Relationship Between Structure and Mutagenic/Carcinogenic Activity of Short Chain Aliphatic Halocompounds: A Collaborative Project

  • Giorgio Cantelli-Forti
  • G. L. Biagi
  • P. A. Borea
  • G. Bronzetti
  • M. C. Guerra
  • P. Hrelia
  • M. Paolini
  • S. Simi
  • Sandro Grilli


The halogenated hydrocarbons represent one of the most important categories of industrial chemicals owing to their use, production volume, environmental and toxicological activity and, hence most important, potential population risk. They are probably the most ubiquitous in occurrence. A number of these, because of their use as pesticides and aerosol propellents and their high chemical stabilities, have become distributed throughout the biosphere. Occupational exposure, seems to be the major risk1. In fact, several of these compounds are carcinogens in test animals2,3,4 and their acute and chronic toxic effects on liver, kidney and central nervous system have been demonstrated5,6. However, in most cases, no adequate human data are available for estimating risk by halocompounds. They react with nucleophilic substrates by direct attack or after bioactivation by enzymatic systems. The direct reactivity of halocompounds decreases from iodo- to bromo- and chloro-substituted compounds. More generally, halocompounds are enzymatically “activated” to interact with macromolecules. The first metabolic step is an oxidation due to the mixed function oxidase system (MFO) in the presence of cytochrome P-450 with the exception of carbon tetrachloride and halothane metabolism where initial reductive reactions by MFO occur. Oxidation by P-450 dependent-MFO activity results in the addition of radical oxene to the carbon-carbon bond of substrate that leads to epoxide formation.


