Chemical and Mutagenic Specificities of Polycyclic Aromatic Hydrocarbon Carcinogens

  • Anthony Dipple
  • Kimmo Peltonen
  • S. Chau Cheng
  • Helen Ross
  • C. Anita H. Bigger
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 375)


Polycyclic aromatic hydrocarbons are found in some broiled meats, as a product of the cooking process,1 and also in vegetables as a contaminant, thus having a widespread distribution through the environment.2 The hydrocarbons are generated through the process of combustion and it seems unlikely, therefore, that exposure to them will ever be completely eliminated. For this reason, a number of researchers, including ourselves, have focused attention on the mechanism of action of these carcinogens with the idea that an understanding of the details of the process of carcinogenesis might facilitate the development of strategies for intervention, such as chemoprevention.


Polycyclic Aromatic Hydrocarbon Shuttle Vector Reactive Metabolite Mutagenic Selectivity Genotoxic Carcinogen 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    W. Lijinsky, The formation and occurrence of polynuclear aromatic hydrocarbons associated with food, Mutat Res 259:251 (1991).PubMedCrossRefGoogle Scholar
  2. 2.
    A. Dipple, Formation, metabolism, and mechanism of action of polycyclic aromatic hydrocarbons, Cancer Res 43:2422s (1983).PubMedGoogle Scholar
  3. 3.
    P. Sims, P.L. Grover, A. Swaisland, K. Pal, A. Hewer, Metabolic activation of benzo[a]pyrene proceeds by a diol-epoxide, Nature 252:326 (1974).PubMedCrossRefGoogle Scholar
  4. 4.
    A. Dipple, R.C. Moschel, C.A.H. Bigger, Polynuclear aromatic carcinogens, in: Chemical Carcinogens, C.E. Searle, ed., American Chemical Society, Washington, D.C., pp. 41–163 (1984).Google Scholar
  5. 5.
    A.M. Jeffrey, K.W. Jennette, S.H. Blobstein, I.B. Weinstein, F.A. Beland, R.G. Harvey, H. Kasai, I. Miura, K. Nakanishi, Benzo[a]pyrene-nucleic acid derivative found in vivo: Structure of a benzo[a]pyrene dihydrodiol epoxide-guanosine adduct, J Am Chem Soc 98:5714 (1976).PubMedCrossRefGoogle Scholar
  6. 6.
    S.C. Cheng, B.D. Hilton, J.M. Roman, A. Dipple, DNA adducts from carcinogenic and noncarcinogenic enantiomers of benzo[a]pyrene dihydrodiol epoxide, Chem Res Toxicol 2:334 (1989).PubMedCrossRefGoogle Scholar
  7. 7.
    A. Dipple, J.T. Sawicki, R.C. Moschel, C.A.H. Bigger, 7,12-Dimethylbenz[a]anthracene-DNA interactions in mouse embryo cell cultures and mouse skin, in: Extrahepatic Drug Metabolism and Chemical Carcinogenesis, J. Rydstrom, J. Montelius, M. Bengtsson, eds., Elsevier, Amsterdam, pp. 439–448 (1983).Google Scholar
  8. 8.
    J.T. Sawicki, R.C. Moschel, A. Dipple, Involvement of both syn-and anti-dihydrodiolepoxides in the binding of 7,12-dimethylbenz[a]anthracene to DNA in mouse embryo cell cultures, Cancer Res 43:3212 (1983).PubMedGoogle Scholar
  9. 9.
    A. Dipple, M. Pigott, R.C. Moschel, N. Costantino, Evidence that binding of the 7,12-Dimethylbenz[a]anthracene to DNA in mouse embryo cell cultures results in extensive substitution of both adenine and guanine residues, Cancer Res 43:4132 (1983).PubMedGoogle Scholar
  10. 10.
    A. Dipple, M.A. Pigott, C.A.H. Bigger, D.M. Blake, 7,12-Dimethylbenz[a]anthracene-DNA binding in mouse skin: Response of different mouse strains and effects of various modifiers of carcinogenesis, Carcinogenesis 5:1087 (1984).PubMedCrossRefGoogle Scholar
  11. 11.
