The Liver as Origin and Target of Reactive Intermediates Exemplified by the Progesterone Derivative, Cyproterone Acetate

  • L. R. Schwarz
  • S. Werner
  • J. Topinka
  • U. Andrae
  • I. Neumann
  • T. Wolff
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 387)


Since the middle of the last century it is known that chemicals can cause liver injury (cf. Zimmerman, 1978). In 1860, a severe fatty liver in man was ascribed to phosphorous intoxication. During the first half of the 20th century several hepatotoxins have been extensively studied and in the second half of this century it became clear that in many cases enzymatically ‘activated’ metabolites of xenobiotics are responsible for the toxic effects observed (cf. Zimmerman, 1978; Hinson et al., 1994). The liver was found to express the highest concentrations and greatest variety of xenobiotic metabolizing enzymes in the body (cf. Zimmerman, 1978; Watkins, 1990). This high metabolic capacity turned out to be a primary cause of the liver specificity of toxic xenobiotics. Chemically induced liver damage may have three main manifestations (Fig. 1).


Human Hepatocyte Cyproterone Acetate Adduct Level Cytochrome P450 Isoenzyme Synthetic Steroid 
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  1. Aksoy, I.A., Sochorová V. and Weinshilboum, R. 1993, Human liver dehydroepiandrosterone sulfotransferase: Nature and extent of individual variation, Clin. Pharmacol. Ther. 54: 498–506.PubMedCrossRefGoogle Scholar
  2. Andrae, U., Homfeldt, H., Vogl, L., Lichtmannegger, J., and Summer, K.H. 1988, 2-Nitropropane induces DNA repair synthesis in rat hepatocytes in vitro and in vivo, Carcinogenesis 9: 811–815.PubMedCrossRefGoogle Scholar
  3. Brattin, W.J., Glende, E.A. and Recknagel, R.O. 1985, Pathological mechanisms in carbon tetrachloride hepatotoxicity, J. Free Radic. Biol. Med. 1: 27–38.PubMedCrossRefGoogle Scholar
  4. Bursch, W., Lauer, B., Timmermann-Trosiener, I., Barthel, G., Schuppler, J., and Schulte-Hermann, R. 1984, Controlled death (apoptosis) of normal and putative preneoplastic cells in rat liver following withdrawal of tumor promoters, Carcinogenesis 5: 453–458.PubMedCrossRefGoogle Scholar
  5. Cao, J., Leibold E., Beisker, W., Schranner T., Nüsse M. and Schwarz, L.R. 1993, Flow cytometric analysis of in vitro micronucleus induction in hepatocytes treated with carcinogens, Toxic, in Vitro 7: 447–451.CrossRefGoogle Scholar
  6. Czich, A., Bartsch, I., Dogra, S., Hornhardt, S., and Glatt, H.R. 1994, Stable heterologous expression of hydroxysteroid sulphotransferase in Chinese hamster V79 cells and their use for toxicological investigations, Chemico-Biological Interaction 92: 119–128.CrossRefGoogle Scholar
  7. Deml, E., Schwarz L.R. and Oesterle, D. 1993, Initiation of enzyme-altered foci by the synthetic steriod cyproterone acetate in rat liver foci bioassay, Carcinogenesis 14: 1229–1231.PubMedCrossRefGoogle Scholar
  8. Gupta, R.C. 1984, Non-random binding of the carcinogen N-hydroxy-2-acetylaminofluorene to repetitive sequences of rat liver DNA in vivo, Proc. Natl. Acad. Sci. USA 81: 6943–6947.PubMedCrossRefGoogle Scholar
  9. Gupta, R.C. 1985, Enhanced sensitivity of 32P-postlabeling analysis of aromatic carcinogen adducts, Cancer Res. 45: 5656–5662.PubMedGoogle Scholar
