Role of Mixed-Function Oxidases in the Formation of Biological Reactive Intermediates

  • Dennis V. Parke
  • Costas Ioannides
Part of the Advances in Experimental Medicine and Biology book series (AEMB)


It is now well-known that many toxic chemicals are converted into reactive intermediates by the action of the microsomal mixed-function oxidases. This enzyme system, which comprises cytochromes P-450 and cytochrome P-450 reductase, is a ubiquitous system found in every living organism which has been investigated, including bacteria, yeasts and flowering plants. The system varies with the type of living organism, with its stage of development, and with the tissue in which the mixed-function oxidase is located; it may be found in the cytoplasm (bacteria), the endoplasmic reticulum (yeast), and the endoplasmic reticulum or mitochondria (mammals) (Hodgson, 1979 see Figure 1). It is perhaps of significance that in the transition from the unicellular bacteria to the multicellular organisation of yeasts, cytochrome P-450 is transferred from the cytoplasm to the endoplasmic reticulum (Wiseman, et al, 1978), where, as with higher organisms, it may be involved in the multicellular organ izat ion.


Endoplasmic Reticulum Reactive Intermediate Chemical Carcinogen Body Mass Ratio Oxygen Insertion 
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  1. Anderson, L.C., Gahmberg, C.G., Sumes, M.A., Teerenhovi, L. and Vuopio, P., 1979, Cell surface glycoprotein analysis: A diagnostic tool in human leukaemias, Int. J. Cancer 23:306.Google Scholar
  2. Benford, D.J., Bridges, J.W. and Parke, D.V., 1980, Activation of hepatic microsomal biphenyl 2-hydroxylation by corticosteroids, Xenobiotica 10: 329.Google Scholar
  3. Booth, J., Boyland, E. and Cooling, C., 1967, The respiration of human liver tissue, Biochem. Pharmac. 16:721.Google Scholar
  4. Chance, B., Sies, H. and Boveris, A., 1979, Hydroperoxide metabolism in mammalian organisms, Physiol. Rev. 59:527.Google Scholar
  5. Chatterjee, S.K. and Kim, V., 1978, Fucosyl transferase activity in metastasising and non-metastasising rat mammary carcinomas, J. Natl. Cancer Inst. 61:151.Google Scholar
  6. Cohen, G. and Cederbaum, A.I., 1979, Chemical evidence for production of hydroxyl radicals during microsomal electron transfer, Science 204: 66.Google Scholar
  7. Conney, A.H., Wood, A.W., Levin, W., Lu, A.Y.H., Chang, R.L., Wislocki, R.G., Goode, R.L., Holder, G.M., Dansette, P.M., Yagi, H. and Jerina, D.M., 1977, Metabolism and Biological activity of benzo(a)pyrene and its metabolic products, in: “Biological reactive intermediates”, D.J. Jollow, J.J. Kocsis, R. Snyder and H. Vainio, eds., Plenum Press, New York and London.Google Scholar
  8. Creaven, P.J., Parke, D.V. and Williams, R.T., 1965, A fluorimetric study of the hydroxylation of biphenyl in vitro by liver preparations of various species, Biochem. J. 96:879.Google Scholar
  9. Creaven, P.J. and Parke, D.V., 1966, The stimulation of hydroxylation by carcinogenic and non-carcinogenic compounds, Biochem. Pharmac. 15:7.Google Scholar
  10. Delauney, J. and Shapira, G., 1974, Ribosomes and cancer, Biomed. 20: 327.Google Scholar
  11. Delaforge, M., Ioannides, C. and Parke, D.V., 1980a, Mechanism of ligand binding of safrole to cytochrome P-450, in: “Microsomes, Drug Oxidations and Chemical Carcinogenesis”, Vol.I, M.J. Coon, A.H. Conney, R.W. Estabrook, H.V. Gelboin, J.R. Gillette and P.J. O’Brien, eds., Academic Press, London.Google Scholar
  12. Delaforge, M., Ioannides, C. and Parke, D.V., 1980b, Ligand binding of safrole to cytochrome P-450, Arch. Toxicol. Supp1. 4: 45.Google Scholar
  13. Delaforge, M., Ioannides, C. and Parke, D.V., 1980c, Inhibition of cytochrome P-448 mixed-function oxidase activity following administration of 9-hydroxy-ellipticine to rats, Chemico.-Biol. Interactions 32:101.Google Scholar
  14. Franklin, M., 1977, Inhibition of mixed-function oxidations by substrates forming reduced cytochrome P-450 metabolite-intermediate complexes, Pharmac. Therap. 2:227.Google Scholar
  15. Freeman, H.J., Kim, Y. and Kim, Y.S., 1978, Glycoprotein metabolism in normal proximal and distal rat colon and changes associated with 1,2dimethylhydrazine-induced colonic neoplasia, Cancer Res. 38: 3385.Google Scholar
  16. Guengerich, F.P., 1979, Isolation and purification of cytochrome P-450, and the existence of multiple forms, Pharmac. Therap. 6:99.Google Scholar
  17. Harris, R., Williams, D.C. and Parke, D.V., 1980, Unpublished data.Google Scholar
  18. Hodgson, E., 1979, Comparative aspects of the distribution of cytochrome P-450 dependent mono-oxygenase system: an overview. DrugMetabolism Rev. 10: 15.Google Scholar