    C.A.H. Bigger, J.T. Sawicki, D.M. Blake, L.G. Raymond, A. Dipple, Products of binding of 7,12-dimethylbenz[a]anthracene to DNA in mouse skin, Cancer Res 43:5647 (1983).PubMedGoogle Scholar
  12. 12.
    J.A. Milner, M.A. Pigott, A. Dipple, Selective effects of selenium on 7,12-dimethylbenz[a]-anthracene-DNA binding in fetal mouse cell cultures, Cancer Res 45:6347 (1985).PubMedGoogle Scholar
  13. 13.
    S.C. Cheng, A.S. Prakash, M.A. Pigott, B.D. Hilton, H. Lee, R.G. Harvey, A. Dipple, A metabolite of the carcinogen 7,12-dimethylbenz[a]anthracene that reacts predominantly with adenine residues in DNA, Carcinogenesis 9:1721 (1988).PubMedCrossRefGoogle Scholar
  14. 14.
    S.K. Agarwal, J.M. Sayer, H.J.C. Yeh, L.K. Pannell, B.D. Hilton, M.A. Pigott, A. Dipple, H. Yagi, D.M. Jerina, Chemical characterization of DNA adducts derived from the configurationally isomeric benzo[c]phenanthrene-3,4-diol 1,2-epoxides, J Am Chem Soc 109:2497 (1987).CrossRefGoogle Scholar
  15. 15.
    D.B. Reardon, A.S. Prakash, B.D. Hilton, J.M. Roman, J. Pataki, R.G. Harvey, A. Dipple, Characterization of 5-methylchrysene-1,2-dihydrodiol-3,4-epoxide-DNA adducts, Carcinogenesis 8:1317 (1987).PubMedCrossRefGoogle Scholar
  16. 16.
    K. Peltonen, S.C. Cheng, B.D. Hilton, H. Lee, C. Cortez, R.G. Harvey, A. Dipple, Effect of bay region methyl group on reactions of anti-benz[a]anthracene 3,4-dihydrodiol 1,2-epoxides with DNA, J Org Chem 56:4181 (1991).CrossRefGoogle Scholar
  17. 17.
    A. Dipple, K. Peltonen, S.C. Cheng, B.D. Hilton, Chemistry of DNA adduct formation by dihydrodiol epoxides of polycyclic aromatic hydrocarbons, in: Polycyclic Aromatic Compounds: Synthesis, Properties, Analytical Measurements, Occurence and Biological Effects, P. Garrigues, M. Lamotte, eds., Gordon and Breach, Philadelphia, pp. 811–820 (1993).Google Scholar
  18. 18.
    A. Dipple, M.A. Pigott, S.K. Agarwal, H. Yagi, J.M. Sayer, D.M. Jerina, Optically active benzo[c]phenanthrene diol epoxides bind extensively to adenine in DNA, Nature 327:535 (1987).PubMedCrossRefGoogle Scholar
  19. 19.
    W. Levin, R.L. Chang, A. Wood, D.R. Thakker, H. Yagi, D.M. Jerina, A.H. Conney, Tumorigenicity of optical isomers of the diastereomeric bay region 3,4-diol epoxides of benzo[c]phenanthrene 3,4-diol-1,2-epoxides, Cancer Res 46:2257 (1986).PubMedGoogle Scholar
  20. 20.
    J.A. Vericat, S.C. Cheng, A. Dipple, Absolute configuration of 7,12-dimethyl-benz[a]anthracene-DNA adducts in mouse epidermis, Cancer Lett 57:237 (1991).PubMedCrossRefGoogle Scholar
  21. 21.
    H. Schmeiser, A. Dipple, M.E. Schurdak, E. Randerath, K. Randerath, Comparison of 32P postlabeling and high pressure liquid Chromatographic analyses for 7,12-dimethylbenz[a]-anthracene-DNA adducts, Carcinogenesis 9:633 (1988).PubMedCrossRefGoogle Scholar
  22. 22.
    S.C. Cheng, A.S. Prakash, M.A. Pigott, B.D. Hilton, J.M. Roman, H. Lee, R.G. Harvey, A. Dipple, Characterization of 7,12-dimethylbenz[a]anthracene-adenine nucleoside adducts, Chem Res Toxicol 1:216 (1988).PubMedCrossRefGoogle Scholar
  23. 23.