  10. Hinson, J.A., Pumford, N.J., and Nelson, S.D. 1994, The role of metabolic activation in drug toxicity, Drug Metabol Rev. 26: 395–412.CrossRefGoogle Scholar
  11. Hobkirk, R. 1985, Steroid sulfotransferases and steroid sulfate sulfatases: Characteristics and biological roles, Can. J. Biochem. Cell Biol. 63: 1127–1144.PubMedCrossRefGoogle Scholar
  12. Hiimpel, M, Nieuweboer, B., Düsterberg, B. and Wendt, H., 1979, Die Pharmakokinetik von Cyproteronacetat beim Menschen, In Androgenisierungserscheinungen bei der Frau (J. Hammerstein et al., Eds.) Exerpta Medica.Google Scholar
  13. Kasper, P., Gerhard, A., Kaufmann, G., Madle, H. and Müller, L., 1993, Further investigations into the gentoxicity of cyproterone acetate. Abstract of a poster presented at the 23rd Ann. Meeting of the European Environmental Mutagen Society (EEMS) in Barcelona, 27. Sept.-2. Oct. 1993.Google Scholar
  14. Kemp, C.J., Leary, C.N., and Drinkwater, N.R. 1989, Promotion of murine hepatocarcinogenesis by testosterone is androgen receptor-dependent but not cell autonomous, Proc. Natl. Acad. Sci. 86: 7505–7509.PubMedCrossRefGoogle Scholar
  15. Lang, R. and Redmann, U., 1979, Non-mutagenicity of some sex hormones in the Ames Salmonella/microsome mutagenicity test. Mutation Res. 67: 361–365.PubMedCrossRefGoogle Scholar
  16. Lang, R. and Reimann, R. 1993, Studies for a genotoxic potential of some endogenous and exogenous sex steroids. I. Communication: Examination for the induction of gene mutations using the Ames Salmonella / Microsome Test and the HGPRT Test in V79 cells, Environ. Molec. Mutag. 21: 272–304.CrossRefGoogle Scholar
  17. Lau, S.S., and Monks, T.J. 1988, The contribution of bromobenzene to our current understanding of chemically-induced toxicities, Life Sci. 42: 1259–1269.PubMedCrossRefGoogle Scholar
  18. Martin, J.L., Kenna, J.G., Martin, B.M., Thomassen, D., Reed, G.F., and Pohl, L.R. 1993, Halothane patients have serum antibodies that react with protein disulfide isomerase, Hepatology 18: 858–863.PubMedCrossRefGoogle Scholar
  19. Mulder, G.J., 1981, Sulfate availability in vivo, In Sulfation of Drugs and Related Compounds (G.J. Mulder, Ed.) pp. 31–52. CRC Press, Boca Raton.Google Scholar
  20. Okuda, H., Nojima, H., Watanabe, N., and Watabe, T. 1989, Sulphotransferase-mediated activation of the carcinogen 5-hydroxymethyl-chrysene, Biochem. Pharmacol. 38: 3003–3009.PubMedCrossRefGoogle Scholar
  21. Pitot, H.C., and Dragan, Y.P., 1994, Chemical induction of hepatic neoplasia, In Liver: Biology and Pathobiology, 3rd edition (I.M. Arias, Ed.), pp. 1467–1498. Raven Press, New York.Google Scholar
  22. Plaa, G.L., 1991, Toxic responses of the liver, In Casarett and Doull’s Toxicology (C.D. Klaassen, M.O. Amdur, and J. Doull, Eds.), pp. 286–309. Macmillan Publishing Company, New York.Google Scholar
  23. Porter, L.E., van Thiel, D.H., and Eagon, P.K. 1987, Estrogens and progestins as tumor inducers, Seminars in Liver Disease 7: 24–31.PubMedCrossRefGoogle Scholar
  24. Schulte-Hermann, R., Ohde, G., Schuppler, J., and Timmermann-Trosiener, I. 1981, Enhanced proliferation of putative preneoplastic cells in rat liver following treatment with the tumor promoters phenobarbital, hexachlorocyclohexane, steroid compounds, and nafenopin, Cancer Res. 41: 2556–2562.PubMedGoogle Scholar
  25. Schulte-Hermann, R., Timmermann-Trosiener, I., and Schuppler, J. 1983, Promotion of spontaneous preneoplastic cells in rat liver as a possible explanation of tumor production by nonmutagenic compounds, Cancer Res. 43: 839–844.PubMedGoogle Scholar
