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Chemical Mutagens pp 61–79Cite as

The Detection of Chemical Mutagens/Carcinogens by DNA Repair and Mutagenesis in Liver Cultures

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Abstract

A number of rapid in vitro tests for identifying chemicals or mixtures, synthetic or naturally occurring, with a potential for adverse health effects such as carcinogenicity and mutagenicity have been devised in recent years. For a variety of reasons, no single system has emerged or is likely to emerge as sufficient for testing the wide variety of chemicals that require evaluation. Thus, the need to develop a battery of tests has been recognized.(p1,p2) In all short-term tests, there are two principal components: the metabolizing system and the endpoint that is measured. A battery should be composed of tests that involve different metabolic capabilities or end-points of different, but clear, biological significance. The use of intact mammalian cells in a battery offers potential advantages in both components, by providing intracellular metabolism of chemicals within the target cell and the end-points of DNA damage,((sup5–5) mutagenesis,p(6–8) and transformation,p(9-11) the biological significance of which is readily apparent. The goal of the work to be described in this review has been to develop sensitive and reliable mammalian cell systems that could be useful as part of a test battery for the screening of chemicals. The cell systems developed have utilized cells derived from liver because liver possesses the broadest capability of any organ for metabolizing chemical carcinogens (see Section 3). Although transformation studies are an integral part of this effort,p(12-14) only studies involving DNA repair and mutagenesis are presented here.

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References

  1. W. G. Flamm, A Tier system approach to mutagen testing, Mutation Res. 26, 329–333 (1974).

    Article  CAS  Google Scholar 

  2. B. A. Bridges, Use of a three-tier protocol for evaluation of long-term toxic hazards, particularly mutagenicity and carcinogenicity, in: Screening Tests in Chemical Carcinogenesis (R. Montesano, H. Bartsch, and L. Tomatis, eds.), pp. 549–559, International Agency for Research in Cancer, Lyons, France (1976).

    Google Scholar 

  3. J. D. Regan and R. B. Setlow, Repair of chemical damage to human DNA, in: Chemical Mutagens: Principles and Methods for Their Detection, Vol. 3 (A. Hollaender, ed.), pp. 151–170, Plenum Press, New York (1973).

    Google Scholar 

  4. J. E. Cleaver, R. Goth, and E. C. Friedberg, Value of measurements of DNA repair levels in predicting carcinogenic potential of chemicals, in: Screening Tests In Chemical Carcinogenesis (R. Montesano, H. Bartsch, and L. Tomatis, eds.), pp. 639–655, International Agency for Research on Cancer, Lyons, France (1976).

    Google Scholar 

  5. H. F. Stich, R. H. C. San, P. Lam, J. Koropatnick, and L. Lo, Unscheduled DNA synthesis of human cells as a short-term assay for chemical carcinogens, in: Origins of Human Cancer (H. H. Hiatt, J. D, Watson, and J. A. Winsten, eds.), pp 1499–1512, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1977).

    Google Scholar 

  6. E. H. Y. Chu, Induction and analysis of gene mutations in mammalian cells in culture, in: Chemical Mutagens: Principles and Methods for Their Detection, Vol. 1 (A. Hollaender, ed.), pp 411–444, Plenum Press, New York (1971).

    Google Scholar 

  7. D. Clive, W. G. Flamm, and J. B. Patterson, Specific-locus mutational assay systems for mouse lymphoma cells, in: Chemical Mutagens: Principles and Methods for Their Detection, Vol. 3 (A. Hollaender, ed.), pp. 79–103, Plenum Press, New York (1973).

    Google Scholar 

  8. E. Huberman, Cell-mediated mutagenicity of different loci in mammalian cells by carcinogenic polycyclic hydrocarbons, in: Screening Tests in Chemical Carcinogenesis (R. Montesano, H. Bartsch, and L. Tomatis, eds.), pp. 521–532, International Agency for Research on Cancer, Lyons, France (1976).

    Google Scholar 

  9. Y. Berwald and L. Sachs, In vitro transformation of normal cells to tumor cells by carcinogenic hydrocarbons, J. Natl. Cancer Inst. 35, 641–661 (1965).

