. 35.
    E.D. Wills, Lipid peroxide formation in microsomes, relationship of hydroxylation to lipid peroxide formation, Biochem. J., 113:333 (1969).Google Scholar
  36. 36.
    M. Jacobson, W. Levin, A.Y.H. Lu, A.H. Conney, and R. Kuntzman, The rate of pentobarbital and acetanilide metabolism by liver microsomes: a function of lipid peroxidation and degradation of cytochrome P-450 heure, Drug. Metab. Disp. 1:766 (1973).Google Scholar
  37. 37.
    E.D. Wills and A.E. Wilkinson, The effect of irradiation on lipid peroxide formation in subcellular fractions, Radiation Res., 31: 732 (1967).Google Scholar
  38. 38.
    W.A. Pryor, The role of free radical reactions in biological systems, in: “Free Radicals in Biology,” W.A. Pryor, ed., Vol. I, Academic Press, N.Y., p. 1 (1976).CrossRefGoogle Scholar
  39. 39.
    W.T. Roubal and A.L. Tappel, Polymerization of proteins induced by free-radical lipid peroxidation, Arch. Biochem. Biophys. 113:150 (1966).Google Scholar
  40. 40.
    W.T. Roubal, Free radicals, malonaldehyde, and protein damage in lipid-protein systems, Lipids 6: 63 (1971).Google Scholar
  41. 41.
    E.D. Wills, Effects of lipid peroxidation on membrane bound enzymes of the endoplasmic reticulum, Biochem. J., 123:983 (1971).Google Scholar
  42. 42.
    R.O. Rechnagel, Carbon tetrachloride hepatotoxicity, Pharmacol. Rev. 19:145 (1967).Google Scholar
  43. 43.
    R.O. Rechnagel and E.A. Glende, Jr., Carbon tetrachloride hepatotoxicity: an example of lethal cleavage, CRC Crit. Res. Toxicol. 2:263 (1973).Google Scholar
  44. 44.
    G. Sipes, G. Krishna, and J.R. Gillette, Bioactivation of carbon tetrachloride, chloroform, and bromotrichloroethane: role of cytochrome P-450, Life Sci. 20: 1541 (1977).Google Scholar
  45. 45.
    P. Hochstein and L. Ernster, ADP-activated lipid peroxidation coupled to TPNH oxidase system of microsomes, Biochem. Biophys. Res. Commun. 12:388 (1963).Google Scholar
  46. 46.
    P. Hochstein, K. Nordenbrand, and L. Ernster, Evidence for the involvement of iron in the ADP-activated peroxidation of lipids in microsomes and mitochondria, Biochem. Biophys. Res. Commun. 14:323 (1964).CrossRefGoogle Scholar
  47. 47.
    S. Arrenius, G. Dallner, and L. Ernster, Inhibition of TPNHlinked lipid peroxidation of liver microsomes by drugs undergoing oxidative demethylation, Biochem. Biophys. Res. Commun. 14:329 (1964).Google Scholar
  48. 48.
    R. Nilsson, S. Orrenius, and L. Ernster, The TPNH-dependent oxidation of luminol catalyzed by rat liver microsomes, Biochem. Biophys. Res. Commun. 17:303 (1964).Google Scholar
  49. 49.
    T.C. Pederson and S.D. Aust, NADPH-dependent lipid peroxidation catalyzed by purified NADPH-cytochrome c reductase from rat liver microsomes, Biochem. Biophys. Res. Commun. 48:789 (1972).CrossRefGoogle Scholar
  50. 50.
    T.C. Pederson, J.A. Buege, and S.D. Aust, Microsomal electron transport, the role of reduced nicotinamide adenine dinucleotide phosphate-cytochrome c reductase in liver microsomal lipid peroxidation, J. Biol. Chem., 248:7134 (1973).Google Scholar
  51. S.D. Aust, D.L. Roerig, and T.C. Pederson, Evidence for superoxide generation by NADPH-cytochrome c reductase of rat liver microsomes, Biochem. Biophys. Res. Commun. 47:113 (1972).Google Scholar
  52. 52.
    I. Fridovich, Oxygen radicals, hydrogen peroxide, and oxygen toxicity, in: “Free radicals in biology,” W.A. Pryor, ed., Vol. I, Academic Press, New York, p. 239 (1976).Google Scholar
  53. 53.
    J. McCord and I. Fridovich, The utility of superoxide dismutase in studying free radical reactions, J. Biol. Chem. 245:1374 (1970).Google Scholar
  54. 54.
    K. Fong, P.B. McCay, J.L. Poyer, B.B. Keele, and H. Misra, Evidence that peroxidation of liposomal membranes is initiated by hydroxyl radicals produced during flavin enzyme activity, J. Biol. Chem. 248:7792 (1973).Google Scholar
