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The Flavin-Containing Monooxygenase (EC 1.14.13.8)

  • Ernest Hodgson
  • Patricia E. Levi
Part of the NATO ASI Series Advanced Science Institutes Series book series (NSSA, volume 202)

Abstract

The flavin-containing monooxygenase (EC 1.14.13.8) (FMO), originally described as an amine oxidase, was subsequently shown to be a versatile sulfur oxidase, the early studies being summarized by Ziegler (1). The FMO has been shown more recently to be a phosphorus oxidase (2,3). This enzyme and the cytochrome P450-dependent monooxygenase system are the two principal enzymes that catalyze the oxidation of lipophilic xenobiotics to electrophilic products capable of further metabolism, either to readily excretable conjugation products or to reactive intermediates with potential for adverse effects. Much of what is known about the substrate specificity of the FMO, is summarized in a recent review (4). Purification of pig liver FMO was accomplished some time ago (5) and the ability of the solubilized enzyme to catalyze the oxidation of the same wide variety of nucleophilic nitrogen, sulfur and phosphorus compounds as the membrane-bound enzyme has been established (1-5). The physiological role for this enzyme is not well known but may be involved in the maintenance of cellular thiol:disulfide ratios by the oxidation of cysteamine to cystamine (6).

Keywords

Rabbit Lung Primary Aliphatic Amine Piperonyl Butoxide Microsomal Oxidation Nucleophilic Nitrogen 
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.