Quantitative Structure Activity Relationship Fragile Site Logarithmic Growth Phase Mixed Function Oxidase Mixed Function Oxidase System 
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  1. 1.
    IARC 1979, Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to humans, IARC, Lyon, Vol. 20.Google Scholar
  2. 2.
    E. K. Weisburger, Carcinogenicity studies on halogenated hydrocarbons, Environ. Health Perspec. 21:7 (1977).CrossRefGoogle Scholar
  3. 3.
    L. Fishbein, Potential halogenated industrial carcinogenic and mutagenic chemicals, II. Halogenated saturated hydrocarbons, Sci. Total Environ. 11:163 (1979).PubMedCrossRefGoogle Scholar
  4. 4.
    L. Fishbein, Potential halogenated industrial carcinogenic and mutagenic chemicals, III. Alkane, Sci. Total Environ. 12:170 (1980).Google Scholar
  5. 5.
    W. F. Von Ottigen, “The Halogenated Hydrocarbons of Industrial and Toxicological Importance”, Elsevier, Amsterdam (1964).Google Scholar
  6. 6.
    W. M. Kluwe and J. B. Hook, Metabolism of nephrotoxic haloalkanes, Fed. Proc. 39:3129 (1980).PubMedGoogle Scholar
  7. 7.
    G. Cantelli-Forti and G. Bronzetti, Mutagenesis and carcinogenesis of halogenated ethylenes, Ann. N. Y. Acad. Sci, in press (1986).Google Scholar
  8. 8.
    F. K. Zimmermann, R. Kern and H. Rasenberger, A yeast strain for simultaneous detection of induced mitotic crossing-over, mitotic gene conversion and reverse mutation, Mutat. Res. 28:381 (1975).CrossRefGoogle Scholar
  9. 9.
    G. Cantelli-Forti and G. Bronzetti, Improvements in in vitro genotoxicity tests, in: “In Vitro Short-Term Assays”, N. Loprieno and C. Pantarotto, eds., Plenum Press, New York, in press (1987).Google Scholar
  10. 10.
    G. Cantelli-Forti, M. Paolini, P. Hrelia, C. Corsi, G. L. Biagi and G. Bronzetti, NADPH-generating system: influence on microsomal mono-oxygenase stability during incubations for liver microsomal assay with rat and mouse S9 fractions, Mutat. Res. 129:291 (1984).CrossRefGoogle Scholar
  11. 11.
    B. N. Ames, J. McCann and E. Yamasaki, Methods for detecting carcinogens and mutagens with the Salmonella/mammalian microsome mutagenicity test, Mutat. Res. 31:347 (1975).PubMedCrossRefGoogle Scholar
  12. 12.
    D. M. Maron and B. N. Ames, Revised methods for the Salmonella mutagenicity test, in: “Handbook of Mutagenicity test procedures”, B. J. Kilbery, M. Legator, W. Nichols and C. Ramel, eds., 2nd Ed., Elsevier Science Publisher, Amsterdam (1984).Google Scholar
  13. 13.
    D. K. Ford and G. Yerganian, Observation on the chromosomes of Chinese hamster cells in tissue cultures, J. Natl. Cancer Inst. 21:393 (1958).PubMedGoogle Scholar
  14. 14.
    C. M. Colella, G. Rainaldi and A. Piras, 8-Azaguanine versus 6-thiogua-nine: influence on frequency and expression time of induced HGPRT-mutations in Chinese hamster V79 cells, Mutat. Res. 107:397 (1983).PubMedCrossRefGoogle Scholar
  15. 15.
    M. A. Seabright, A rapid banding technique for human chromosomes, Lancet 2:971 (1971).PubMedCrossRefGoogle Scholar
  16. 16.
    G. Cantelli-Forti, M. Paolini, P. Hrelia, E. Sapigni and G. L. Biagi, Effects of Metronidazole, Azanidazole and Azathioprine on cytochrome P-450 and various mono-oxygenase activities in hepatic microsomes from control and induced mice, Arch. Toxicol. suppl. 11:264 (1987).Google Scholar
  17. 17.
    R. A. Lubet, R. T. Mayer, J. W. Cameron, W. N. Raymond, D. M. Burke, T. Wolff and F. P. Guengerich, Dealkylation of pentoxyresorufin: a rapid and sensitive assay for measuring induction of cytochrome(s) P-450 by phenobarbital and other xenobiotics in the rat, Arch. Biochem. Biophys. 238:43 (1985).PubMedCrossRefGoogle Scholar
  18. 18.
    A. V. Klotz, J. J. Stageman and C. Walsh, An alternative 7-ethoxyresorufin O-deethylase activity assay: a continuous visible spectro-photometric method for measurement of cytochrome P-450 monooxygenase activity, Anal. Biochem. 140:138 (1984).PubMedCrossRefGoogle Scholar
  19. 19.
    J. L. Bailey, “Techniques in Protein Chemistry”, Elsevier, Amsterdam (1967).Google Scholar
  20. 20.
    G. E. P. Box and W. G. Hunter, “Statistics for Experiments”, Wiley, New York (1978).Google Scholar
  21. 21.
    S. Simi and L. Vatteroni, Methotrexate induced fragile sites in different Chinese hamster cell lines, Proc. IX Meeting of the European Association for Cancer Research, Helsinki (1987).Google Scholar
  22. 22.
    M. Le Beau and J. D. Rowley, Heritable fragile site in cancer, Nature 308:607 (1984).CrossRefGoogle Scholar
  23. 23.
    I. K. Gadi, J. J. Harrison and R. Sagzer, Genetic analysis of tumorigenesis, XVI. Chromosome changes in azacytidine and insulin induced tumorigenesis, Somat. Cell and Molec. Genet. 10:521 (1984).CrossRefGoogle Scholar
  24. 24.
    R. L. Stalling, B. D. Grawford, R. J. Black and E. H. Chang, Assignment of Ras proto-oncogenes in Chinese hamster: implications for mammalian gene linkage conservation and neoplasia, Cytogenet. and Cell Genet. 43:2 (1986).CrossRefGoogle Scholar
  25. 25.
    J. J. Yunis, A. L. Soreng and A. E. Bowe, Fragile sites are targets of diverse mutagens and carcinogens, Oncogene 1:59 (1987).PubMedGoogle Scholar
  26. 26.
    C. Hansch and A. J. Leo, “Substituent Constants for Correlation Analysis in Chemistry and Biology”, John Wiley, New York (1979).Google Scholar
  27. 27.
    G. L. Biagi, A. M. Barbaro, M. C. Guerra, G. Cantelli-Forti, G. Aicardi and P. A. Borea, Quantitative relationship between structure and mutagenic activity in a series of 5 nitroimidazoles, Teratogen. Carcin. Mut. 3:429 (1983).CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1988

Authors and Affiliations

  • Giorgio Cantelli-Forti
    • 1
  • G. L. Biagi
    • 1
  • P. A. Borea
    • 2
  • G. Bronzetti
    • 3
  • M. C. Guerra
    • 1
  • P. Hrelia
    • 4
  • M. Paolini
    • 1
  • S. Simi
    • 3
  • Sandro Grilli
    • 5
  1. 1.Istituto di FarmacologiaUniversità degli StudiBolognaItaly
  2. 2.Istituto di FarmacologiaUniversità degli StudiFerraraItaly
  3. 3.Istituto di Mutagenesi e Differenziamento del CNRPisaItaly
  4. 4.Division of Environmental ToxicologyThe University of Texas Medical BranchGalvestonUSA
  5. 5.Istituto di CancerologiaUniversità degli StudiBolognaItaly

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