    CAS  Google Scholar 

  10. C. Heidelberger, Oncogenic transformation of rodent cell lines by chemical carcinogens, in: Origins of Human Cancer (H. H. Hiatt, J. D. Watson, and J. A. Winsten, eds.), pp. 1513–1520, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1977).

    Google Scholar 

  11. J. A. DiPaolo, Quantitative aspects of in vitro chemical carcinogenesis, in: Chemical Carcinogenesis (P. O. P. Ts'o and J. A. DiPaolo, eds.), pp. 443–455, Marcel Dekker, New York (1974).

    Google Scholar 

  12. G. M. Williams, J. M. Elliott, and J. H. Weisburger, Carcinoma after malignant conversion in vitro of epithelial-like cells from rat liver following exposure to chemical carcinogens, Cancer Res. 33, 606–612 (1973).

    CAS  Google Scholar 

  13. G. M. Williams, The study of chemical carcinogenesis using cultured rat liver cells, in: Gene Expression and Carcinogenesis in Cultured Liver (L. E. Gerschenson and E. B. Thompson, eds.), pp. 480–487, Academic Press, New York (1975).

    Google Scholar 

  14. G. M. Williams, The use of liver epithelial cultures for the study of chemical carcinogenesis, Am. J. Pathol 85, 739–753 (1976).

    CAS  Google Scholar 

  15. G. M. Williams, The significance of rodent liver tumors in bioassay, Presented at the Toxicology Forum, Aspen, Colorado, July, 1977.

    Google Scholar 

  16. G. M. Williams, A comparison of in vivo and in vitro metabolic activations systems, in: Critical Reviews in Toxicology-Strategies for Short-term Testing for Mutagens/Carcinogens (B. Butterworth, ed.), pp. 96–97, C. R. C. Press, West Palm Beach, Fla. (1979).

    Google Scholar 

  17. G. M. Williams, A comparison of in vivo and in vitro metabolic activations systems, in: Critical Reviews in Toxicology-Strategies for Short-term Testing for Mutagens/Carcinogens (B. Butterworth, ed.), pp. 96–97, C. R. C. Press, West Palm Beach, Fla. (1979).

    Google Scholar 

  18. P. Brookes, H. Druckrey, L. Ehrenberg, B. Lagerlof, J. Litwin, and G. M. Williams, The relation of cancer induction and genetic damage, in: Evaluation of Genetic Risks of Environmental Chemicals (C. Ramel, ed.), Ambio Special Report No. 3, pp. 15–16 (1973).

    Google Scholar 

  19. J. A. Miller, Carcinogenesis by chemicals: An overview: G. H. A. Clowes Memorial Lecture, Cancer Res. 30, 559–(1970).

    CAS  Google Scholar 

  20. E. C. Miller and J. A. Miller, The mutagenicity of chemicals, in: Chemical Mutagens: Principles and Methods for Their Detection, Vol. 1 (A. Hollaender, ed.), pp. 83–119, Plenum Press, New York (1971).

    Google Scholar 

  21. N. J. Van Abbe, Letter to the editor: Bacterial mutagenicity and carcinogenic potential, Food Cosmet. Toxicol. 14, 519 (1976).

    Google Scholar 

  22. J. H. Weisburger and G. M. Williams, Metabolism of chemical carcinogens, in: Cancer: A Comprehensive Treatise, Vol. 1 (F. F. Becker, ed.), pp. 185–234, Plenum Press, New York (1975).

    Google Scholar 

  23. J. McCann and B. N. Ames, Detection of carcinogens as mutagens in the Salmonella/ microsome test: Assay of 300 chemicals, Proc. Natl. Acad. Sei. U.S.A. 72, 5135–5139 (1975).

    Article  CAS  Google Scholar 

  24. I. Schmeltz, J. Tosk, and G. M. Williams, Comparison of the metabolic profiles of benzo(a)pyrene obtained from primary cell cultures and subcellular fractions derived from normal and methylcholanthrene-induced rat liver, Cancer Lett. 5, 81–89, (1978).

