Bioactivation of Xenobiotics by Flavin-Containing Monooxygenases

  • Daniel M. Ziegler
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 283)


Flavoproteins are ubiquitous in nature but the ones referred to as flavin-containing monooxygenases, or simply by the acronym FMO, share a catalytic mechanism distinctly different from all other known oxidases or monooxygenases bearing flavin, heme or other redox active prosthetic groups. Like other mammalian monooxygenases, FMO’s require NADPH and oxygen as cosubstrates for the oxygenation of the third substrate but they differ in that the third substrate is not required for the generation of the enzyme bound oxygenating intermediate. Kinetic studies on mechanism (Poulsen and Ziegler, 1979, Beaty and Ballou, 1981a, 1981b) have shown that the xenobiotic substrate is not required for flavin reduction by NADPH nor for reoxidation of dihydroflavin by molecular oxygen. The latter reaction produces the 4a-hydroperoxyflavin which, in FMO, is stabilized by the protein microenvironment around the prosthetic group. The enzyme is apparently present within the cell in this form and any soft nucleophile that can gain access to the enzyme-bound oxygenating intermediate will be oxidized. Precise fit of substrate to enzyme is not necessary, and FMO catalyzes at the same maximum velocity the oxidation of compounds that possess few, if any structural features in common (Ziegler, 1988). These flavoproteins apparently discriminate between physiologically essential and xenobiotic soft nucleophiles by excluding the former rather than by selectively binding the latter. This property is largely responsible for the exceptionally broad specificity of these enzymes. Steric parameters controlling access of nucleophiles to the hydroperoxyflavin apparently differ in various forms of FMO.


Protein Thiol Rabbit Lung Mixed Disulfide Futile Cycle Xenobiotic Substrate 
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  1. Bacq, A. M. (1975). In Sulfur Containing Radioprotective Agents (A. M. Bacq, ed.) p. 8, Pergammon Press, Oxford.Google Scholar
  2. Barker, E. A. and Smukler, E. A. (1972). Altered Microsome Function During Acute Thioacetamide Poisoning. Mol. Pharmacol. 8, 318–326.Google Scholar
  3. Barker, E. A. and Smukler, E. A. (1973). Non-hepatic Thioacetamide Injury: I Thymic Corticol Necrosis. Am. J. Pathol. 71, 409–418.Google Scholar
  4. Beaty, N. S. and Ballou, D. P. (1981a). The Reductive Half-Reaction of Liver Microsomal FAD-Containing Monooxygenase. J. Biol. Chem. 256, 4611–4618.Google Scholar
  5. Beaty, N. S. and Ballou, D. P. (1981b). The Oxidative Half-Reaction of Liver Microsomal FAD-Containing Monooxygenase. J. Biol. Chem. 256, 4619–4625.Google Scholar
  6. Cashman, J. R. and Hanzlik, R. P. (1981). Microsomal Oxidation of Thiobenzamide. A Photometric Assay for the Flavin-Containing Monooxygenase. Biophys. Res. Commun. 98, 147–153.Google Scholar
  7. Chieli, E. and Malvaldi, G. (1984). Role of the Microsomal FAD-Containing Monooxygenase in the Liver Toxicity of Thioacetamide S-Oxide. Toxicology 31, 41–52.CrossRefPubMedGoogle Scholar
  8. Chieli, E. and Malvaldi, G. (1985). Role of the P-450 and FAD-Containing Monooxygenases in the Bioactivation of Thioacetamide, Thiobenzamides and Their Sulfoxides. Biochem. Pharmacol. 34, 395–396.Google Scholar