  19. Ioannides, C., Sweatman, B., Richards, R. and Parke, D.V., 1977, Drug metabolism in the ferret: Effects of age, sex and strain. Gen. Pharmac. 8:243.Google Scholar
  20. Lai, C.-S., Grover, T.A. and Piette, L.H., 1979, Hydroxyl radical production in a purified NADPH-cytochrome c (P-450) reductase system. Arch. Biochem. Biophys. 193:373.Google Scholar
  21. Lesca, P., Lecointe, P., Paoletti, C. and Mansuy, D., 1978, Ellipticines as potent inhibitors of aryl hydrocarbon hydroxylase: their binding to microsomal cytochrome P-450 and protective effect against benzo(a)pyrene mutagenicity. Biochem. Pharmac. 27:1203.Google Scholar
  22. Lesca, P., Lecointe, P., Paoletti, C. and Mansuy, D., 1979, Ellipticines as potent inhibitors of microsomes-dependent chemical mutagenesis, Chem.-Biol. Interactions 25:279.Google Scholar
  23. Levin, W., Wood, A.W., Lu, A.Y.H., Ryan, D., West, S., Thakkar, D.R., Yagi, H. and Jerina, D.M., 1977, Role of purified cytochrome P-448 and epoxide hydrase in the activation and detoxication of benzo(a)pyrene, ACS Symposium Series No. 44, Drug Metabolism Concepts, D.M. Jerina, ed., American Chemical Society.Google Scholar
  24. McCoy, E.A. and Rosenkranz, H.S., 1980, Activation of polycyclic aromatic hydrocarbons to mutagens by singlet oxygen: an enhancing effect of atmospheric pollutants, Cancer Lett. 9: 35.Google Scholar
  25. McIntosh, P.R. and O’Toole, K., 1976, The interaction of ribosomes and membranes in animal cells, Biochim. Biophys. Acta 457:171.Google Scholar
  26. McPherson, F.J., Bridges, J.W. and Parke, D.V., 1976, Studies on the nature of the in vitro inhancement of biphenyl 2-hydroxylation provoked by some chemical carcinogens, Biochem. Pharmac. 25:1345.Google Scholar
  27. Nebert, D.W., Bigelow, S.W., Okey, A.B., Yahagi, T., Mori, Y., Nagao, M. and Sugimura, T., 1979, Pyrolysis products from amino acids and protein: Highest mutagenicity requires cytochrome P1-450, Proc. Natl. Acad. Sci. USA 76:5929.Google Scholar
  28. O’Gorman, T. and La Mont, J.T., 1978, Glycoprotein synthesis and secretion in human colon cancers and normal colonic mucosa, Cancer Res. 38:2784.Google Scholar
  29. Parke, D.V., 1977, Biochemical aspects of carcinogenesis, in: “Principles of Surgical Oncology”, R.W. Raven, ed., Plenum, London.Google Scholar
  30. Parke, D.V., 1980, The role of the endoplasmic reticulum, in: “Concepts in Drug Metabolism - 2”, P. Jenner and B. Testa, eds., Marcel Dekker, New York.Google Scholar
  31. Parke, D.V. and Gray, T.J.B., 1978, A comparative study of the enzymic and morphological changes of livers of rats fed butylated hydroxytoluene, safrole, Ponceaus MX, or 2-acetamidofluorene, pp.335–346, in: “Primary Liver Tumours”, H. Remmer, H.M. Bolt, P. Bannasch and H. Popper, eds., MTP Press, Lancaster.Google Scholar
  32. Parke, D.V. and Symons, A.M., 1977, The biochemical pharmacology of mucus, in: “Mucus in Health and Disease”, M. Elstein and D.V. Parke, eds., Plenum, New York.Google Scholar
  33. Stier, A., 1980, Redox cycle of stable mixed nitroxides formed from carcinogenic aromatic amines, XenobioLica in press.Google Scholar
  34. Sunshine, G.H., Williams, D.J. and Rabin, B.R., 1971, Putting drugs in their place, Nature, New Biol. 230:133.Google Scholar
  35. Takagi, M., 1977, Binding of polysomes in vitro with endoplasmic reticulum prepared from rat liver II. Possible involvement of cytochrome P-450 in the binding, J. Biochem. 82:1077.Google Scholar
  36. Ullrich, V., King, L.J., Wolf, C.R. and Nastainczyk, W., 1978, Carbenes and free radicals of haloalkanes as toxic intermediates, Advances in Pharmac. Therap. 9:131.Google Scholar
  37. Vaheri, A. and Mosher, D.F., 1978, High molecular weight, cell surface-associated glycoprotein (fibronectin) lost in malignant transformation, Biochim. Biophys. Acta 516:1.Google Scholar
  38. Walker, C.H., 1978, Species differences in microsomal mono-oxygenase activity and their relationship to biological half-lives, Drug Metabolism Rev. 7: 295.Google Scholar
  39. Warren, L., Buck, C.A. and Tuszynski, G.P., 1978, Glycopeptide changes and malignant transformation. A possible role for carbohydrate in malignant behaviour, Biochim. Biophys. Acta 516:97.Google Scholar
  40. Wickramsinghe, R.H. and Villee, R.A., 1975, Early role during chemical evolution for cytochrome P-450 in oxygen detoxication, Nature (Lond.) 256: 509.Google Scholar
  41. Wiseman, A., Lim, T.K., Woods, L.F.J., 1978, Regulation of the biosynthesis of cytochrome P-450 in brewers yeast: role of cyclic AMP, Biochim. Biophys. Acta 544:615.Google Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • Dennis V. Parke
    • 1
  • Costas Ioannides
    • 1
  1. 1.Department of BiochemistryUniversity of Surrey GuildfordSurreyEngland

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