    Article  CAS  Google Scholar 

  25. M. N. Berry, High-yield preparation of morphologically intact isolated parenchzmal cells from rat liver, in; Methods in Enzymology, Vol. XXXII (S. Fleischer and L. Parker, eds.), pp. 625–632, Academic Press, New York (1974).

    Google Scholar 

  26. P. O. Seglen, Preparation of isolated rat liver cells, in: Methods in Cell Biology, Vol. XIII (D. M. Prescott, ed.) pp. 29–83, Academic Press, New York (1975).

    Google Scholar 

  27. D. R. LaBrecque and R B. Howard, The preparation and characterization of intact isolated parenchymal cells from rat liver, in: Methods in Cell Biology, vol. XIV (D. M. Prescott, ed.), pp. 327–340, Academic Press, New York (1976).

    Google Scholar 

  28. G. M. Williams, E. Bermudez, R. H. C. San, P. J. Goldblatt, and M. F. Laspia, Rat hepatocyte primary cultures. IV. Maintenance in defined medium and the role of production of plasminogen activator and other proteases, In Vitro 14, 824–837 (1978).

    Article  CAS  Google Scholar 

  29. G. M. Williams, E. Bermudez, and D. Scaramuzzino, Rat hepatocyte primary cell cultures. III. Improved dissociation and attachment techniques and the enhancement of survival by culture medium, In Vitro 13, 809–817 (1977).

    Article  CAS  Google Scholar 

  30. B. A. Laishes and G. M Williams, Conditions affecting primary cultures of functional adult rat hepatocytes. I. The effect of insulin, In Vitro 12, 521–532 (1976).

    Article  CAS  Google Scholar 

  31. B. A. Laishes and G. M. Williams, Conditions affecting primary cell cultures of functional adult rat hepatocytes. II. Dexamethasone enhanced longevity and maintenance of morphology, In Vitro 21, 821–832 (1976).

    Article  Google Scholar 

  32. G. M. Williams and J. M. Gunn, Long-term cell culture of adult rat liver epithelial cells, Exp. Cell Res. 89, 139–142 (1974).

    Article  CAS  Google Scholar 

  33. G. M. Williams, Primary and long-term culture of adult rat liver epithelial cells, in: Methods in Cell Biology, Vol. XIV (D. M. Prescott, ed.), pp. 357–364, Academic Press, New York (1976).

    Google Scholar 

  34. G. M. Williams, K. Stromberg, and R. Kroes, Cytochemical and ultrastructural alterations associated with confluent growth in cell cultures of epithelial-like cells from rat liver, Lab. Invest. 29, 293–303 (1973).

    CAS  Google Scholar 

  35. P. S. Guzelian, D. M. Bissel, and U. A. Meyer, Drug metabolism in adult rat hepatocytes in primary monolayer culture, Gastroenterology 72, 1232–1239 (1977).

    CAS  Google Scholar 

  36. G. Michalopoulos, G. L. Sattler, and H. C. Pitot, Maintenance of microsomal cytochromes b5 and P-450 in primary cultures of parenchymal liver cells on collagen membranes, Life Sci. 18, 1139–114 (1976).

    Article  CAS  Google Scholar 

  37. H. L. Leffert, T. Moran, R. Boorstein, and K. S. Koch, Procarcinogen activation and hormonal control of cell proliferation in differentiated primary adult rat liver cell cultures Nature (London) 267, 58–61, (1977).

    Article  CAS  Google Scholar 

  38. J. B. Iodine, J. M. Elliott, M. J. Wilson, and E. K. Weisburger, Rat liver cells in culture: Effect of storage, long-term culture, and transformation on some enzyme levels, In Vitro 12, 541–553 (1976).

    Article  Google Scholar 

  39. J. P. Whitlock, H. V. Gelboin, and H. G. Coon, Variation in aryl hydrocarbon (benzo[tf] pyrene) hydroxylase activity in heteroploid and predominantly diploid rat liver cells in culture, /. Cell Biol. 70, 217–225 (1976).

    Article  CAS  Google Scholar 

  40. R. H. C. San and H. F. Stich, DNA repair synthesis of cultured human cells as a rapid bioassay for chemical carcinogens, Int. J. Cancer, 16, 284–291 (1975).