  9. Dannan, G. A. and Guengerich, F. P. (1982). Immunochemical Comparison and Quantitation of Microsomal Flavin-Containing Monooxygenase in Various HogGoogle Scholar
  10. Mouse, Rat, Rabbit, Dog and Human Tissues. Mo/. Pharmacol. 22, 787–794.Google Scholar
  11. Fitzhugh, O. A. and Nelson, A. A. (1948). Liver Tumors in Rats Fed Thiourea or Thioacetamide. Science 108, 626–628.CrossRefPubMedGoogle Scholar
  12. Frederick, C. B., Mays, J. B., Ziegler, D. M., Guengerich, F. P. and Kadlubar, F. F. (1982). Cytochrome P-450 and Flavin-Containing Monooxygenase-Catalyzed Formation of the Carcinogen N-Hydroxy-2-Aminofluorene and Its Covalent Binding to Nuclear DNA. Cancer Res. 42, 2671–2677.PubMedGoogle Scholar
  13. Hanzlik, R. P., Cashman, J. P. and Traiger, G. J. (1980). Relative Hepatotoxicity of Thiobenzamides and Thiobenzamide-S-Oxides in the Rat. Toxicol. Appl. Pharmacol. 55, 260–272.Google Scholar
  14. Kreiter, P. A., Ziegler, D. M., Hill, K. A. and Burk, R. F. (1984). Increased Biliary GSSG Efflux from Rat Livers Perfused with Thiocarbamide Substrates for the Flavin-Containing Monooxygenase. Mol. Pharmacol. 26, 122–127.Google Scholar
  15. Liener, J. E. (1980). Toxic Constituents of Plant Foodstuff (J. E. Liener, ed.) 2nd edition, Academic Press Inc., New York.Google Scholar
  16. Lovenberg, W. (1973). Some Vaso-and Psychoactive Substances in Food: Amines, Stimulants, Depressants and Hallucinogens in Toxicants Occurring Naturally in Foods (F. M. Strong, L. Atkin, J. M. Coon, D. W. Fassett, B. J. Wilson and I. A. Wolff) pp. 170–188, National Academy of Sciences, Washington, D.C.Google Scholar
  17. Millard, W. J., Sagar, S. M., Landis, D. M. D., Martin, J. B. and Badger, T. M. (1982). Cysteamine: A Potent and Specific Depletor of Pituitary Prolactin. Science 217, 452–0454.Google Scholar
  18. Nagata, T., Williams, D. E. and Ziegler, D. M. (1990). Substrate Specificities of Rabbit Lung and Porcine Liver Flavin-Containing Monooxygenases: Differences Due to Substrate Size. Chem. Res. Toxicol. (submitted).Google Scholar
  19. Pelroy, R. A., Gandolfi, A. J. (1980). Use of a Mixed Function Amine Oxidase for Metabolic Activation in the Ames/Salmonella Assay System. Mutat. Res. 72, 329–334.Google Scholar
  20. Poulsen, L. L., Hyslop, R. M. and Ziegler, D. M. (1979). S-Oxygenation of N-Substituted Thioureas Catalyzed by the Liver Microsomal FAD-Containing Monooxygenase. Arch. Biochem. Biophys. 198, 78–98.Google Scholar
  21. Poulsen, L. L., Taylor, K., Williams, D. E., Masters, B. S. S. and Ziegler, D. M. (1986). Substrate Specificity of the Rabbit Lung Flavin-Containing Monooxygenase for Amines: Oxidation Products of Primary Alkylamines. Mol. Pharmacol. 30, 680685.Google Scholar
  22. Poulsen, L. L. and Ziegler, D. M. (1977). Microsomal Mixed-Function OxidaseDependent Renaturation of Reduced Ribonuclease. Arch. Biochem. Biophys. 183, 563–570.Google Scholar
  23. Poulsen, L. L. and Ziegler, D. M. (1979). The Liver Microsomal FAD-Containing Monooxygenases: Spectral Characterization and Kinetic Studies. J. Biol. Chem. 254, 6449–6455.Google Scholar
  24. Prough, R. A. and Moloney, S. J. (1985). “Hydrazines” in Bioactivation of ForeignGoogle Scholar
  25. Compounds (M. M. Anders, ed.) pp. 433–446, Academic Press Inc., New York.Google Scholar