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References

  1. 1.
    D. M. Zeigler, Microsomal flavin-containing monooxygenation of nucleophilic nitrogen and sulfur compounds, in: “Enzymatic Basis of Detoxication”, W.B. Jakoby, ed., Academic Press, New York (1980).Google Scholar
  2. 2.
    N. P. Hajjar and E. Hodgson, “Flavin adenine dinucleotide-dependent monooxygenase as an activation enzyme, in: “Biological Reactive Intermediates — II, Part B”, R. Snyder, D. V. Parke, J. J. Kocsis, D. J. Jollow, C. G. Gibson and C. M. Witmer, eds., Plenum Press, New York (1982).Google Scholar
  3. 3.
    B. P. Smyser and E. Hodgson, Metabolism of phosphorus-containing compounds by pig liver microsomal FAD-containing monooxygenase, Biochem. Pharacol. 34:1145–1150 (1985).CrossRefGoogle Scholar
  4. 4.
    D. M. Zeigler, Flavin-containing monooxygenases: catalytic mechanism and substrate specificities, Drug Metab. Rev. 9:1–32 (1988).CrossRefGoogle Scholar
  5. 5.
    D. M. Zeigler and L. L. Poulsen, Hepatic microsomal mixed-function amine oxidase, in: Methods in Enzymology”, S. Fleisher and L. Packer, eds., New York (1978).Google Scholar
  6. 6.
    D. M. Zeigler and L. L. Poulsen, Protein disulfide bond synthesis: a possible intracellular mechanism, Trends Biochem. Sci. 2:79–82 (1977).CrossRefGoogle Scholar
  7. 7.
    P. J. Sabourin, B. P. Smyser and E. Hodgson, Purification of the flavin-containing monooxygenase from mouse and pig liver microsomes, Int. J. Biochem. 16:713–720 (1984).PubMedCrossRefGoogle Scholar
  8. 8.
    E. Hodgson and P. E. Levi, Species, organ and cellular variation in the flavin-containing monooxygenase, Drug Metabol. and Drug Interact. 6:219–233 (1989).CrossRefGoogle Scholar
  9. 9.
    D. M. Zeigler, p. 297 in: “Microsomes and Drug Oxidations, J. Miners, D. J. Birkett, R. Drew and M. McManus, eds., Taylor and Francis, London (1988).Google Scholar
  10. 10.
    E. Hodgson, E. and P. E. Levi, The flavin-containing monooxygenase as a sulfur oxidase, in: “Metabolism of Xenobiotics”, J.W. Gorrod, H. Oelschlager and J. Caldwell, eds., Taylor and Francis, London (1988).Google Scholar
  11. 11.
    D. E. Williams, S. E. Hale, A. S. Muerhoff and B. S. S. Masters, Rabbit lung flavin-containing monooxygenase. Purification, characterization, and induction during pregnancy, Mol. Pharmacol. 28:381–390 (1985).PubMedGoogle Scholar
  12. 12.
    R. E. Tynes, P. J. Sabourin, E. Hodgson and R. M. Philpot, Formation of hydrogen peroxide and nhydroxylated amines catalyzed by pulmonary flavin-containing monooxygenases in the presence of primary alkylamines, Arch. Biochem. Biophys. 251:654–664 (1986).PubMedCrossRefGoogle Scholar
  13. 13.
    P. Hlavica and M. Kehl, The role of cytochrome P-450 and mixed-function amine oxidase in the N-oxidation of N,N-dimethylaniline, Biochem. J. 164:487–496 (1977).PubMedGoogle Scholar
  14. 14.
    S. Hamill and D. Y. Cooper, The role of cytochrome P-450 in the dual pathways of N-demethylation of N,N-dimethylaniline by hepatic microsomes, Xenobiotica 14:139–149 (1984).PubMedCrossRefGoogle Scholar
  15. 15.
    R. E. Tynes and E. Hodgson, Oxidation of thiobenzamide by the FAD-containing and cytochrome P-450-dependent monooxygenases of liver and lung microsomes, Biochem. Pharmacol. 32:3419–3428 (1983).PubMedCrossRefGoogle Scholar
  16. 16.
    R. E. Tynes and E. Hodgson, The measurement of FAD-containing monooxygenase activity in microsomes containing cytochrome P-450, Xenobiotica 14:515–520 (1984).PubMedCrossRefGoogle Scholar
  17. 17.
    S. Kinsler, P. E. Levi and E. Hodgson, Hepatic and extrahepatic microsomal oxidation of phorate by the cytochrome P-450 and FAD-containing monooxygenase systems in the mouse, Pestic. Biochem. Physiol.31: 54–60 (1988).CrossRefGoogle Scholar
  18. 18.
    S. Kinsler, P. E. Levi and E. Hodgson, Relative contributions of the cytochrome p-450 and flavin-containing monooxygenases to the microsomal oxidation of phorate following treatment of mice with phenobarbital, hydrocortisone, acetone, and piperonyl butoxide. In press.Google Scholar
  19. 19.
    P. E. Levi and E. Hodgson, Stereospecificity in the oxidation of phorate and phorate sulphoxide by purified FAD-containing monooxygenase and cytochrome P-450 isozymes, Xenobiotica 18:29–39 (1988).PubMedCrossRefGoogle Scholar
  20. 20.
    P.E. Levi and E. Hodgson, Metabolites resulting from oxidative and reductive processes, in: “Intermediary Xenobiotic Metabolism in Animals”, D. J. Hutson and G. D. Paulson, eds., Taylor and Francis, London (1988).Google Scholar
  21. 21.
    P. W. Hale, Jr. and A. Poklis, Thioridazine-5-sulfoxide diastereoisomers in serum and urine from rat and man following chronic thioridazine administration, J. Anal. Tox. 9179–201 (1985).Google Scholar
  22. 22.