    Article  CAS  Google Scholar 

  41. G. M. Williams, Carcinogen-induced DNA repair in primary rat liver cell cultures: A possible screen for chemical carcinogens, Cancer Lett. 1, 231–236 (1976).

    Article  CAS  Google Scholar 

  42. G. M. Williams, The detection of chemical carcinogens by unscheduled DNA synthesis in rat liver primary cell cultures, Cancer Res. 37, 1845–1851 (1977).

    CAS  Google Scholar 

  43. G. M. Williams, Further improvements in the hepatocyte DNA repair test for carcinogens: Detection of carcinogenic biphenyl derivatives, Cancer Lett.-4, 69–75 (1978).

    Google Scholar 

  44. B.J. Bryant, The incorporation of tritium from thymidine into proteins of the mouse, J. Cell Biol. 29, 29–36 (1966).

    Article  CAS  Google Scholar 

  45. C. G. D. Morley and H. S. Kingdon, Use of 3H thymidine for measurement of DNA synthesis in rat liver—a warning Anal. Biochem. 45, 298–305 (1972).

    Article  CAS  Google Scholar 

  46. G. M. Williams, C. Tong, and J. J. Berman, Characterization of analog resistance and purine metabolism of adult rat-liver epithelial cell 8-azaguanine-resistant mutants, Mutat. Res. 49, 103–115 (1978).

    Article  CAS  Google Scholar 

  47. C. Tong and G. M. Williams, Induction of purine analog-resistant mutants in adult rat liver epithelial lines by metabolic activation-dependent and -independent carcinogens, Mutat. Res. 58, 339–352 (1978).

    Article  CAS  Google Scholar 

  48. J. Berman, C. Tong, and G. M. Williams, Differences between rat liver epithelial and fibroblast cells in sensitivity to 8-azaguanine and metabolism of purines, In Vitro 13, 196 (1977).

    Google Scholar 

  49. J. J. Berman, C. Tong, and G. M. Williams, Enhancement of mutagenesis during cell replication of cultured liver epithelial cells, Cancer Lett. 4, 277–283 (1978).

    Article  CAS  Google Scholar 

  50. R. H. C. San and G. M. Williams, Rat hepatocyte primary cell culture-mediated mutagenesis of adult rat liver epithelial cells by procarcinogens, Proc. Soc. Exp. Biol. Med. 156, 534–538 (1977).

    CAS  Google Scholar 

  51. J. H. Weisburger, L. A. Cohen, and E. L. Wynder, On the etiology and metabolic epidemiology of the main human cancers, in: Origins of Human Cancer (H. H. Hiatt, J. D. Watson, and J. A. Winster, eds.), pp. 567–602 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1977).

    Google Scholar 

  52. J. H. Weisburger, L. A. Cohen, and E. L. Wynder, On the etiology and metabolic epidemiology of the main human cancers, in: Origins of Human Cancer (H. H. Hiatt, J. D. Watson, and J. A. Winster, eds.), pp. 567–602 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York (1977).

    Google Scholar 

  53. J. H. Weisburger and G. M. Williams, Decision point approach to carcinogen testing, in: Structural Correlation of Carcinogenesis and Mutagenesis (I. M. Asher and C. Zervos, eds.), pp. 45–52, FDA Office of Science, Rockville, Maryland (1978).

    Google Scholar 

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Authors and Affiliations

  1. Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York, 10595, USA

    Gary M. William

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  1. Gary M. William
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Editors and Affiliations

  1. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

    Frederick J. de Serres

  2. Associated Universities, Inc., Washington, D. C., USA

    Alexander Hollaender

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© 1980 Plenum Press, New York

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William, G.M. (1980). The Detection of Chemical Mutagens/Carcinogens by DNA Repair and Mutagenesis in Liver Cultures. In: de Serres, F.J., Hollaender, A. (eds) Chemical Mutagens. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-3072-1_3

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  • DOI: https://doi.org/10.1007/978-1-4613-3072-1_3

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-3074-5

  • Online ISBN: 978-1-4613-3072-1

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