  55. 55.
    M.M. King, E.K. Lai, and P.B. McCay, Singlet oxygen production associated with enzyme-catalyzed lipid peroxidation in liver microsomes, J. Biol. Chem. 250:6496 (1975).Google Scholar
  56. 56.
    C. Lai, T.A. Grover, and L.H. Piette, Hydroxyl radical production in a purified NADPH-cytochrome c (P-450) reductase system, Arch. Biochem. Biophys. 193:373 (1979).Google Scholar
  57. 57.
    P.B. McCay, P.M. Pfeifer, and W.H. Stipe, Vitamin E protection of membrane lipids during electron transport functions, Ann. N.Y. Acad. Sci. 203:62 (1972).Google Scholar
  58. 58.
    F. Haber, and J. Weiss, The catalytic decomposition of hydrogen peroxide by iron salts, Proc. Roy. Soc. (London) A147:332, (1934).Google Scholar
  59. 59.
    B.A. Svingen, J.A. Buege, F.O. O’Neal, and S.D. Aust, The mechanism of NADPH-dependent lipid peroxidation, the propagation of lipid peroxidation, J. Biol. Chem. 254:5892 (1979).Google Scholar
  60. 60.
    B.A. Svingen, F.O. O’Neal and S.D. Aust, The role of superoxide and singlet oxygen in lipid peroxidation, Photochem. Photobiol. 28:803 (1978).CrossRefGoogle Scholar
  61. 61.
    E.J. Rauckman, G.M. Rosen, and B.B. Kitchell, Superoxide radical as an intermediate in the oxidation of hydroxylamines by mixed function amine oxidase, Mol. Pharmacol. 15:131 (1979).Google Scholar
  62. 62.
    T.F. Slater, The inhibitory effects in vitro of phenothiazines and other drugs on lipid-peroxidation systems in rat liver microsomes, and their relationship to the liver necrosis produced by carbon tetrachloride, Biochem. J., 106:155 (1968).Google Scholar
  63. 63.
    G.M. Rosen, E.J. Rauckman and K.W. Hanck, Selective bioreduction of nitroxides by rat liver microsomes, Toxicol. Lett. 1:71 (1977).Google Scholar
  64. 64.
    W. Levin, A.Y.H. Lu, M. Jacobson, and R. Kuntzman, Lipid peroxidation and the degradation of cytochrome P-450 heme, Arch. Biochem. Biophys. 158:842 (1973).Google Scholar
  65. 65.
    E. Jeffery, A. Kotake, R. Azhary, and G.J. Mannering, Effects of linoleic acid hydroperoxide on the hepatic monooxygenase systems of microsomes from untreated, phenobarbital-treated, and 3-methylcholanthrene-treated rats, Mol. Pharmacol. 13: 415 (1977).Google Scholar
  66. 66.
    D.M. Ziegler and L.L. Poulsen, Hepatic microsomal mixed function amine oxidase, in: “Methods in Enzymology,” S. Fleischer and L. Packer, Eds., 52:142 (1978).Google Scholar
  67. 67.
    B.S.S. Masters, C.H. Williams, Jr., and H. Kamin, The preparation and properties of microsomal TPNH-cytochrome c reductase from pig liver, in: “Methods in Enzymology,” R.W. Estabrook and M.E. Prillman, Eds., Vol. X, Academic Press, New York, p. 565 (1967).Google Scholar
  68. 68.
    C. Lai and L.H. Piette, Hydroxyl radical production involved in lipid peroxidation of rat liver microsomes, Biochem. Biophys. Res. Commun. 78:51 (1977).Google Scholar
  69. 69.
    E. Finkelstein, G.M. Rosen, and E.J. Rauckman, Spin trapping of superoxide and hydroxyl radical: practical aspects, Arch. Biochem. Biophys. 200:1 (1980).Google Scholar
  70. 70.
    G.A. Hamilton, Chemical models and mechanisms for oxygenases, in: “Molecular Mechanisms of Oxygen Activation,” Osamic Hayaishi, ed., Academic Press, New York, p. 405 (1974).Google Scholar

Copyright information

© Springer Science+Business Media New York 1980

Authors and Affiliations

  • Julia D. George
    • 1
  • Gerald M. Rosen
    • 1
  • Elmer J. Rauckman
    • 1
  • Daniel M. Ziegler
    • 2
  1. 1.Departments of Pharmacology and SurgeryDuke University Medical CenterDurhamUSA
  2. 2.Clayton Foundation Biochemical Institute and Department of ChemistryThe University of Texas at AustinAustinUSA

Personalised recommendations