Metabolism of Chemical Carcinogens by Tracheobronchial Tissues

  • Herman Autrup
  • Roland C. Grafstrom
  • Curtis C. Harris
Part of the Basic Life Sciences book series


Chemical carcinogens are a large group of naturally occurring and man-made compounds of diverse molecular structures. These compounds are ubiquitous in the human environment in the food chain, the water supply, and the atmosphere and they enter the human body through the surface epithelium. The surface area of the lower respiratory tract, approximately 25 m2, is directly exposed to some of these compounds during inhalation. In addition, chemical carcinogens and their metabolites can also reach the lung via the systemic route.


High Pressure Liquid Chromatography Epoxide Hydrolase Chemical Carcinogen Polynuclear Aromatic Hydrocarbon Aryl Hydrocarbon Hydroxylase 
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  1. 1.
    Nettesheim P., and R.A. Griesemer., 1978. Experimental models for studies of respiratory tract carcinogenesis. In: Pathogenesis and Therapy of Lung Cancer. C.C. Harris, ed. Marcel Dekker, Inc.: New York. pp. 75–188.Google Scholar
  2. 2.
    Steele. V.E., A.C. Marchok, and G.M. Cohen., 1980. Transformation of rat tracheal epithelial cells by benzo[a]pyrene and its metabolites. Cancer Lett. 8: 291–298.PubMedCrossRefGoogle Scholar
  3. 3.
    Serabjit-Singh, C.J., C.R. Wolf, R.M. Philpot, and C.G. Plopper., 1980. Cytochrome P-450: Localization in rabbit lung. Science 207: 1469–70.PubMedCrossRefGoogle Scholar
  4. 4.
    Boyd, M.R. 1977. Evidence for the Clara cell as a site of cytochrome P-450 dependent mixed-function oxidase activity in lung. Nature 269: 713–715.PubMedCrossRefGoogle Scholar
  5. 5.
    Vadi, H., B. Jernstrom, and S. Orrenius., 1976. Recent studies on benzo[a]pyrene metabolism in rat liver and lung. In: Carcinogenesis–A Comprehensive Survey. R. Freudenthal, and P.W. Jones, eds. Raven Press: New York. pp. 45–61.Google Scholar
  6. 6.
    Sipal. Z., T. Ahlenius, A. Bergstrand, L. Rodriquez, and S.W. Jakobsson. 1979. Oxidative biotransformation of benzo[a]pyrene by human lung microsomal fractions prepared from surgical specimens. Xenobiotica 9: 633–645.PubMedCrossRefGoogle Scholar
  7. 7.
    Prough, R.A., Z. Sipal, and S.W. Jakobsson. 1977. Metabolism of benzo[a]pyrene by human lung microsomal fractions. Life Sci. 21: 1629–1636.PubMedCrossRefGoogle Scholar
  8. 8.
    McManus, M.E., A.R. Boobis, G.M. Pacifici, R.Y. Frempong, M.J. Brodie, G.C. Kahn, C. Whyte, and D.S. Davies. 1979. Xenobiotic metabolism in the human lung. Life Sci. 26: 481–487.CrossRefGoogle Scholar
  9. 9.
    Mitchell, C.E. 1980. Induction of aryl hydrocarbon hydroxylase in Chinese hamsters and mice following intratracheal instillation of benzo[a]pyrene. Res. Comm. Chem. Pathol. Pharmacol. 28: 65–78.Google Scholar
  10. 10.
    Dansette, P.M., K. Alexandrov, R. Azerad, and C.H. Frayssinet. 1979. The effect of some mixed-function oxidase inducers on aryl hydrocarbon hydroxylase and epoxide hydrase in nuclei and microsomes from rat liver and lung: The effect of cigarette smoke. Eur. J. Cancer 18: 915–922.Google Scholar
  11. 11.
    Simberg, N., and P. Uotila. 1978. Stimulatory effect of cigarette smoke on the metabolism and covalent binding of benzo[a]pyrene in the trachea of the rat. Int. J. Cancer 22: 28–31.Google Scholar
  12. 12.
    Juchau, M.R., T. DiGiovanni, M.J. Namkung, and A.H. Jones. 1979. A comparison of the capacity of fetal and adult liver, lung, and brain to convert polycyclic aromatic hydrocarbons to mutagenic and cytotoxic metabolites in mice and rats. Toxicol. Appl. Pharmacol. 49: 171–178.Google Scholar
  13. 13.