    J.A. Vericat, S.C. Cheng, A. Dipple, Absolute stereochemistry of the major 7,12-dimethyl-benz[a]anthracene-DNA adducts formed in mouse cells, Carcinogenesis 10:567 (1989).PubMedCrossRefGoogle Scholar
  24. 24.
    M.M. Seidman, K. Dixon, A. Razzaque, R.J. Zagursky, M.L. Berman, A shuttle vector plasmid for studying carcinogen-induced point mutations in mammalian cells, Gene 38:233 (1985).PubMedCrossRefGoogle Scholar
  25. 25.
    M. Seidman, The development of transient SV40 based shuttle vectors for mutagenesis studies: Problems and solutions, Mutat Res 220:55 (1989).PubMedCrossRefGoogle Scholar
  26. 26.
    C.A.H. Bigger, J. St. John, H. Yagi, D.M. Jerina, A. Dipple, Mutagenic specificities of four stereoisomeric benzo[c]phenanthrene dihydrodiol epoxides, Proc Natl Acad Sci USA 89:368 (1992).PubMedCrossRefGoogle Scholar
  27. 27.
    K.H. Kraemer, M.M. Seidman, Use of supF, an Escherichia coli tyrosine suppressor tRNA gene, as a mutagenic target in shuttle-vector plasmids, Mutat Res 220:61 (1989).PubMedCrossRefGoogle Scholar
  28. 28.
    C.A.H. Bigger, J. Strandberg, H. Yagi, D.M. Jerina, A. Dipple, Mutagenic specificity of a potent carcinogen, benzo[c]phenanthrene (4R,3S)-dihydrodiol (2S,lR)-epoxide, which reacts with adenine and guanine in DNA, Proc Natl Acad Sci USA 86:2291 (1989).PubMedCrossRefGoogle Scholar
  29. 29.
    C.A.H. Bigger, D.H. Flickinger, J. St. John, R.G. Harvey, A. Dipple, Preferential mutagenesis at G.C base pairs by the anti 3,4-dihydrodiol 1,2-epoxide of 7-methylbenz[a]anthracene, Mol Carcinogen 4:176 (1991).CrossRefGoogle Scholar
  30. 30.
    C.A.H. Bigger, D.J. Flickinger, J. Strandberg, J. Pataki, R.G. Harvey, A. Dipple, Mutational specificity of the anti 1,2-dihydrodiol 3,4-epoxide of 5-methylchrysene, Carcinogenesis 11:2263 (1990).PubMedCrossRefGoogle Scholar
  31. 31.
    J.-L. Yang, V.M. Maher, J.J. McCormick, Kinds of mutation formed when a shuttle vector containing adducts of (+/−)-7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo-[α]pyrene replicates in human cells, Proc Natl Acad Sci USA 84:3787 (1987).PubMedCrossRefGoogle Scholar
  32. 32.
    H. Ross, C.A.H. Bigger, H. Yagi, D.M. Jerina, A. Dipple, Sequence specificity in the interaction of the four stereoisomeric benzo[c]phenanthrene dihydrodiol epoxides with the supF gene, Cancer Res 53:1273 (1993).PubMedGoogle Scholar
  33. 33.
    A. Dipple, C.J. Michejda, E.K. Weisburger, Metabolism of chemical carcinogens, Pharmacol Ther 27:265 (1985).PubMedCrossRefGoogle Scholar
  34. 34.
    E.C. Miller, J.A. Miller, Mechanisms of chemical carcinogens: Nature of proximate carcinogens and interactions with macromolecules, Pharmacol Rev 18:805 (1966).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Anthony Dipple
    • 1
  • Kimmo Peltonen
    • 2
  • S. Chau Cheng
    • 3
  • Helen Ross
    • 1
  • C. Anita H. Bigger
    • 4
  1. 1.Chemistry of Carcinogenesis Laboratory, ABL-Basic Research ProgramNCI-Frederick Cancer Research and Development CenterFrederickUSA
  2. 2.Department of Industrial Hygiene and ToxicologyInstitute of Occupational HealthHelsinkiFinland
  3. 3.Clinical Research AssociatesNew YorkUSA
  4. 4.Microbiological AssociatesRockvilleUSA

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