  26. Prough, R. A., Freeman, P. C. and Hines, R. N. (1981). The Oxidation of Hydrazine Derivatives Catalyzed by the Purified Microsomal FAD-Containing Monooxygenase. J. Biol. Chem. 256, 4178–4184.Google Scholar
  27. Prough, R. A. and Ziegler, D. M. (1977). The Relative Participation of Liver Microsomal Amine Oxidase and Cytochrome P-450 in N-Demethylation Reactions. Arch. Biochem. Biophysic. 180, 363–373.Google Scholar
  28. Richter, C. P. (1952). The Physiology and Cytology of Pulmonary Edema and Pleural Effusion Produced in Rats by Alpha-naphthyl Thiourea. J. Thoracic Cardiovac. Surg. 23, 66–91.Google Scholar
  29. Sagar, S. M., Landry, D., Millard, W. J., Badger, T. M., Arnold, M. A. and Martin, J. B. (1982). Depletion of Somatostatin-Like Immunoreactivity in the Rat Central Nervous System by Cysteamine. J. Neuroscience 2, 225–231.Google Scholar
  30. Selye, H. and Szabo, S. (1973). Experimental Model for Production of Perforating Duodenal Ulcers by Cysteamine in the Rat. Nature 244, 458–459.CrossRefPubMedGoogle Scholar
  31. Smith, R. L. and Williams, R. T. (1961). The Metabolism of Arylthioureas I. The Metabolism of 1,3-Diphenyl-2-thiourea (Thiocarbanilide) and Its Derivatives. J. Med. Pharma. Chem. 4, 97–107.Google Scholar
  32. Sterling, C. J. M. (1974). The Sulfinic Acids and Their Derivatives. Int. J. Sulfur Chem. 6, 277–316.Google Scholar
  33. Tynes, R. E. and Philpot, R. M. (1987). Tissue and Species-Dependent Expression of Multiple Forms of Mammalian Microsomal Flavin-Containing Monooxygenase. Mol. Pharmacol. 31, 569–574.Google Scholar
  34. Tynes, R. E., Sabourin, P. J. and Hodgson, E. (1985). Identification of Distinct HepaticGoogle Scholar
  35. and Pulmonary Forms of Microsomal Flavin-Containing Monooxygenase in theGoogle Scholar
  36. Mouse and Rabbit. Biochem. Biophy. Res. Commun. 126, 1069–1075.Google Scholar
  37. Williams, D. E., Hale, S. E., Meurhoff, A. S. and Masters, B. S. S. (1984a). Rabbit LungGoogle Scholar
  38. Flavin-Containing Monooxygenase: Purification, Characterization and Induction During Pregnancy. Mol. Pharmacol. 28, 381–390.Google Scholar
  39. Williams, D. E., Ziegler, D. M., Nordin, D. J., Hale, S. E. and Masters, B. S. S. (1984b). Rabbit Lung Flavin-Containing Monooxygenase is Immunochemically and Catalytically Distinct from the Liver Enzyme. Biochem. Biophys. Res. Commun. 125, 116–122.Google Scholar
  40. Ziegler, D. M. (1988). Flavin-Containing Monooxygenases: Catalytic Mechanism and Substrate Specificities. Drug Meta. Revs. 19, 1–32.Google Scholar
  41. Ziegler, D. M., Ansher, S. S., Nagata, T., Kadlubar, F. F. and Jakoby, W. B. (1988). N-Methylation: Potential Mechanism for Metabolic Activation of Carcinogenic Primary Arylamines. Proc. Natl. Acad. Sci. USA 85, 2514–2517.Google Scholar
  42. Ziegler, D. M., Poulsen, L. L. and Richerson, R. B. (1983). Oxidative Metabolism of Sulfur-Containing Radioprotective Agents in Radioprotective and Anticarcinogens (D. F. Nygaard and M. G. Simic, eds.) pp. 191–202, Academic Press Inc., New York.Google Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • Daniel M. Ziegler
    • 1
  1. 1.Clayton Foundation Biochemical Institute and Department of ChemistryThe University of Texas at AustinAustinUSA

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