    Sabadie, N., H.B. Richter-Reichhelm, R. Saracci, U. Mohr, and H. Bartsch. 1981. Studies on inter-individual differences in oxidative benzo[a]pyrene metabolism by normal and tumorous surgical lung specimens from 105 lung cancer patients. Int. J. Cancer 24: 417–426.Google Scholar
  14. 14.
    Kouri, R.E., T. Rude, P.E. Thomas, and C.E. Whitmire. 1976. Studies on pulmonary aryl hydrocarbon hydroxylase activity in inbred strains of mice. Chem.-Biol. Interact. 13: 317–331.Google Scholar
  15. 15.
    Kouri, R.E., H.L. Billups, T.H. Rude, C.E. Whitmire, B. Sass, and C.J. Henry. 1980. Correlations of inducibility of aryl hydrocarbon hydroxylase with susceptibility to 3-methylcholanthrene-induced lung cancer. Cancer Lett. 9: 277–284.PubMedCrossRefGoogle Scholar
  16. 16.
    Oesch, F., and H. Schmassmann. 1979. Species and organ specificity of the trans-stilbene oxide-induced effects on epoxide hydratase and benzo[a]pyrene monooxygenase activity in rodents. Biochem. Pharmacol. 28: 171–176.Google Scholar
  17. 17.
    Oesch, F., H. Schmassmann, E. Ohnhaus, U. Althaus, and T. Lorenz. 1980. Monooxygenase, epoxide hydrolase, and glutathione-S-transferase activities in human lung. Variation between groups of bronchogenic carcinoma and noncancer patients and inter-individual differences. Carcinogenesis 1: 827–835.Google Scholar
  18. 18.
    Hundley, S.G., and R.I. Freudenthal. 1977. Comparison of benzo[a]pyrene metabolism by liver and lung microsomal enzymes from 3-methylcholanthrene-treated rhesus monkeys and rats. Cancer Res. 37: 244–249.PubMedGoogle Scholar
  19. 19.
    Gehly, E.B., W.E. Fahl, C.R. Jefcoate and C. Heidelberger. 1979. The metabolism of benzo[a]pyrene by cytochrome P-450 in transformable and non-transformable C3H mouse fibroblast. J. Biol. Chem. 254: 5041–5048.Google Scholar
  20. 20.
    Bornstein, W.A., M.D. Lamden, A.H.L. Chuang, R.L. Gross, P.M. Newberne, and E. Bresnick. 1978. Inability of vitamin A deficiency to alter benzo[a]pyrene metabolism in Syrian hamsters. Cancer Res. 38: 1497–1501.PubMedGoogle Scholar
  21. 21.
    Teel, R.W., and W.H.T. Douglas. 1980. Aryl hydrocarbon hydroxylase activity in type II alveolar lung cells. Experientia 36: 107.PubMedCrossRefGoogle Scholar
  22. 22.
    Teel, R.W. 1979. Induction of aryl hydrocarbon in primary cultures of type II alveolar lung cells and binding of metabolically activated benzo[a]pyrene to nuclear macromolecules. Cancer Lett. 7: 349–355.PubMedCrossRefGoogle Scholar
  23. 23.
    Stoner, G.D., C.C. Harris, A. Autrup, B.F. Trump, E.W. Kingsbury, and G.A. Myers. 1978. Explant culture of human peripheral lung tissues. I. Metabolism of benzo[a]pyrene. Lab. Invest. 38: 685–692.Google Scholar
  24. 24.
    Mehta, R., M. Meredith-Brown, and G.M. Cohen. 1979. Metabolism and covalent binding of benzo[a]pyrene in human peripheral lung. Chem.-Biol. Interact. 28: 345–358.Google Scholar
  25. 25.
    Lechner, J.F., A. Haugen, H. Autrup, I.A. McClendon, B.F. Trump, and C.C. Harris. 1981. Clonal growth of epithelial cells from normal adult human bronchus. Cancer Res. 41: 2294–2304.PubMedGoogle Scholar
  26. 26.
    Cohen, G.M., P. Uotila, J. Hartiala, L.-M. Suolinna, N. Simberg, and 0. Pelkonen. 1979. Metabolism and covalent binding of [3H]benzo[a]pyrene by isolated perfused lung and short-term tracheal organ culture of cigarette-exposed rats. Cancer Res. 37: 2147–2155.Google Scholar
  27. 27.
    Autrup, H., F.C. Wefald, A.M. Jeffrey, H. Tate, R.D. Schwartz, B.F. Trump, and C.C. Harris. 1980. Metabolism of benzo[a]pyrene by cultured tracheobronchial tissues from mice, rats, hamsters, bovine, and humans. Int. J. Cancer 25: 293–300.Google Scholar
  28. 28.