  26. Schulte-Hermann, R., Ochs, H., Bursch, W., and Parzefall, W. 1988, Quantitative structure-activity studies on effects of sixteen different steroids on growth and monooxygenases of rat liver, Cancer Res. 48: 2462–2468.PubMedGoogle Scholar
  27. Schuppler, J., and Günzel, P. 1979, Liver tumors and steroid hormones in rats and mice, Arch. Toxicol. 2: 181–195.CrossRefGoogle Scholar
  28. Schwarz, L.R. 1980, Modulation of sulfation and glucuronidation of 1-naphthol in isolated rat liver cells, Arch. Toxicol. 44: 137–145.PubMedCrossRefGoogle Scholar
  29. Schwarz, L.R. 1984, Sulfation of 1-naphthol in isolated rat hepatocytes, Hoppe-Seyler’s Z. Physiol. Chem. 365: 43–48.PubMedCrossRefGoogle Scholar
  30. Schwarz, L.R., and Greim, H., 1986, Environmental chemicals in hepatocarcinogenesis: The mechanism of tumor promoters, In Progress in Liver Diseases, vol. VIII (H. Popper and F. Schaffner Eds.), pp. 581–595. Grune & Stratton, Orlando, New York.Google Scholar
  31. Steinberg, P., and Oesch, F., 1992, Liver cell specific toxicity of xenobiotics, Tissue Specific Toxicity: Biochemical Mechanisms (W. Dekant and H.-G. Neumann, Eds.), pp. 117–137. Academic Press, London.Google Scholar
  32. Strom, S.C., Jirtle, R.L., Jones, R.S., Novicki, D.L., Rosenberg, M.R., Novotny, A., Irons, G., McLain, J.R., and Michalopoulos, G. 1982, Isolation, culture and transplantation of human hepatocytes, JNCI, J. Natl. Cancer Inst. 68: 771–778.Google Scholar
  33. Topinka, J., Andrae, U, Schwarz, L.R., and Wolff, T. 1993, Cyproterone acetate generates DNA adducts in rat liver and in primary rat hepatocyte cultures, Carcinogenesis 14: 423–427.PubMedCrossRefGoogle Scholar
  34. Vermeulen, N.P.E., Bessems, J.G.M, and van de Straat, R. 1992, Molecular aspects of paracetamol-induced hepatotoxicity and its mechanism-based prevention, Drug Metabolism Reviews 24: 367–407.PubMedCrossRefGoogle Scholar
  35. Watkins III, J.B., Thierau, D., and Schwarz, L.R. 1992, Biotransformation in carcinogen-induced diploid and polyploid hepatocytes separated by centrifugal elutriation, Cancer Res. 52: 1149–1154.PubMedGoogle Scholar
  36. Yager, J.D., Zurlo, J., and Ni, N. 1991, Sex hormones and tumor promotion in liver, Proc. Soc. Exp. Biol. Med. 198: 667–674.PubMedCrossRefGoogle Scholar
  37. Watkins, P.B. 1990, Role of cytochromes P450 in drug metabolism and hepatotoxicity, Semin. Liver Dis. 10: 235–250.PubMedCrossRefGoogle Scholar
  38. Waxman, DJ. 1988, Interactions of hepatic cytochromes P450 with steroid hormones: Regioselectivity and stereoselectivity of steroid metabolism and hormonal regulation of rat P450-enzyme expression, Biochem. Pharmacol. 37: 71–84.PubMedCrossRefGoogle Scholar
  39. Zimmermann, HJ., 1978, The adverse effects of drugs and other chemicals on the liver,. In Hepatotoxicity. Appleton-Century-Crofts, New York.Google Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • L. R. Schwarz
    • 1
  • S. Werner
    • 1
  • J. Topinka
    • 2
  • U. Andrae
    • 1
  • I. Neumann
    • 1
  • T. Wolff
    • 1
  1. 1.Institut für ToxikologieGSF-Forschungszentrum für Umwelt und GesundheitNeuherbergGermany
  2. 2.Regional Hygiene Institute of Central BohemiaPrague 4Czech Republic

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