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Polycyclic aromatic hydrocarbons and possible metabolites: Convertogenic activity in yeast and tumor initiating activity in mouse skin

Polycyclische aromatische Kohlenwasserstoffe und mögliche Metaboliten: Konvertogene Wirkung bei Hefe und Tumor-initiierende Wirkung an der Mäusehaut


The diploid respiratory-deficient strain of yeast D4-RDII was used to assay PAH and urethane as well as some oxygenated derivatives of PAH and the (aliphatic) epoxide hydrolase inhibitor TCPO for convertogenic (mutagenic) activity. As a positive control, the convertogenic ultimate rat liver carcinogen NOAcAAF was used. PAH and urethane were found inactive as convertogens, TCPO was weakly active, whereas oxygenated electrophilic derivatives of PAH, such as K-region oxides, were found strong convertogens. For comparison, some convertogenic key compounds were assayed for their tumorinitiating activity in mouse skin in the standardized system using TPA as a promoter. PAH were stronger initiators than all oxygenated derivatives of PAH tested. TCPO alone exhibited very weak, if any, initiating activity. It was unable to modify initiation to any significant extent, if administered 5 min prior to administration of an initiator.

In the absence of correlation between convertogenic and initiating activity the question of the chemical nature of “ultimate initiators” of mouse skin carcinogenesis awaits further investigation.


Am atmungsdefizienten diploiden Hefestamm D4-RDII wurde die konvertogene (mutagene) Wirkung von PAH, Urthan, einigen sauerstoffhaltigen PAH-Derivaten und des (aliphatischen) Epoxidhydrolase-Inhibitors TCPO untersucht. Als positive Kontrolle diente die konvertogene “Wirkform” des Rattenlebercarcinogens NOAcAAF. PAH und Urethan waren nicht konvertogen, TCPO zeigte eine geringe Wirkung, während elektrophile PAH-Derivate wie die K-Region-Oxide stark konvertogen wirkten. Einige konvertogene Schlüsselsubstanzen wurden zum Vergleich auf ihre tumorinitiierende Wirkung an der Mäusehaut im standardisierten Experiment mit TPA als Promoter geprüft. PAH erwiesen sich als stärkere Initiatoren als alle ihre entsprechenden sauerstoffhaltigen Derivate. TCPO allein zeigt—wenn überhaupt — nur geringe Wirkung. Wenn TCPO 5 min vor einem Initiator appliziert wurde, hatte es keinen nennenswerten Einfluß auf die Initiation.

Auf Grund der mangelnden Korrelation zwischen konvertogener und initiierender Wirkung sind weitere Untersuchungen zum Problem der chemischen Natur der „Wirkformen” von Initiatoren der Carcinogenese der Mäusehaut erforderlich.

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polycyclic aromatic hydrocarbon(s)




thin-layer chromatography




  1. Ames BN, Sims P, Grover PL (1972) Epoxides of carcinogenic polycyclic hydrocarbons are frameshift mutagens. Science 176:4749

    Google Scholar 

  2. Bartsch H, Traut N, Hecker E (1971) On the metabolic activation of N-hydroxy-N-2-acetylaminofluorene: II Simultaneous formation of 2-nitroso-fluorene and N-acetoxy-N-2-acetylaminofluorene from N-hydroxy-N-2-acetylaminofluorene via a free radical intermediate. Biochem Biophys Acta 237:556–566

    Google Scholar 

  3. Berry DL, Slaga TJ, Viaje A, Wilson NM, DiGiovanni J, Juchan MR, Selkirk JK (1977) Effect of trichloropropene oxide on the ability of polyaromatic hydrocarbons and their “K-region” oxides to initiate skin tumors in mice and to bind to DNA. J Natl Cancer Inst 58:1051–1055

    Google Scholar 

  4. Bigger CAH, Tomaszewski JE, Dipple A (1978) Differences between products of binding of 7,12-dimethylbenz(a)anthracene to DNA in mouse skin and in a rat liver microsomal system. Biochem Biophys Res Commun 80:229–235

    Google Scholar 

  5. Brookes P (1977) Mutagenicity of polycyclic aromatic hydrocarbons. Mutation Res 39:257–284

    Google Scholar 

  6. Bürki K, Stoming TA, Bresnick E (1974a) Effects of an epoxide hydrase inhibitor on the in vitro binding of polycyclic hydrocarbons to DNA and on skin carcinogenesis. J Natl Cancer Inst 52:785–788