    Selkirk, J.K. 1977. Divergence of metabolic activation systems for short-term mutagenesis assays. Nature 270: 604–607.PubMedCrossRefGoogle Scholar
  29. 29.
    Autrup, H., A.M. Jeffrey, and C.C. Harris. 1980. Metabolism of benzo[a]pyrene by cultured human tissues. In: Polynuclear aromatic hydrocarbons: Chemistry and biological effects. A. Bjorseth and A.J. Dennis, eds. Battelle Press: Columbus. pp. 89–106.Google Scholar
  30. 30.
    Kahl, G.F., E. Klaus, C. Legraverend, D.W. Nebert, and 0. Pelkonen. 1979. Formation of benzo[a]pyrene metabolite-nucleoside adducts in isolated perfused rat and mouse liver and in mouse lung slices. Biochem. Pharmacol. 28: 1051–1056.Google Scholar
  31. 31.
    Glatt, H.R., R. Billings, K.L. Platt, and F. Oesch. 1981. Improvement of the correlation of the bacterial mutagenicity with carcinogenicity of benzo[a]pyrene and four of its major metabolites by activation with intact liver cells instead of cell homogenate. Cancer Res. 41: 270–277.PubMedGoogle Scholar
  32. 32.
    A.K.M. Shamsuddin, L.A. Barrett, and B.F. Trump. 1978. Explant culture of rat colon: A model system for studying metabolism of chemical carcinogens. In Vitro 14: 868–877.Google Scholar
  33. 33.
    Trump, B., E. McDowell, L. Barrett, A. Frank, and C.C. Harris. 1974. Studies of ultrastructure, cytochemistry, and organ culture of human bronchial epithelium. In: Experimental Lung Cancer. E. Karbe, and J.J. Park, eds. Springer-Verlag: New York. pp. 548–588.CrossRefGoogle Scholar
  34. 34.
    Autrup, H., R.C. Graftstrom, M. Brugh, J. Lechner, A. Haugen, B.F. Trump, and C.C. Harris. (in press). Comparison of benzo[a]pyrene metabolism in bronchus, colon, esophagus, and duodenum from the same individual. Cancer Res.Google Scholar
  35. 35.
    Harris, C.C., A.L. Frank, C. van Haaften, D.G. Kaufman, R. Connor, F.E. Jackson, L.A. Barrett, E.M. McDowell, and B.F. Trump. 1976. Binding of [3H]benzo[a]pyrene to DNA in cultured human bronchus. Cancer Res. 36: 1011–1018.PubMedGoogle Scholar
  36. 36.
    Autrup, H. 1979. Separation of water-soluble metabolites from cultured human colon. Biochem. Pharmacol. 28: 1727–1730.Google Scholar
  37. 37.
    Yang, S.K., P.P. Roller, and H.V. Gelboin. 1977. Enzymatic mechanism of benzo[a]pyrene conversion to phenols and diols and an improved high pressure liquid chromatographic separation of benzo[a]pyrene derivatives. Biochemistry 16: 3680–3686.PubMedCrossRefGoogle Scholar
  38. 38.
    Jeffrey, A.M., I.B. Weinstein, K.W. Jennette, K. Grezeskowiak, K. Nakanishi, R.G. Harvey, H. Autrup, and C.C. Harris. 1977. Structures of benzo[a]pyrene-nucleic acid adducts formed in human and bovine bronchial explants. Nature 269: 348–350.PubMedCrossRefGoogle Scholar
  39. 39.
    Cohen, G.M., S.M. Haws, B.P. Moore, and J.W. Bridges. 1976. Benzo[a]pyrene-3-yl hydrogen sulphate, a major ethyl acetate-extractable metabolite in human, hamster, and rat lung cultures. Biochem. Pharmacol. 25: 2561–2570.Google Scholar
  40. 40.
    Mehta, R., and G.M. Cohen. 1979. Major differences in the extent of conjugation with glucuronic acid and sulphate in human peripheral lung. Biochem. Pharmacol. 28: 2479–2484.Google Scholar
  41. 41.
    Harris, C.C., H. Autrup, R. Connor, L.A. Barrett, E.M. McDowell, and B.F. Trump. 1976. Inter-individual variation in binding of benzo[a]pyrene to DNA in cultured human bronchi. Science 194: 1067–1069.PubMedCrossRefGoogle Scholar
  42. 42.
    Cohen, G.M., R. Mehta, and M. Meredith-Brown. 1979. Large inter-individual variations in metabolism of benzo[a]pyrene by peripheral lung tissues from lung cancer patients. Int. J. Cancer 24: 129–133.Google Scholar
  43. 43.
