Abstract
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).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
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.
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.
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.
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.
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.
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.
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.
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.
Gupta, R.C. 1985, Enhanced sensitivity of 32P-postlabeling analysis of aromatic carcinogen adducts, Cancer Res. 45: 5656–5662.
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.
Hobkirk, R. 1985, Steroid sulfotransferases and steroid sulfate sulfatases: Characteristics and biological roles, Can. J. Biochem. Cell Biol. 63: 1127–1144.
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.
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.
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.
Lang, R. and Redmann, U., 1979, Non-mutagenicity of some sex hormones in the Ames Salmonella/microsome mutagenicity test. Mutation Res. 67: 361–365.
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.
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.
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.
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.
Okuda, H., Nojima, H., Watanabe, N., and Watabe, T. 1989, Sulphotransferase-mediated activation of the carcinogen 5-hydroxymethyl-chrysene, Biochem. Pharmacol. 38: 3003–3009.
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.
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.
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.
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.
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.
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.
Schuppler, J., and Günzel, P. 1979, Liver tumors and steroid hormones in rats and mice, Arch. Toxicol. 2: 181–195.
Schwarz, L.R. 1980, Modulation of sulfation and glucuronidation of 1-naphthol in isolated rat liver cells, Arch. Toxicol. 44: 137–145.
Schwarz, L.R. 1984, Sulfation of 1-naphthol in isolated rat hepatocytes, Hoppe-Seyler’s Z. Physiol. Chem. 365: 43–48.
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.
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.
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.
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.
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.
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.
Yager, J.D., Zurlo, J., and Ni, N. 1991, Sex hormones and tumor promotion in liver, Proc. Soc. Exp. Biol. Med. 198: 667–674.
Watkins, P.B. 1990, Role of cytochromes P450 in drug metabolism and hepatotoxicity, Semin. Liver Dis. 10: 235–250.
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.
Zimmermann, HJ., 1978, The adverse effects of drugs and other chemicals on the liver,. In Hepatotoxicity. Appleton-Century-Crofts, New York.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1996 Springer Science+Business Media New York
About this chapter
Cite this chapter
Schwarz, L.R., Werner, S., Topinka, J., Andrae, U., Neumann, I., Wolff, T. (1996). The Liver as Origin and Target of Reactive Intermediates Exemplified by the Progesterone Derivative, Cyproterone Acetate. In: Snyder, R., et al. Biological Reactive Intermediates V. Advances in Experimental Medicine and Biology, vol 387. Springer, Boston, MA. https://doi.org/10.1007/978-1-4757-9480-9_32
Download citation
DOI: https://doi.org/10.1007/978-1-4757-9480-9_32
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4757-9482-3
Online ISBN: 978-1-4757-9480-9
eBook Packages: Springer Book Archive