    Google Scholar 

  7. Bürki K, Wheeler JE, Akamatsu Y, Scribner JE, Cancelas G, Bresnick E (1974b) Early differential effects of 3-methylcholanthrene and its “K-region” epoxide in mouse skin. Possible implications in the twostage mechanism of tumorigenesis. J Natl Cancer Inst 53:967–976

    Google Scholar 

  8. McCann J, Choi E, Yamasaki E, Ames B (1975) Detection of carcinogens as mutagenes in the salmonella/microsome test: assay of 300 chemicals. Proc Natl Acad Sci USA 72:5135–5139

    Google Scholar 

  9. Dannenberg H (1966) Zur Frage der Wechselwirkung zwischen Nukleinsäuren und aromatischen Kohlewasserstoffen und Aminen. 17. Kolloquium der Gesellschaft für physiologische Chemie, 21/23. April 1966 in Mosbach/Baden. Springer Berlin Heidelberg New York pp 96–104

    Google Scholar 

  10. Dipple A, Nebzydoski JA (1978) Evidence for the involvement of a diol epoxide in the binding of 7,12-dimethylbenz(a)anthracene to DNA in cells in culture. Chem Biol Interact 20:17–26

    Google Scholar 

  11. Flesher JW, Harvey RG, Sydnor KL (1976) Oncogenicity of K-region epoxides of benzo(a)pyrene and 7,12-dimethylbenz(a)anthracene. Int J Cancer 18:351–353

    Google Scholar 

  12. Friesel H (1978) Zur Wechselwirkung aktivierter Stoffwechselprodukte von polycyclischen aromatischen Kohlenwasserstoffen mit makromolekularen Zellbestandteilen. Dissertation, Heidelberg

  13. Friesel H, Hecker E (1977) Reaction of arene oxides with nucleosides. Cancer Lett 3:169–175

    Google Scholar 

  14. Hecker E (1971) Isolation and characterization of the cocarcinogenic principles from croton oil. In: Busch H (ed) Methods in cancer res, Vol VI. Academic Press, New York London, pp 439–484

    Google Scholar 

  15. Hecker E (1979) Diterpene ester type modulators of carcinogenesis —New findings in the mechanism of chemical carcinogenesis and in the etiology of human tumors. In: Miller EC et al. (eds) Naturally occurring carcinogens-mutagens and modulators of carcinogenesis. Japan Science Press, Tokyo and University Press, Baltimore, pp 263–286

    Google Scholar 

  16. Hecker E, Schmidt R (1974) Phorbolesters—the irritants and cocarcinogens of croton tiglium L. Progr Chem Org Natur Prod 31:377–467

    Google Scholar 

  17. Hecker E, Friesel H, Schmidt R, Siebert D, Marquardt H (1979) Role of cocarcinogens in chemical oncogenesis and mutagenesis. In: Margison Gp (ed) Advances in medical oncology, research and education. Proceedings of the XII. International Cancer Congress, Buenos Aires 1978, Vol 1: Carcinogenesis. Pergamon Press, Oxford New York, pp 207–212

    Google Scholar 

  18. Jerina DM, Lehr R, Schaefer-Ridder M, Yagi H, Karle JM, Thakker DR, Wood AW, Lu AYH, Ryan D, West S, Levin W, Conney AH (1977) Bay region epoxides of dihydrodiols: a concept which may explain the mutagenic and carcinogenic activity of benzo(a)pyrene and benzo(a)anthracene. In: Hiatt HH, Watson JD, Winsten JA (eds) Origins of human cancer, Cold Spring Harbor conferences on cell Proliferation, Vol 4. Cold Spring Harbor, New York, pp 638–658

  19. Levin W, Thakker DR, Wood A, Chang RL, Lehr RE, Jerina DM, Conney AH (1978) Evidence that benzo(a)anthracene 3,4-Diol-1,2-epoxide is an ultimate carcinogen on mouse skin. Cancer Res 38:1705–1710

    Google Scholar 

  20. Marquardt H, Zimmermann FK, Dannenberg H, Neumann HG, Bodenberger A, Metzler M (1970) Die genetische Wirkung von aromatischen Aminen und ihren Derivaten: Induktion mitotischer Konversionen bei der Hefe Saccharomyces cerevisiae. Z Krebsforsch 74:412–433