    Harris, C.C., H. Autrup, G. Stoner, and B.F. Trump. 1978. Model systems using human lung for carcinogenesis studies. In: Pathogenesis and Therapy of Lung Cancer. C. Harris, ed. M. Dekker: New York. pp. 559–597.Google Scholar
  44. 44.
    Wigley, C.B., R.F. Newbold, J. Amos, and P. Brookes. 1979. Cell-mediated mutagenesis in cultured Chinese hamster cells by polycyclic hydrocarbons: Mutagenicity and DNA reaction related to carcinogenicity in a series of compounds. Int. J. Cancer 23: 691–696.Google Scholar
  45. 45.
    Newbold, R.F., P. Brookes, and R.G. Harvey. 1979. A quantitative comparison of the mutagenicity of carcinogenic polycyclic hydrocarbon derivatives in cultured mammalian cells. Int. J. Cancer 24: 203–209.Google Scholar
  46. 46.
    Moore, P., and B.S. Strauss. 1979. Sites of inhibition of in vitro DNA synthesis in carcinogen-and UV-treated (0 x 174 DNA. Nature 278: 664–666.PubMedCrossRefGoogle Scholar
  47. 47.
    Sagher, D., R.G. Harvey, W.-T. Hsu, and S.B. Weiss. 1979. Effect of benzo[a]pyrenediolepoxide on infectivity and in vitro translation of phage MS2 RNA. Proc. Natl. Acad. Sci. USA 76: 620–624.Google Scholar
  48. 48.
    Yamaura, I., H. Marquardt, and L.F. Cavelieri. 1978. Effects of benzo[a]pyrene adducts on DNA synthesis in vitro. Chem.-Biol. Interact. 23: 399–407.Google Scholar
  49. 49.
    Jack, P., and P. Brookes. 1980. The binding of benzo[a]pyrene to DNA components of differing sequence complexity. Int. J. Cancer 25: 789–795.Google Scholar
  50. 50.
    Pulkrabek, P., S. Leffler, D. Grunberger, and I.B. Weinstein. 1979. Modification of deoxyribonucleic acid by a diol epoxide of BP. Relation to deoxyribonucleic acid structure and confirmation and effects on transfectional activity. Biochemistry 18: 5128–5134.Google Scholar
  51. 51.
    Autrup, H., R.D. Schwartz, J.M. Essigmann, L. Smith, B.F. Trump, and C.C. Harris. 1980. Metabolism of aflatoxin B1, benzo[a]pyrene and 1,2-dimethylhydrazine by cultured rat and human colon. Teratogen. Carcinogen. and Mutagen. 1: 3–13.Google Scholar
  52. 52.
    Grafstrom, R.G., H. Autrup, and C.C. Harris. (MS). Metabolism of benzo[a]pyrene by explant cultures of tracheobronchial, esophageal, and colonic tissues from three different rat strains.Google Scholar
  53. 53.
    Cerutti, P., K. Shinohara, M.-L. Ide, and J. Remsen. 1978. Formation and repair of benzo[a]pyrene-induced DNA damage in mammalian cells. In: Polycyclic Hydrocarbons and Cancer, Volume 2. H.V. Gelboin, and P.O.P. T’so, eds. Academic Press: New York. pp. 203–212.Google Scholar
  54. 54.
    Ivanovic, V., N.E. Geacintor, H. Yamasaki, and I.B. Weinstein. 1978. DNA and RNA adducts formed in hamster embryo cell cultures exposed to benzo[a]pyrene. Biochemistry 17: 1597–1603.PubMedCrossRefGoogle Scholar
  55. 55.
    Dipple, A. 1976. Polynuclear aromatic hydrocarbons. American Chemical Society monograph 173: 245–314.Google Scholar
  56. 56.
    DiGiovanni, J., J.R. Romson, D. Linville, and M.R. Juchau. 1979. Covalent binding of polynuclear aromatic hydrocarbons to adenine correlates with tumorigenesis in mouse skin. Cancer Lett. 7: 39–43.PubMedCrossRefGoogle Scholar
  57. 57.
    King, H.W.S., M.R. Osborne, and P. Brookes. 1979. The in vitro and in vivo reactions at the N7-position of guanine of the ultimate carcinogen derived from benzo[a]pyrene. Chem.-Biol. Interact. 24: 345–353.Google Scholar
  58. 58.
    Haseltine, W.A., K.M. Lo, and A.D. D’Andrea. 1980. Preferred sites of strand-scission in DNA modified by anti-diol epoxide of benzo[a]pyrene. Science 209: 929–931.PubMedCrossRefGoogle Scholar
  59. 59.