    C. C. Kilts, K. S. Patrick, G. R. Breese and R. B. Mailman, Simultaneous determination of thioridazine and its S-oxidized and N-demethylated metabolites using high performance liquid chromatography on radially compressed silica, J. Chromatog. 231:377–391 (1982).CrossRefGoogle Scholar
  23. 23.
    C. D. Kilts, R. B. Mailman, E. Hodgson and G. R. Breese, Simultaneous determination of thioridazine and its sulfoxidized metabolites by HPLC use in clinical and preclinical metabolic studies, Federation Proceedings 40:283 (1981).Google Scholar
  24. 24.
    P. W. Hale, Jr. and A. Poklis, Cardiotoxicity of thioridazine and two stereoisomeric forms of thioridazine-5-sulfoxide in the isolated perfused rat heart, Tox. Appl. Pharmacol. 86:44–55 (1986).CrossRefGoogle Scholar
  25. 25.
    G. A. Dannan and F. P. Guengerich, Immunochemical comparison and quantitation of microsomal flavin-containing monooxygenases in varioius hog, mouse, rat, rabbit, dog and human tissues, Mol. Pharmacol. 22:787–794 (1982).PubMedGoogle Scholar
  26. 26.
    R. E. Tynes and E. Hodgson, Catalytic activity and substrate specificity of the flavin-containing monooxygenase in microsomal systems: characterization of the hepatic, pulmonary and renal enzymes of the mouse, rabbit and rat, Arch. Biochem. Biophys. 240:77–93 (1985).PubMedCrossRefGoogle Scholar
  27. 27.
    P. J. Sabourin and E. Hodgson, Characterization of the purified microsomal FAD-containing monooxygenase from mouse and pig liver, Chem. Biol. Interactions 51:125–139 (1984).CrossRefGoogle Scholar
  28. 28.
    P. J. Sabourin, R. E. Tynes, B. P. Smyser and E. Hodgson, The FAD-containing monooxygenase of lung and liver tissue from rabbit, mouse and pig: species and tissue differences, in: “Biological Reactive Intermediates III”, J. J. Kocsis, D. J. Jollow, C. M. Witmer, J. O. Nelson and R. Synder, eds., Plenum Press, New York (1986).Google Scholar
  29. 29.
    R. E. Tynes and R. M. Philpot, Tissue and speciesdependent expression of multiple forms of mammalian microsomal flavin-containing monooxygenase. Mol. Pharmacol. 31:569–574 (1987).PubMedGoogle Scholar
  30. 30.
    M. E. McManus, I. Stupans, W. Burgess, J. A. Koenig, P. de la M Hall and D. J. Birkett, Flavin containing monooxygenase activity in human liver microsomes, Drug Metab. Disp. 15:256–261 (1987).Google Scholar
  31. 31.
    M. Agosin and G. T. Ankley, Conversion of N,N-dimethylaniline to N,N-dimethylaniline-N-oxide by a cytosolic flavin-containing enzyme from Trypanaosoma cruzi, Drug Metabol. Disp. 15:200–203 (1987).Google Scholar
  32. 32.
    B. P. Smyser, P. J. Sabourin and E. Hodgson, Oxidation of pesticides by purified microsomal FAD-containing monooxygenase from mouse and pig liver, Pestic. Biochem. Physiol. 24:368–374 (1985).CrossRefGoogle Scholar
  33. 33.
    R. E. Tynes and E. Hodgson, Magnitude of involvement of the mammalian flavin-containing monooxygenase in the microsomal oxidation of pesticides, J. Agric. Food Chem. 33:471–479 (1985).CrossRefGoogle Scholar
  34. 34.
    T. R. Devereux, R. M. Philpot and J. R. Fouts, The effects of Hg2+ on rabbit hepatic and pulmonary solubilized, partially purified N,N-dimethylaniline N-oxidases, Chem. Biol. Interact. 19:277–297 (1977).CrossRefGoogle Scholar
  35. 35.
    Y. Ohmiya and H. M. Mehendale, Metabolism of chlorpromazine by pulmonary microsomal enzymes in the rat and rabbit, Biochem. Pharmacol. 31:157–162 (1982).PubMedCrossRefGoogle Scholar
  36. 36.
    Y. Ohmiya and H. M. Mehendale, Species differences in pulmonary N-oxidation of chlorpromazine and imipramine, Pharmacology 28:289–295 (1984).PubMedCrossRefGoogle Scholar
  37. 37.
    R. E. Tynes, P. J. Sabourin, and E. Hodgson, Identification of distinct hepatic and pulmonary forms of microsomal flavin-containing monooxygenase in the mouse and rabbit, Biochem. Biophys.Res. Commun. 126:1069–1075 (1985).PubMedCrossRefGoogle Scholar
  38. 38.
    D. E. Williams, D. M. Ziegler, D. J. Nordin, S. E. Hale, and B. S. S. Masters, Rabbit lung flavin-containing monooxygenase is immunochemically and catalytically distinct from the liver enzyme, Biochem. Biophys. Res. Commun. 125:116–122 (1984).PubMedCrossRefGoogle Scholar
  39. 39.
    L. L. Poulsen, K. Taylor, D. E. Williams, B. S. S. Masters, Substrate specificity of the rabbit lung flavin-containing monooxygenase for amines: oxidation products of primary alkylamines, Mol. Pharmanol. 30:680–685 (1986).Google Scholar
  40. 40.
    T. G. Osimitz and A. P. Kulkarni, Oxidative metabolism of xenobiotcs during pregnancy: significance of microsomal flavin-containing monooxygenase. Biochem. Biophys. Res. Commun. 4:1164–1171 (1982).CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Ernest Hodgson
    • 1
  • Patricia E. Levi
    • 1
  1. 1.Department of ToxicologyNorth Carolina State UniversityRaleighUSA

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