    Google Scholar 

  21. Miller JA (1970) Carcinogenesis by chemicals: An overview —G.H.A. Clowes memorial lecture. Cancer Res 30:559–576

    Google Scholar 

  22. Miller EC, Miller JA (1971) The mutagenicity of chemical carcinogens: Correlations, problems and interpretations. In: Hollaender A (ed) Chemical mutagens — principles and methods for their detection, Vol 1. Plenum, New York, pp 83–119

    Google Scholar 

  23. Oltmanns O, Bacher A, Lingens F, Zimmermann FK (1969) Biochemical and genetic classification of riboflavine deficient mutants of saccharomyces cerevisiae. Mol Gen Genetics 105:306–313

    Google Scholar 

  24. Roe FJC, Carter RL, Mitchley BCV, Peto R, Hecker E (1972) On the persistence of tumor initiation and the acceleration of tumor progression in mouse skin tumorigenesis. Int J Cancer 9:264–273

    Google Scholar 

  25. Siebert D (1973a) Beiträge zur Mutagenitätsprüfung von Abbau-und Umbauprodukten genetisch inaktiver Chemotherapeutika und Pestizide an Hefen. Dissertation, Freiburg/Br

  26. Siebert D (1973b) A new method for testing genetically active metabolites. Urinary assay with cyclophosphamide (Endoxan, Cytoxan) and saccharomyces cerevisiae. Mutation Res 17:307–314

    Google Scholar 

  27. Siebert D (1974) Comparison of the genetic activity of cyclophosphamide, ifosfamide, and trofosfamide in host-mediated assays with the gene conversion system of yeast. Z Krebsforsch 81:261–267

    Google Scholar 

  28. Siebert D (1975) Host mediated assay with yeast and rats using probenecid (Benemid) to block the renal tubular excretion of cyclophosphamide metabolites. Mutat Res 28:57–61

    Google Scholar 

  29. Sims P, Grover PL (1974) Epoxides in polycyclic aromatic hydrocarbon metabolism and carcinogenesis. Adv Cancer Res 20:165–274

    Google Scholar 

  30. Slaga TJ, Viaje A, Berry DL, Bracken W (1976) Skin tumor-initiating ability of benzo(a) pyrene 4,5-7,8-and 7,8-diol-9,10-epoxides and 7,8-diol. Cancer Lett 2:115–122

    Google Scholar 

  31. Slaga TJ, Hubermann E, Selkirk JK, Harvey RG, Bracken M (1978) Carcinogenicity and mutagenicity of benz(a)anthracene diols and dipolepoxides. Cancer Res 38:1699–1704

    Google Scholar 

  32. Slaga TJ, Gleason GL, Di Giovanni J, Sukumaran KB, Harvey RG (1979) Potent tumor-initiating activity of the 3,4-Dihydrodiol of 7,12-Dimethylbenz(a)anthracene in mouse skin. Cancer Res 39:1934–1936

    Google Scholar 

  33. Zimmermann FK (1968) The effect of liquid holding on chemical-induced lethality and mitogenic gene conversion in saccharomyces cerevisiae. Molec Gen Genetics 103:11–20

    Google Scholar 

  34. Zimmermann FK (1969) Genetic effects of polynuclear hydrocarbons: Induction of mitotic gene conversion. Z Krebsforsch 72:65–71

    Google Scholar 

  35. Zimmermann FK (1971) Induction of mitotic gene conversion by mutagens. Mutat Res 11:327–337

    Google Scholar 

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Corresponding author

Correspondence to E. Hecker.

Additional information

In part PhD-thesis of H. Friesel (Friesel 1978)

This investigation was supported, in part, by grants III B 4-7291-MT 403 a and 307-7291-MT-424 of the Bundesminister für Forschung und Technologie, Bonn, Federal Republic of Germany, under a joint contract with the Institut für Biochemie, Deutsches Krebsforschungszentrum, Heidelberg

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Siebert, D., Marquardt, H., Friesel, H. et al. Polycyclic aromatic hydrocarbons and possible metabolites: Convertogenic activity in yeast and tumor initiating activity in mouse skin. J Cancer Res Clin Oncol 102, 127–139 (1981).

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Key words

  • Polycyclic aromatic hydrocarbons
  • K-region oxides
  • Gene conversion in yeast
  • Tumor initiation in mouse skin
  • Ultimate carcinogens
  • Ultimate initiators


  • Polycyclische aromatische Kohlenwasserstoffe
  • K-Region-Oxide
  • Genkonversion in Hefe
  • Tumor-Initiation an der Mäusehaut
  • Wirkformen von Carcinogenen
  • Wirkformen von Initiatoren