    Phillips, D.H., P.L. Grover, and P. Sims. 1978. A quantitative determination of the covalent binding of a series of polycyclic hydrocarbons to DNA in mouse skin. Int. J. Cancer 23: 201–208.Google Scholar
  60. 60.
    Seifried, H.E., D.J. Birkett, W. Levin, A.Y.H. Lu, A.H. Conney, and D.M. Jerina. 1977. Metabolism of benzo[a]pyrene: Effect of 3-methylcholanthrene pretreatment on metabolism by microsomes from lungs of genetically “responsive” and “non-responsive” mice. Arch. Biochem. Biophys. 178: 256–263.Google Scholar
  61. 61.
    Mass, M.J., and D.G. Kaufman. 1979. Benzo[a]pyrene quinone metabolism in tracheal organ cultures. Biochem. Biophys. Res. Comm. 89: 885–892.Google Scholar
  62. 62.
    Deutsch, J., R.P. Vatsis, M.J. Coon, J.C. Leutz, and H.V. Gelboin. 1979. Catalytic activity and stereoselectivity of purified form of rabbit liver microsomal cytochrome P-450 in the oxygenation of the (-)and (+)-enantioners of trans 7,8-diohydroxy-7,8 dihydrobenzo[a]pyrene. Molec. Pharmacol. 16: 1011–1018.Google Scholar
  63. 63.
    Namkung, M.J., and M.R. Juchau. 1980. On the capacity of human placental enzymes to catalyze the formation of diols by benzo[a]pyrene. Toxicol. Appl. Pharmacol. 55: 253–259.Google Scholar
  64. 64.
    Harris, C., V. Genta, A. Frank, D. Kaufman, L. Barrett, E.M. McDowell, and B.F. Trump. 1974. Carcinogenic polynuclear hydrocarbons bind to macromolecules in cultured human bronchi. Nature 252: 68–69.PubMedCrossRefGoogle Scholar
  65. 65.
    Harris, C.C., H. Autrup, G. Stoner, S.K. Yang, J.C. Leutz, H.V. Gelboin, J.K. Selkirk, R.J. Connor, L.A. Barrett, R.T. Jones, E.M. McDowell, and B.F. Trump. 1977. Metabolism of benzo[a]pyrene and 7,12-dimethylbenz[a]anthracene in cultured human tissues: Bronchus and pancreatic duct. Cancer Res. 37: 3349–3355.Google Scholar
  66. 66.
    Yang, S.K., H.V. Gelboin, B.F. Trump, H. Autrup, and C.C. Harris. 1977. Metabolic activation and DNA binding of benzo[a]pyrene in cultured human bronchus. Cancer Res. 37: 1207–1212.Google Scholar
  67. 67.
    Harris, C.C., H. Autrup, G.D. Stoner, E.M. McDowell, B.F. Trump, and P. Schafer. 1977. Metabolism of dimethylnitrosamine and 1,2-dimethylhydrazine in cultured human bronchi. Cancer Res. 37: 2309–2311.PubMedGoogle Scholar
  68. 68.
    Harris, C.C., H. Autrup, G.D. Stoner, E.M. McDowell, B.F. Trump, and P. Schafer. 1977. Metabolisms of acyclic and cyclic N-nitrosamines in cultured human bronchus. J. Natl. Cancer Inst. 59: 1401–1406.Google Scholar
  69. 69.
    Kroeger-Koepke, M.B., and C.J. Michejda. 1979. Evidence for several dimethylase enzymes in the oxidation of dimethylnitrosamine and phenylmethylnitrosamine by rat liver fractions. Cancer Res. 39: 1587–1591.PubMedGoogle Scholar
  70. 70.
    Den Engelse, L., M. Gebbink, and P. Emmelot. 1975. Studies on lung tumors. III. Oxidative metabolism of dimethylnitrosamine by rodent and human lung tissue. Chem.-Biol. Interact. 11: 535–544.Google Scholar
  71. 71.
    Autrup, H., J.M. Essigmann, R.G. Croy, B.F. Trump, G.N. Wogan, and C.C. Harris. 1979. Metabolism of aflatoxin B1 and identification of the major aflatoxin B1-DNA adducts formed in cultured human bronchus and colon. Cancer Res. 39: 694–698.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1983

Authors and Affiliations

  • Herman Autrup
    • 1
  • Roland C. Grafstrom
    • 1
  • Curtis C. Harris
    • 1
  1. 1.Human Tissue Studies Section, Laboratory of Experimental PathologyNational Cancer InstituteBethesdaUSA

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